Acute Coronary Syndromes

Many more people are at risk for early cardiovascular events because of raised lipoprotein(a) levels than from having familial hypercholesterolemia (FH), a new study suggests.

The Danish study set out to try and establish a level of Lp(a) that would be associated with a cardiovascular risk similar to that seen with FH. As there are many different definitions of FH, results showed a large range of Lp(a) values that corresponded to risk levels of the different FH definitions.

However, if considering one of the broadest FH definitions (from MEDPED – Make Early Diagnoses, Prevent Early Deaths), which is the one most commonly used in the United States, results showed that the level of cardiovascular risk in patients with this definition of FH is similar to that associated with Lp(a) levels of around 70 mg/dL (0.7 g/L).

“While FH is fairly unusual, occurring in less than 1% of the population, levels of Lp(a) of 70 mg/dL or above are much more common, occurring in around 10% of the White population,” Børge Nordestgaard, MD, Copenhagen University Hospital, said in an interview. Around 20% of the Black population have such high levels, while levels in Hispanics are in between.

“Our results suggest that there will be many more individuals at risk of premature MI or cardiovascular death because of raised Lp(a) levels than because of FH,” added Dr. Nordestgaard, the senior author of the current study.

Dr. Nordestgaard explained that FH is well established to be a serious condition. “We consider FH to be the genetic disease that causes the most cases of early heart disease and early death worldwide.”

“But we know now that raised levels of Lp(a), which is also genetically determined, can also lead to an increased risk of cardiovascular events relatively early in life, and when you look into the numbers, it seems like high levels of Lp(a) could be more common than FH. We wanted to try and find the levels of Lp(a) that corresponded to similar cardiovascular risk as FH.”

The Danish study was published  in the Journal of the American College of Cardiology.

The authors note that the 2019 joint European Society of Cardiology and European Atherosclerosis Society guidelines suggested that an Lp(a) level greater than 180 mg/dL (0.8 g/L) may confer a lifetime risk for heart disease equivalent to the risk associated with heterozygous FH, but they point out that this value was speculative and not based on a direct comparison of risk associated with the two conditions in the same population.

For their study, Dr. Nordestgaard and colleagues analyzed information from a large database of the Danish population, the Copenhagen General Population Study, including 69,644 individuals for whom data on FH and Lp(a) levels were available. As these conditions are genetically determined, and the study held records on individuals going back several decades, the researchers were able to analyze event rates over a median follow up time of 42 years. During this time, there were 4,166 cases of myocardial infarction and 11,464 cases of atherosclerotic cardiovascular disease (ASCVD).

Results showed that Lp(a) levels associated with MI risk equivalent to that of clinical FH ranged from 67 to 402 mg/dL depending on the definition used for FH. The Lp(a) level corresponding to the MI risk of genetically determined FH was 180 mg/dL.

In terms of risk of ASCVD events, the levels of Lp(a) corresponding to the risk associated with clinical FH ranged from 130 to 391 mg/dL, and the Lp(a) level corresponding to the ASCVD risk of genetically determined FH was 175 mg/dL.

“All these different definitions of FH may cause some confusion, but basically we are saying that if an individual is found to have an Lp(a) above 70 mg/dL, then they have a similar level of cardiovascular risk as that associated with the broadest definition of FH, and they should be taken as seriously as a patient diagnosed with FH,” Dr. Nordestgaard said.

He estimated that these individuals have approximately a doubling of cardiovascular risk, compared with the general population, and risk increases further with rising Lp(a) levels.

The researchers also found that if an individual has both FH and raised Lp(a) they are at very high risk, as these two conditions are independent of each other.

Although a specific treatment for lowering Lp(a) levels is not yet available, Dr. Nordestgaard stresses that it is still worth identifying individuals with raised Lp(a) as efforts can be made to address other cardiovascular risk factors.

“We know raised Lp(a) increases cardiovascular risk, but there are also many other factors that likewise increase this risk, and they are all additive. So, it is very important that individuals with raised Lp(a) levels address these other risk factors,” he said. “These include stopping smoking, being at healthy weight, exercising regularly, eating a heart-healthy diet, and aggressive treatment of raised LDL, hypertension, and diabetes. All these things will lower their overall risk of cardiovascular disease.”

And there is the promise of new drugs to lower Lp(a) on the horizon, with several such products now in clinical development.

Dr. Nordestgaard also points out that as Lp(a) is genetically determined, cascade screening of close relatives of the individual with raised Lp(a) should also take place to detect others who may be at risk.

Although a level of Lp(a) of around 70 mg/dL confers similar cardiovascular risk than some definitions of FH, Dr. Nordestgaard says lower levels than this should also be a signal for concern. 

“We usually say Lp(a) levels of 50 mg/dL are when we need to start to take this seriously. And it’s estimated that about 20% of the White population will have levels of 50 mg/dL or over and even more in the Black population,” he added. 
 

‘Screen for both conditions’

In an accompanying editorial, Pamela Morris, MD, Medical University of South Carolina, Charleston; Jagat Narula, MD, Icahn School of Medicine, New York; and Sotirios Tsimikas, MD, University of California, San Diego, say “the weight of evidence strongly supports that both genetic lipid disorders, elevated Lp(a) levels and FH, are causally associated with an increased risk of premature ASCVD and should be carefully considered in risk assessment and management for ASCVD risk reduction.”

Catherine Hackett/MDedge News

Dr. Morris told this news organization that the current study found a very large range of Lp(a) levels that conferred a similar cardiovascular risk to FH, because of the many different definitions of FH in use.

“But this should not take away the importance of screening for raised Lp(a) levels,” she stressed.  

“We know that increased Lp(a) levels signal a high risk of cardiovascular disease. A diagnosis of FH is also a high-risk condition,” she said. “Both are important, and we need to screen for both, but it is difficult to directly compare the two conditions because the different definitions of FH get in the way.”

Dr. Morris agrees with Dr. Nordestgaard that raised levels of Lp(a) may actually be more important for the population risk of cardiovascular disease than FH, as the prevalence of increased Lp(a) levels is higher.

“Because raised Lp(a) levels are more prevalent than confirmed FH, the risk to the population is greater,” she said.  

Dr. Morris points out that cardiovascular risk starts to increase at Lp(a) levels of 30 mg/dL (75 nmol/L).

The editorialists recommend that “in addition to performing a lipid panel periodically according to evidence-based guidelines, measurement of Lp(a) levels should also be performed at least once in an individual’s lifetime for ASCVD risk assessment.”

They conclude that “it is vital to continue to raise awareness among clinicians and patients of these high-risk genetic lipid disorders. Our understanding of both disorders is rapidly expanding, and promising novel therapeutics may offer hope for prevention of cardiovascular disease in patients with elevated Lp(a) levels in the future.”

This work was supported by Copenhagen University Hospital – Herlev Gentofte, Denmark, and the Danish Beckett-Foundation. The Copenhagen General Population Study is supported by the Copenhagen County Foundation and Copenhagen University Hospital – Herlev Gentofte. Dr. Nordestgaard has been a consultant and a speaker for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Silence Therapeutics, Abbott, and Esperion.

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

Many more people are at risk for early cardiovascular events because of raised lipoprotein(a) levels than from having familial hypercholesterolemia (FH), a new study suggests.

The Danish study set out to try and establish a level of Lp(a) that would be associated with a cardiovascular risk similar to that seen with FH. As there are many different definitions of FH, results showed a large range of Lp(a) values that corresponded to risk levels of the different FH definitions.

However, if considering one of the broadest FH definitions (from MEDPED – Make Early Diagnoses, Prevent Early Deaths), which is the one most commonly used in the United States, results showed that the level of cardiovascular risk in patients with this definition of FH is similar to that associated with Lp(a) levels of around 70 mg/dL (0.7 g/L).

“While FH is fairly unusual, occurring in less than 1% of the population, levels of Lp(a) of 70 mg/dL or above are much more common, occurring in around 10% of the White population,” Børge Nordestgaard, MD, Copenhagen University Hospital, said in an interview. Around 20% of the Black population have such high levels, while levels in Hispanics are in between.

“Our results suggest that there will be many more individuals at risk of premature MI or cardiovascular death because of raised Lp(a) levels than because of FH,” added Dr. Nordestgaard, the senior author of the current study.

Dr. Nordestgaard explained that FH is well established to be a serious condition. “We consider FH to be the genetic disease that causes the most cases of early heart disease and early death worldwide.”

“But we know now that raised levels of Lp(a), which is also genetically determined, can also lead to an increased risk of cardiovascular events relatively early in life, and when you look into the numbers, it seems like high levels of Lp(a) could be more common than FH. We wanted to try and find the levels of Lp(a) that corresponded to similar cardiovascular risk as FH.”

The Danish study was published  in the Journal of the American College of Cardiology.

The authors note that the 2019 joint European Society of Cardiology and European Atherosclerosis Society guidelines suggested that an Lp(a) level greater than 180 mg/dL (0.8 g/L) may confer a lifetime risk for heart disease equivalent to the risk associated with heterozygous FH, but they point out that this value was speculative and not based on a direct comparison of risk associated with the two conditions in the same population.

For their study, Dr. Nordestgaard and colleagues analyzed information from a large database of the Danish population, the Copenhagen General Population Study, including 69,644 individuals for whom data on FH and Lp(a) levels were available. As these conditions are genetically determined, and the study held records on individuals going back several decades, the researchers were able to analyze event rates over a median follow up time of 42 years. During this time, there were 4,166 cases of myocardial infarction and 11,464 cases of atherosclerotic cardiovascular disease (ASCVD).

Results showed that Lp(a) levels associated with MI risk equivalent to that of clinical FH ranged from 67 to 402 mg/dL depending on the definition used for FH. The Lp(a) level corresponding to the MI risk of genetically determined FH was 180 mg/dL.

In terms of risk of ASCVD events, the levels of Lp(a) corresponding to the risk associated with clinical FH ranged from 130 to 391 mg/dL, and the Lp(a) level corresponding to the ASCVD risk of genetically determined FH was 175 mg/dL.

“All these different definitions of FH may cause some confusion, but basically we are saying that if an individual is found to have an Lp(a) above 70 mg/dL, then they have a similar level of cardiovascular risk as that associated with the broadest definition of FH, and they should be taken as seriously as a patient diagnosed with FH,” Dr. Nordestgaard said.

He estimated that these individuals have approximately a doubling of cardiovascular risk, compared with the general population, and risk increases further with rising Lp(a) levels.

The researchers also found that if an individual has both FH and raised Lp(a) they are at very high risk, as these two conditions are independent of each other.

Although a specific treatment for lowering Lp(a) levels is not yet available, Dr. Nordestgaard stresses that it is still worth identifying individuals with raised Lp(a) as efforts can be made to address other cardiovascular risk factors.

“We know raised Lp(a) increases cardiovascular risk, but there are also many other factors that likewise increase this risk, and they are all additive. So, it is very important that individuals with raised Lp(a) levels address these other risk factors,” he said. “These include stopping smoking, being at healthy weight, exercising regularly, eating a heart-healthy diet, and aggressive treatment of raised LDL, hypertension, and diabetes. All these things will lower their overall risk of cardiovascular disease.”

And there is the promise of new drugs to lower Lp(a) on the horizon, with several such products now in clinical development.

Dr. Nordestgaard also points out that as Lp(a) is genetically determined, cascade screening of close relatives of the individual with raised Lp(a) should also take place to detect others who may be at risk.

Although a level of Lp(a) of around 70 mg/dL confers similar cardiovascular risk than some definitions of FH, Dr. Nordestgaard says lower levels than this should also be a signal for concern. 

“We usually say Lp(a) levels of 50 mg/dL are when we need to start to take this seriously. And it’s estimated that about 20% of the White population will have levels of 50 mg/dL or over and even more in the Black population,” he added. 
 

‘Screen for both conditions’

In an accompanying editorial, Pamela Morris, MD, Medical University of South Carolina, Charleston; Jagat Narula, MD, Icahn School of Medicine, New York; and Sotirios Tsimikas, MD, University of California, San Diego, say “the weight of evidence strongly supports that both genetic lipid disorders, elevated Lp(a) levels and FH, are causally associated with an increased risk of premature ASCVD and should be carefully considered in risk assessment and management for ASCVD risk reduction.”

Catherine Hackett/MDedge News

Dr. Morris told this news organization that the current study found a very large range of Lp(a) levels that conferred a similar cardiovascular risk to FH, because of the many different definitions of FH in use.

“But this should not take away the importance of screening for raised Lp(a) levels,” she stressed.  

“We know that increased Lp(a) levels signal a high risk of cardiovascular disease. A diagnosis of FH is also a high-risk condition,” she said. “Both are important, and we need to screen for both, but it is difficult to directly compare the two conditions because the different definitions of FH get in the way.”

Dr. Morris agrees with Dr. Nordestgaard that raised levels of Lp(a) may actually be more important for the population risk of cardiovascular disease than FH, as the prevalence of increased Lp(a) levels is higher.

“Because raised Lp(a) levels are more prevalent than confirmed FH, the risk to the population is greater,” she said.  

Dr. Morris points out that cardiovascular risk starts to increase at Lp(a) levels of 30 mg/dL (75 nmol/L).

The editorialists recommend that “in addition to performing a lipid panel periodically according to evidence-based guidelines, measurement of Lp(a) levels should also be performed at least once in an individual’s lifetime for ASCVD risk assessment.”

They conclude that “it is vital to continue to raise awareness among clinicians and patients of these high-risk genetic lipid disorders. Our understanding of both disorders is rapidly expanding, and promising novel therapeutics may offer hope for prevention of cardiovascular disease in patients with elevated Lp(a) levels in the future.”

This work was supported by Copenhagen University Hospital – Herlev Gentofte, Denmark, and the Danish Beckett-Foundation. The Copenhagen General Population Study is supported by the Copenhagen County Foundation and Copenhagen University Hospital – Herlev Gentofte. Dr. Nordestgaard has been a consultant and a speaker for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Silence Therapeutics, Abbott, and Esperion.

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

Many more people are at risk for early cardiovascular events because of raised lipoprotein(a) levels than from having familial hypercholesterolemia (FH), a new study suggests.

The Danish study set out to try and establish a level of Lp(a) that would be associated with a cardiovascular risk similar to that seen with FH. As there are many different definitions of FH, results showed a large range of Lp(a) values that corresponded to risk levels of the different FH definitions.

However, if considering one of the broadest FH definitions (from MEDPED – Make Early Diagnoses, Prevent Early Deaths), which is the one most commonly used in the United States, results showed that the level of cardiovascular risk in patients with this definition of FH is similar to that associated with Lp(a) levels of around 70 mg/dL (0.7 g/L).

“While FH is fairly unusual, occurring in less than 1% of the population, levels of Lp(a) of 70 mg/dL or above are much more common, occurring in around 10% of the White population,” Børge Nordestgaard, MD, Copenhagen University Hospital, said in an interview. Around 20% of the Black population have such high levels, while levels in Hispanics are in between.

“Our results suggest that there will be many more individuals at risk of premature MI or cardiovascular death because of raised Lp(a) levels than because of FH,” added Dr. Nordestgaard, the senior author of the current study.

Dr. Nordestgaard explained that FH is well established to be a serious condition. “We consider FH to be the genetic disease that causes the most cases of early heart disease and early death worldwide.”

“But we know now that raised levels of Lp(a), which is also genetically determined, can also lead to an increased risk of cardiovascular events relatively early in life, and when you look into the numbers, it seems like high levels of Lp(a) could be more common than FH. We wanted to try and find the levels of Lp(a) that corresponded to similar cardiovascular risk as FH.”

The Danish study was published  in the Journal of the American College of Cardiology.

The authors note that the 2019 joint European Society of Cardiology and European Atherosclerosis Society guidelines suggested that an Lp(a) level greater than 180 mg/dL (0.8 g/L) may confer a lifetime risk for heart disease equivalent to the risk associated with heterozygous FH, but they point out that this value was speculative and not based on a direct comparison of risk associated with the two conditions in the same population.

For their study, Dr. Nordestgaard and colleagues analyzed information from a large database of the Danish population, the Copenhagen General Population Study, including 69,644 individuals for whom data on FH and Lp(a) levels were available. As these conditions are genetically determined, and the study held records on individuals going back several decades, the researchers were able to analyze event rates over a median follow up time of 42 years. During this time, there were 4,166 cases of myocardial infarction and 11,464 cases of atherosclerotic cardiovascular disease (ASCVD).

Results showed that Lp(a) levels associated with MI risk equivalent to that of clinical FH ranged from 67 to 402 mg/dL depending on the definition used for FH. The Lp(a) level corresponding to the MI risk of genetically determined FH was 180 mg/dL.

In terms of risk of ASCVD events, the levels of Lp(a) corresponding to the risk associated with clinical FH ranged from 130 to 391 mg/dL, and the Lp(a) level corresponding to the ASCVD risk of genetically determined FH was 175 mg/dL.

“All these different definitions of FH may cause some confusion, but basically we are saying that if an individual is found to have an Lp(a) above 70 mg/dL, then they have a similar level of cardiovascular risk as that associated with the broadest definition of FH, and they should be taken as seriously as a patient diagnosed with FH,” Dr. Nordestgaard said.

He estimated that these individuals have approximately a doubling of cardiovascular risk, compared with the general population, and risk increases further with rising Lp(a) levels.

The researchers also found that if an individual has both FH and raised Lp(a) they are at very high risk, as these two conditions are independent of each other.

Although a specific treatment for lowering Lp(a) levels is not yet available, Dr. Nordestgaard stresses that it is still worth identifying individuals with raised Lp(a) as efforts can be made to address other cardiovascular risk factors.

“We know raised Lp(a) increases cardiovascular risk, but there are also many other factors that likewise increase this risk, and they are all additive. So, it is very important that individuals with raised Lp(a) levels address these other risk factors,” he said. “These include stopping smoking, being at healthy weight, exercising regularly, eating a heart-healthy diet, and aggressive treatment of raised LDL, hypertension, and diabetes. All these things will lower their overall risk of cardiovascular disease.”

And there is the promise of new drugs to lower Lp(a) on the horizon, with several such products now in clinical development.

Dr. Nordestgaard also points out that as Lp(a) is genetically determined, cascade screening of close relatives of the individual with raised Lp(a) should also take place to detect others who may be at risk.

Although a level of Lp(a) of around 70 mg/dL confers similar cardiovascular risk than some definitions of FH, Dr. Nordestgaard says lower levels than this should also be a signal for concern. 

“We usually say Lp(a) levels of 50 mg/dL are when we need to start to take this seriously. And it’s estimated that about 20% of the White population will have levels of 50 mg/dL or over and even more in the Black population,” he added. 
 

‘Screen for both conditions’

In an accompanying editorial, Pamela Morris, MD, Medical University of South Carolina, Charleston; Jagat Narula, MD, Icahn School of Medicine, New York; and Sotirios Tsimikas, MD, University of California, San Diego, say “the weight of evidence strongly supports that both genetic lipid disorders, elevated Lp(a) levels and FH, are causally associated with an increased risk of premature ASCVD and should be carefully considered in risk assessment and management for ASCVD risk reduction.”

Catherine Hackett/MDedge News

Dr. Morris told this news organization that the current study found a very large range of Lp(a) levels that conferred a similar cardiovascular risk to FH, because of the many different definitions of FH in use.

“But this should not take away the importance of screening for raised Lp(a) levels,” she stressed.  

“We know that increased Lp(a) levels signal a high risk of cardiovascular disease. A diagnosis of FH is also a high-risk condition,” she said. “Both are important, and we need to screen for both, but it is difficult to directly compare the two conditions because the different definitions of FH get in the way.”

Dr. Morris agrees with Dr. Nordestgaard that raised levels of Lp(a) may actually be more important for the population risk of cardiovascular disease than FH, as the prevalence of increased Lp(a) levels is higher.

“Because raised Lp(a) levels are more prevalent than confirmed FH, the risk to the population is greater,” she said.  

Dr. Morris points out that cardiovascular risk starts to increase at Lp(a) levels of 30 mg/dL (75 nmol/L).

The editorialists recommend that “in addition to performing a lipid panel periodically according to evidence-based guidelines, measurement of Lp(a) levels should also be performed at least once in an individual’s lifetime for ASCVD risk assessment.”

They conclude that “it is vital to continue to raise awareness among clinicians and patients of these high-risk genetic lipid disorders. Our understanding of both disorders is rapidly expanding, and promising novel therapeutics may offer hope for prevention of cardiovascular disease in patients with elevated Lp(a) levels in the future.”

This work was supported by Copenhagen University Hospital – Herlev Gentofte, Denmark, and the Danish Beckett-Foundation. The Copenhagen General Population Study is supported by the Copenhagen County Foundation and Copenhagen University Hospital – Herlev Gentofte. Dr. Nordestgaard has been a consultant and a speaker for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Silence Therapeutics, Abbott, and Esperion.

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

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.

CHICAGO – Another major study appears to back the use of intravenous iron repletion in patients with heart failure (HF) and iron deficiency, strengthening largely consistent evidence, researchers say, that the treatment may improve symptoms and prevent some HF-related hospital admissions.

To be sure, the IRONMAN trial, which compared intravenous iron versus usual care in such patients – most with reduced ejection fraction and not hospitalized – failed to show a benefit for its primary endpoint. The 18% reduction in risk for HF hospitalization or cardiovascular (CV) death seen in the trial, however encouraging, can only be called a trend (P = .07).

But the intervention showed signs of benefit for some secondary endpoints, including quality of life scores, and hinted at such an effect on HF hospitalization. Risk for the latter endpoint dropped 20% (P = .085) over a median follow-up of 2.7 years.

The findings “build upon the other data we have that correcting iron deficiency can help improve well-being, and particularly reduce the risk of hospitalization, in a broad range of [HF] patients,” said Paul Kalra, MD, of the University of Glasgow and Portsmouth (England) Hospitals University NHS Trust.

The tested regimen “was well tolerated with no safety concerns” and offers “reassurance about the long-term safety” of the intravenous iron it used, ferric derisomaltose (MonoFerric), in patients with HF, Dr. Kalra said at a media briefing on the trial.

The remarks preceded his formal presentation of IRONMAN at the American Heart Association scientific sessions. Dr. Kalra is also lead author on the trial’s publication in The Lancet.

IRONMAN strengthens the base of evidence supporting intravenous iron in HF with iron deficiency, especially chronic HF in outpatients, Dr. Kalra and others said. It also supports efficacy for a form of intravenous iron not previously tested in a major HF trial.

Still, “the totality of data are now supporting intravenous iron per se,” regardless of the iron agent used, said Dr. Kalra. But ferric derisomaltose may have dosing advantages, he observed, “and we’ve now got these long-term safety data.”

The strongest prior support for intravenous iron in HF came from hospitalized patients who received it as ferric carboxymaltose (Ferinject) and were followed only 12 months. That was in the AFFIRM-AHF trial, published 2 years ago, which also missed its primary endpoint – the same one used in IRONMAN. Some outcomes in the two trials were similar.

The risk for HF hospitalization or CV death for intravenous iron therapy, compared with usual care, in AFFIRM-AHF fell 21% (P = .059), missing significance but apparently driven by a 26% drop in risk for HF readmissions (P = .013). But neither that trial nor IRONMAN suggested a benefit for CV mortality on its own.
 

The COVID effect

In IRONMAN, Dr. Kalra said, usual care could include oral iron supplementation, which 17% of patients in the control group received. That could potentially have kept the intravenous iron group from making a better showing for the primary endpoint, he proposed.

And some iron doses and other treatments were missed by a substantial number of patients in both groups who entered the trial after the United Kingdom’s national lockdown in response to the COVID-19 pandemic, he observed. “Patients were not able to come into hospitals for research visits, or in fact when they were able, may not have wanted to.”

So, the group conducted a “prespecified” sensitivity analysis that excluded the 9% of patients enrolled by the end of March 2020, about the time of the first lockdown, and followed the remainder for another 6 months.

In that analysis, risk for HF hospitalization or CV death declined 24% in the intravenous iron group, a marginal but significant result (P = .047) that was dominated by an improvement in HF hospitalizations.
 

Effects on guidelines

The intravenous iron recommendations in the European HF guidelines refer only to ferric carboxymaltose without mentioning other forms, such as ferric derisomaltose, “but this is now a class effect given the similarities between AFFIRM-AHF and IRONMAN,” said Gregory D. Lewis, MD, Mass General Brigham, Boston, invited discussant for Dr. Kalra’s presentation at the AHA session.

“In the United States, we relegate IV iron to improvement in functional capacity as a comorbidity of heart failure. Perhaps this role will expand,” added Dr. Lewis, who is medical director of his center’s heart transplant program.

He also wondered aloud whether the purported clinical benefits of intravenous iron in HF patients with iron deficiency, not as yet supported by a significant primary-endpoint showing in one of the major trials, currently justify expansion of its use in practice.

“With the benefits of IV iron on exercise capacity and quality of life, and the safety of administering high doses of IV iron,” potentially reducing HF polypharmacy, he noted, “should we be considering IV iron more commonly for utilization in our patients even if we find that heart failure hospitalizations and mortality are only modestly improved?”

IRONMAN “asked whether there’s benefit to IV iron in the longer term,” Kiran Musunuru, MD, PhD, MPH, University of Pennsylvania,Philadelphia, observed at the media briefing. As the trial was reported, “that does in fact, seem to be the case,” said Dr. Musunuru, who was not involved in IRONMAN.

Therefore, he said, “this study reinforces the message that we should be routinely monitoring our heart failure patients for iron deficiency and supplementing them as needed.”

A commentary linked to the IRONMAN publication agreed. The trial “increases the evidence base for the treatment of iron deficiency with intravenous iron supplementation,” wrote the editorialists, led by Theresa A. McDonagh, MD, King’s College Hospital and School of Cardiovascular Sciences, London.

Patients with acute or chronic HF, iron deficiency, and reduced or mildly reduced ejection fractions “should be offered treatment with intravenous iron to reduce their risk of hospital admission for heart failure,” they concluded.
 

Mostly reduced-EF outpatients

The open-label, blinded-endpoint IRONMAN trial, conducted at 70 centers in the United Kingdom, entered adults with HF, ejection fractions 45% or lower within the previous 2 years, and iron deficiency defined as transferrin saturation less than 20% or serum ferritin levels below 100 mcg/L, the report states. They were either hospitalized for HF, had such a hospitalization within the past 6 months, or were outpatients with elevated natriuretic peptide levels; the third category accounted for two thirds of the trial population.

Of the 1,137 randomized patients, 569 were assigned to receive intravenous ferric derisomaltose at weight- and hemoglobin-adjusted dosages; 568 went to the usual-care group.

• HF hospitalization or CV death: RR, 0.76 (95% confidence interval, 0.58-1.00; P = .047)
• HF hospitalization: RR 0.76 (95% CI, 0.56-1.03; P = .077)

Fewer patients in the intravenous iron group experienced serious cardiac adverse events, 36% compared with 43% in for those on usual care, P = .016.

The recently updated European Society of Cardiology guidelines for HF made it a class 1 recommendation to assess iron status in every patient, Kalra observed. “It doesn›t specify how frequently, but I think we should be thinking about every 4-6 months.”

Dr. Kalra disclosed receiving research grants from Pharmacosmos; and consulting or lecturing for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, Pharmacosmos, Servier, and Vifor Pharma. Dr. Musunuru disclosed significant ownership interest in Verve Therapeutics and Variant Bio. Dr. Lewis disclosed relationships with NXT, American Regent, and RIVUS; and receiving research grants from Cytokinetics and Amgen.

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

CHICAGO – Another major study appears to back the use of intravenous iron repletion in patients with heart failure (HF) and iron deficiency, strengthening largely consistent evidence, researchers say, that the treatment may improve symptoms and prevent some HF-related hospital admissions.

To be sure, the IRONMAN trial, which compared intravenous iron versus usual care in such patients – most with reduced ejection fraction and not hospitalized – failed to show a benefit for its primary endpoint. The 18% reduction in risk for HF hospitalization or cardiovascular (CV) death seen in the trial, however encouraging, can only be called a trend (P = .07).

But the intervention showed signs of benefit for some secondary endpoints, including quality of life scores, and hinted at such an effect on HF hospitalization. Risk for the latter endpoint dropped 20% (P = .085) over a median follow-up of 2.7 years.

The findings “build upon the other data we have that correcting iron deficiency can help improve well-being, and particularly reduce the risk of hospitalization, in a broad range of [HF] patients,” said Paul Kalra, MD, of the University of Glasgow and Portsmouth (England) Hospitals University NHS Trust.

The tested regimen “was well tolerated with no safety concerns” and offers “reassurance about the long-term safety” of the intravenous iron it used, ferric derisomaltose (MonoFerric), in patients with HF, Dr. Kalra said at a media briefing on the trial.

The remarks preceded his formal presentation of IRONMAN at the American Heart Association scientific sessions. Dr. Kalra is also lead author on the trial’s publication in The Lancet.

IRONMAN strengthens the base of evidence supporting intravenous iron in HF with iron deficiency, especially chronic HF in outpatients, Dr. Kalra and others said. It also supports efficacy for a form of intravenous iron not previously tested in a major HF trial.

Still, “the totality of data are now supporting intravenous iron per se,” regardless of the iron agent used, said Dr. Kalra. But ferric derisomaltose may have dosing advantages, he observed, “and we’ve now got these long-term safety data.”

The strongest prior support for intravenous iron in HF came from hospitalized patients who received it as ferric carboxymaltose (Ferinject) and were followed only 12 months. That was in the AFFIRM-AHF trial, published 2 years ago, which also missed its primary endpoint – the same one used in IRONMAN. Some outcomes in the two trials were similar.

The risk for HF hospitalization or CV death for intravenous iron therapy, compared with usual care, in AFFIRM-AHF fell 21% (P = .059), missing significance but apparently driven by a 26% drop in risk for HF readmissions (P = .013). But neither that trial nor IRONMAN suggested a benefit for CV mortality on its own.
 

The COVID effect

In IRONMAN, Dr. Kalra said, usual care could include oral iron supplementation, which 17% of patients in the control group received. That could potentially have kept the intravenous iron group from making a better showing for the primary endpoint, he proposed.

And some iron doses and other treatments were missed by a substantial number of patients in both groups who entered the trial after the United Kingdom’s national lockdown in response to the COVID-19 pandemic, he observed. “Patients were not able to come into hospitals for research visits, or in fact when they were able, may not have wanted to.”

So, the group conducted a “prespecified” sensitivity analysis that excluded the 9% of patients enrolled by the end of March 2020, about the time of the first lockdown, and followed the remainder for another 6 months.

In that analysis, risk for HF hospitalization or CV death declined 24% in the intravenous iron group, a marginal but significant result (P = .047) that was dominated by an improvement in HF hospitalizations.
 

Effects on guidelines

The intravenous iron recommendations in the European HF guidelines refer only to ferric carboxymaltose without mentioning other forms, such as ferric derisomaltose, “but this is now a class effect given the similarities between AFFIRM-AHF and IRONMAN,” said Gregory D. Lewis, MD, Mass General Brigham, Boston, invited discussant for Dr. Kalra’s presentation at the AHA session.

“In the United States, we relegate IV iron to improvement in functional capacity as a comorbidity of heart failure. Perhaps this role will expand,” added Dr. Lewis, who is medical director of his center’s heart transplant program.

He also wondered aloud whether the purported clinical benefits of intravenous iron in HF patients with iron deficiency, not as yet supported by a significant primary-endpoint showing in one of the major trials, currently justify expansion of its use in practice.

“With the benefits of IV iron on exercise capacity and quality of life, and the safety of administering high doses of IV iron,” potentially reducing HF polypharmacy, he noted, “should we be considering IV iron more commonly for utilization in our patients even if we find that heart failure hospitalizations and mortality are only modestly improved?”

IRONMAN “asked whether there’s benefit to IV iron in the longer term,” Kiran Musunuru, MD, PhD, MPH, University of Pennsylvania,Philadelphia, observed at the media briefing. As the trial was reported, “that does in fact, seem to be the case,” said Dr. Musunuru, who was not involved in IRONMAN.

Therefore, he said, “this study reinforces the message that we should be routinely monitoring our heart failure patients for iron deficiency and supplementing them as needed.”

A commentary linked to the IRONMAN publication agreed. The trial “increases the evidence base for the treatment of iron deficiency with intravenous iron supplementation,” wrote the editorialists, led by Theresa A. McDonagh, MD, King’s College Hospital and School of Cardiovascular Sciences, London.

Patients with acute or chronic HF, iron deficiency, and reduced or mildly reduced ejection fractions “should be offered treatment with intravenous iron to reduce their risk of hospital admission for heart failure,” they concluded.
 

Mostly reduced-EF outpatients

The open-label, blinded-endpoint IRONMAN trial, conducted at 70 centers in the United Kingdom, entered adults with HF, ejection fractions 45% or lower within the previous 2 years, and iron deficiency defined as transferrin saturation less than 20% or serum ferritin levels below 100 mcg/L, the report states. They were either hospitalized for HF, had such a hospitalization within the past 6 months, or were outpatients with elevated natriuretic peptide levels; the third category accounted for two thirds of the trial population.

Of the 1,137 randomized patients, 569 were assigned to receive intravenous ferric derisomaltose at weight- and hemoglobin-adjusted dosages; 568 went to the usual-care group.

• HF hospitalization or CV death: RR, 0.76 (95% confidence interval, 0.58-1.00; P = .047)
• HF hospitalization: RR 0.76 (95% CI, 0.56-1.03; P = .077)

Fewer patients in the intravenous iron group experienced serious cardiac adverse events, 36% compared with 43% in for those on usual care, P = .016.

The recently updated European Society of Cardiology guidelines for HF made it a class 1 recommendation to assess iron status in every patient, Kalra observed. “It doesn›t specify how frequently, but I think we should be thinking about every 4-6 months.”

Dr. Kalra disclosed receiving research grants from Pharmacosmos; and consulting or lecturing for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, Pharmacosmos, Servier, and Vifor Pharma. Dr. Musunuru disclosed significant ownership interest in Verve Therapeutics and Variant Bio. Dr. Lewis disclosed relationships with NXT, American Regent, and RIVUS; and receiving research grants from Cytokinetics and Amgen.

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

CHICAGO – Another major study appears to back the use of intravenous iron repletion in patients with heart failure (HF) and iron deficiency, strengthening largely consistent evidence, researchers say, that the treatment may improve symptoms and prevent some HF-related hospital admissions.

To be sure, the IRONMAN trial, which compared intravenous iron versus usual care in such patients – most with reduced ejection fraction and not hospitalized – failed to show a benefit for its primary endpoint. The 18% reduction in risk for HF hospitalization or cardiovascular (CV) death seen in the trial, however encouraging, can only be called a trend (P = .07).

But the intervention showed signs of benefit for some secondary endpoints, including quality of life scores, and hinted at such an effect on HF hospitalization. Risk for the latter endpoint dropped 20% (P = .085) over a median follow-up of 2.7 years.

The findings “build upon the other data we have that correcting iron deficiency can help improve well-being, and particularly reduce the risk of hospitalization, in a broad range of [HF] patients,” said Paul Kalra, MD, of the University of Glasgow and Portsmouth (England) Hospitals University NHS Trust.

The tested regimen “was well tolerated with no safety concerns” and offers “reassurance about the long-term safety” of the intravenous iron it used, ferric derisomaltose (MonoFerric), in patients with HF, Dr. Kalra said at a media briefing on the trial.

The remarks preceded his formal presentation of IRONMAN at the American Heart Association scientific sessions. Dr. Kalra is also lead author on the trial’s publication in The Lancet.

IRONMAN strengthens the base of evidence supporting intravenous iron in HF with iron deficiency, especially chronic HF in outpatients, Dr. Kalra and others said. It also supports efficacy for a form of intravenous iron not previously tested in a major HF trial.

Still, “the totality of data are now supporting intravenous iron per se,” regardless of the iron agent used, said Dr. Kalra. But ferric derisomaltose may have dosing advantages, he observed, “and we’ve now got these long-term safety data.”

The strongest prior support for intravenous iron in HF came from hospitalized patients who received it as ferric carboxymaltose (Ferinject) and were followed only 12 months. That was in the AFFIRM-AHF trial, published 2 years ago, which also missed its primary endpoint – the same one used in IRONMAN. Some outcomes in the two trials were similar.

The risk for HF hospitalization or CV death for intravenous iron therapy, compared with usual care, in AFFIRM-AHF fell 21% (P = .059), missing significance but apparently driven by a 26% drop in risk for HF readmissions (P = .013). But neither that trial nor IRONMAN suggested a benefit for CV mortality on its own.
 

The COVID effect

In IRONMAN, Dr. Kalra said, usual care could include oral iron supplementation, which 17% of patients in the control group received. That could potentially have kept the intravenous iron group from making a better showing for the primary endpoint, he proposed.

And some iron doses and other treatments were missed by a substantial number of patients in both groups who entered the trial after the United Kingdom’s national lockdown in response to the COVID-19 pandemic, he observed. “Patients were not able to come into hospitals for research visits, or in fact when they were able, may not have wanted to.”

So, the group conducted a “prespecified” sensitivity analysis that excluded the 9% of patients enrolled by the end of March 2020, about the time of the first lockdown, and followed the remainder for another 6 months.

In that analysis, risk for HF hospitalization or CV death declined 24% in the intravenous iron group, a marginal but significant result (P = .047) that was dominated by an improvement in HF hospitalizations.
 

Effects on guidelines

The intravenous iron recommendations in the European HF guidelines refer only to ferric carboxymaltose without mentioning other forms, such as ferric derisomaltose, “but this is now a class effect given the similarities between AFFIRM-AHF and IRONMAN,” said Gregory D. Lewis, MD, Mass General Brigham, Boston, invited discussant for Dr. Kalra’s presentation at the AHA session.

“In the United States, we relegate IV iron to improvement in functional capacity as a comorbidity of heart failure. Perhaps this role will expand,” added Dr. Lewis, who is medical director of his center’s heart transplant program.

He also wondered aloud whether the purported clinical benefits of intravenous iron in HF patients with iron deficiency, not as yet supported by a significant primary-endpoint showing in one of the major trials, currently justify expansion of its use in practice.

“With the benefits of IV iron on exercise capacity and quality of life, and the safety of administering high doses of IV iron,” potentially reducing HF polypharmacy, he noted, “should we be considering IV iron more commonly for utilization in our patients even if we find that heart failure hospitalizations and mortality are only modestly improved?”

IRONMAN “asked whether there’s benefit to IV iron in the longer term,” Kiran Musunuru, MD, PhD, MPH, University of Pennsylvania,Philadelphia, observed at the media briefing. As the trial was reported, “that does in fact, seem to be the case,” said Dr. Musunuru, who was not involved in IRONMAN.

Therefore, he said, “this study reinforces the message that we should be routinely monitoring our heart failure patients for iron deficiency and supplementing them as needed.”

A commentary linked to the IRONMAN publication agreed. The trial “increases the evidence base for the treatment of iron deficiency with intravenous iron supplementation,” wrote the editorialists, led by Theresa A. McDonagh, MD, King’s College Hospital and School of Cardiovascular Sciences, London.

Patients with acute or chronic HF, iron deficiency, and reduced or mildly reduced ejection fractions “should be offered treatment with intravenous iron to reduce their risk of hospital admission for heart failure,” they concluded.
 

Mostly reduced-EF outpatients

The open-label, blinded-endpoint IRONMAN trial, conducted at 70 centers in the United Kingdom, entered adults with HF, ejection fractions 45% or lower within the previous 2 years, and iron deficiency defined as transferrin saturation less than 20% or serum ferritin levels below 100 mcg/L, the report states. They were either hospitalized for HF, had such a hospitalization within the past 6 months, or were outpatients with elevated natriuretic peptide levels; the third category accounted for two thirds of the trial population.

Of the 1,137 randomized patients, 569 were assigned to receive intravenous ferric derisomaltose at weight- and hemoglobin-adjusted dosages; 568 went to the usual-care group.

• HF hospitalization or CV death: RR, 0.76 (95% confidence interval, 0.58-1.00; P = .047)
• HF hospitalization: RR 0.76 (95% CI, 0.56-1.03; P = .077)

Fewer patients in the intravenous iron group experienced serious cardiac adverse events, 36% compared with 43% in for those on usual care, P = .016.

The recently updated European Society of Cardiology guidelines for HF made it a class 1 recommendation to assess iron status in every patient, Kalra observed. “It doesn›t specify how frequently, but I think we should be thinking about every 4-6 months.”

Dr. Kalra disclosed receiving research grants from Pharmacosmos; and consulting or lecturing for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, Pharmacosmos, Servier, and Vifor Pharma. Dr. Musunuru disclosed significant ownership interest in Verve Therapeutics and Variant Bio. Dr. Lewis disclosed relationships with NXT, American Regent, and RIVUS; and receiving research grants from Cytokinetics and Amgen.

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

CHICAGO – A new, expanded meta-analysis confirmed the long-known effect that statin treatment has on raising blood glucose levels and causing incident diabetes, but it also documented that these effects are small and any risk they pose to statin users is dwarfed by the cholesterol-lowering effect of statins and their ability to reduce risk for atherosclerotic cardiovascular disease (ASCVD).

Mitchel L. Zoler/MDedge

This meta-analysis of 23 trials with a total of more than 150,000 participants showed that statin therapy significantly increased the risk for new-onset diabetes and worsening glycemia, driven by a “very small but generalized increase in glucose,” with a greater effect from high-intensity statin regimens and a similar but somewhat more muted effect from low- and moderate-intensity statin treatment, David Preiss, MBChB, PhD, reported at the American Heart Association scientific sessions.

Dr. Preiss also stressed that despite this, “the cardiovascular benefits of statin therapy remain substantial and profound” in people regardless of whether they have diabetes, prediabetes, or normoglycemia when they start statin treatment, noting that the impact of even high-intensity statin treatment is “absolutely tiny” increases in hemoglobin A1c and blood glucose.

“This does not detract from the substantial benefit of statin treatment,” declared Dr. Preiss, a metabolic medicine specialist and endocrinologist at Oxford (England) University.
 

Small glycemia increases ‘nudge’ some into diabetes

The data Dr. Preiss reported showed that high-intensity statin treatment (atorvastatin at a daily dose of at least 40 mg, or rosuvastatin at a daily dose of at least 20 mg) led to an average increase in A1c levels of 0.08 percentage points among people without diabetes when their treatment began and 0.24 percentage points among people already diagnosed with diabetes. Blood glucose levels rose by an average of 0.04 mmol/L (less than 1 mg/d) in those without diabetes, and by an average 0.22 mmol/L (about 4 mg/dL) in those with diabetes. People who received low- or moderate-intensity statin regimens had significant but smaller increases.

“We’re not talking about people going from no diabetes to frank diabetes. We’re talking about [statins] nudging a very small number of people across a diabetes threshold,” an A1c of 6.5% that is set somewhat arbitrarily based on an increased risk for developing retinopathy, Dr. Preiss said. ”A person just needs to lose a [daily] can of Coke’s worth of weight to eliminate any apparent diabetes risk,” he noted.
 

Benefit outweighs risks by three- to sevenfold

Dr. Preiss presented two other examples of what his findings showed to illustrate the relatively small risk posed by statin therapy compared with its potential benefits. Treating 10,000 people for 5 years with a high-intensity statin regimen in those with established ASCVD (secondary prevention) would result in an increment of 150 extra people developing diabetes because of the hyperglycemic effect of statins, compared with an expected prevention of 1,000 ASCVD events. Among 10,000 people at high ASCVD risk and taking a high-intensity statin regimen for primary prevention 5 years of treatment would result in roughly 130 extra cases of incident diabetes while preventing about 500 ASCVD events.

In addition, applying the new risk estimates to the people included in the UK Biobank database, whose median A1c is 5.5%, showed that a high-intensity statin regimen could be expected to raise the prevalence of those with an A1c of 6.5% or greater from 4.5% to 5.7%.

Several preventive cardiologists who heard the report and were not involved with the analysis agreed with Dr. Preiss that the benefits of statin treatment substantially offset this confirmed hyperglycemic effect.
 

Risk ‘more than counterbalanced by benefit’

“He clearly showed that the small hyperglycemia risk posed by statin use is more than counterbalanced by its benefit for reducing ASCVD events,” commented Neil J. Stone, MD, a cardiologist and professor of medicine at Northwestern University, Chicago. “I agree that, for those with prediabetes who are on the road to diabetes with or without a statin, the small increase in glucose with a statin should not dissuade statin usage because the benefit is so large. Rather, it should focus efforts to improve diet, increase physical activity, and keep weight controlled.”

Dr. Stone also noted in an interview that in the JUPITER trial, which examined the effects of a daily 20-mg dose of rosuvastatin (Crestor), a high-intensity regimen, study participants with diabetes risk factors who were assigned to rosuvastatin had an onset of diabetes that was earlier than people assigned to placebo by only about 5.4 weeks, yet this group had evidence of significant benefit.

Mitchel L. Zoler/MDedge News

“I agree with Dr. Preiss that the benefits of statins in reducing heart attack, stroke, and cardiovascular death far outweigh their modest effects on glycemia,” commented Brendan M. Everett, MD, a cardiologist and preventive medicine specialist at Brigham and Women’s Hospital in Boston. “This is particularly true for those with preexisting prediabetes or diabetes, who have an elevated risk of atherosclerotic events and thus stand to derive more significant benefit from statins. The benefits of lowering LDL cholesterol with a statin for preventing seriously morbid, and potentially fatal, cardiovascular events far outweigh the extremely modest, or even negligible, increases in the risk of diabetes that could be seen with the extremely small increases in A1c,” Dr. Everett said in an interview.

The new findings “reaffirm that there is a increased risk [from statins] but the most important point is that it is a very, very tiny difference in A1c,” commented Marc S. Sabatine, MD, a cardiologist and professor at Harvard Medical School, Boston. “These data have been known for quite some time, but this analysis was done in a more rigorous way.” The finding of “a small increase in risk for diabetes is really because diabetes has a biochemical threshold and statin treatment nudges some people a little past a line that is semi-arbitrary. It’s important to be cognizant of this, but it in no way dissuades me from treating patients aggressively with statins to reduce their ASCVD risk. I would monitor their A1c levels, and if they go higher and can’t be controlled with lifestyle we have plenty of medications that can control it,” he said in an interview.
 

No difference by statin type

The meta-analysis used data from 13 placebo-controlled statin trials that together involved 123,940 participants and had an average 4.3 years of follow-up, and four trials that compared one statin with another and collectively involved 30,734 participants with an average 4.9 years of follow-up.

The analyses showed that high-intensity statin treatment increased the rate of incident diabetes by a significant 36% relative to controls and increased the rate of worsening glycemia by a significant 24% compared with controls. Low- or moderate-intensity statin regimens increased incident diabetes by a significant 10% and raised the incidence of worsening glycemia by a significant 10% compared with controls, Dr. Preiss reported.

These effects did not significantly differ by type of statin (the study included people treated with atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), nor across a variety of subgroups based on age, sex, race, body mass index, diabetes risk, renal function, cholesterol levels, or cardiovascular disease. The effect was also consistent regardless of the duration of treatment.

Dr. Preiss also downplayed the magnitude of the apparent difference in risk posed by high-intensity and less intense statin regimens. “I suspect the apparent heterogeneity is true, but not quite as big as what we see,” he said.

The mechanisms by which statins have this effect remain unclear, but evidence suggests that it may be a direct effect of the main action of statins, inhibition of the HMG-CoA reductase enzyme.

The study received no commercial funding. Dr. Preiss and Dr. Stone had no disclosures. Dr. Everett has been a consultant to Eli Lilly, Gilead, Ipsen, Janssen, and Provention. Dr. Sabatine has been a consultant to Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.

CHICAGO – A new, expanded meta-analysis confirmed the long-known effect that statin treatment has on raising blood glucose levels and causing incident diabetes, but it also documented that these effects are small and any risk they pose to statin users is dwarfed by the cholesterol-lowering effect of statins and their ability to reduce risk for atherosclerotic cardiovascular disease (ASCVD).

Mitchel L. Zoler/MDedge

This meta-analysis of 23 trials with a total of more than 150,000 participants showed that statin therapy significantly increased the risk for new-onset diabetes and worsening glycemia, driven by a “very small but generalized increase in glucose,” with a greater effect from high-intensity statin regimens and a similar but somewhat more muted effect from low- and moderate-intensity statin treatment, David Preiss, MBChB, PhD, reported at the American Heart Association scientific sessions.

Dr. Preiss also stressed that despite this, “the cardiovascular benefits of statin therapy remain substantial and profound” in people regardless of whether they have diabetes, prediabetes, or normoglycemia when they start statin treatment, noting that the impact of even high-intensity statin treatment is “absolutely tiny” increases in hemoglobin A1c and blood glucose.

“This does not detract from the substantial benefit of statin treatment,” declared Dr. Preiss, a metabolic medicine specialist and endocrinologist at Oxford (England) University.
 

Small glycemia increases ‘nudge’ some into diabetes

The data Dr. Preiss reported showed that high-intensity statin treatment (atorvastatin at a daily dose of at least 40 mg, or rosuvastatin at a daily dose of at least 20 mg) led to an average increase in A1c levels of 0.08 percentage points among people without diabetes when their treatment began and 0.24 percentage points among people already diagnosed with diabetes. Blood glucose levels rose by an average of 0.04 mmol/L (less than 1 mg/d) in those without diabetes, and by an average 0.22 mmol/L (about 4 mg/dL) in those with diabetes. People who received low- or moderate-intensity statin regimens had significant but smaller increases.

“We’re not talking about people going from no diabetes to frank diabetes. We’re talking about [statins] nudging a very small number of people across a diabetes threshold,” an A1c of 6.5% that is set somewhat arbitrarily based on an increased risk for developing retinopathy, Dr. Preiss said. ”A person just needs to lose a [daily] can of Coke’s worth of weight to eliminate any apparent diabetes risk,” he noted.
 

Benefit outweighs risks by three- to sevenfold

Dr. Preiss presented two other examples of what his findings showed to illustrate the relatively small risk posed by statin therapy compared with its potential benefits. Treating 10,000 people for 5 years with a high-intensity statin regimen in those with established ASCVD (secondary prevention) would result in an increment of 150 extra people developing diabetes because of the hyperglycemic effect of statins, compared with an expected prevention of 1,000 ASCVD events. Among 10,000 people at high ASCVD risk and taking a high-intensity statin regimen for primary prevention 5 years of treatment would result in roughly 130 extra cases of incident diabetes while preventing about 500 ASCVD events.

In addition, applying the new risk estimates to the people included in the UK Biobank database, whose median A1c is 5.5%, showed that a high-intensity statin regimen could be expected to raise the prevalence of those with an A1c of 6.5% or greater from 4.5% to 5.7%.

Several preventive cardiologists who heard the report and were not involved with the analysis agreed with Dr. Preiss that the benefits of statin treatment substantially offset this confirmed hyperglycemic effect.
 

Risk ‘more than counterbalanced by benefit’

“He clearly showed that the small hyperglycemia risk posed by statin use is more than counterbalanced by its benefit for reducing ASCVD events,” commented Neil J. Stone, MD, a cardiologist and professor of medicine at Northwestern University, Chicago. “I agree that, for those with prediabetes who are on the road to diabetes with or without a statin, the small increase in glucose with a statin should not dissuade statin usage because the benefit is so large. Rather, it should focus efforts to improve diet, increase physical activity, and keep weight controlled.”

Dr. Stone also noted in an interview that in the JUPITER trial, which examined the effects of a daily 20-mg dose of rosuvastatin (Crestor), a high-intensity regimen, study participants with diabetes risk factors who were assigned to rosuvastatin had an onset of diabetes that was earlier than people assigned to placebo by only about 5.4 weeks, yet this group had evidence of significant benefit.

Mitchel L. Zoler/MDedge News

“I agree with Dr. Preiss that the benefits of statins in reducing heart attack, stroke, and cardiovascular death far outweigh their modest effects on glycemia,” commented Brendan M. Everett, MD, a cardiologist and preventive medicine specialist at Brigham and Women’s Hospital in Boston. “This is particularly true for those with preexisting prediabetes or diabetes, who have an elevated risk of atherosclerotic events and thus stand to derive more significant benefit from statins. The benefits of lowering LDL cholesterol with a statin for preventing seriously morbid, and potentially fatal, cardiovascular events far outweigh the extremely modest, or even negligible, increases in the risk of diabetes that could be seen with the extremely small increases in A1c,” Dr. Everett said in an interview.

The new findings “reaffirm that there is a increased risk [from statins] but the most important point is that it is a very, very tiny difference in A1c,” commented Marc S. Sabatine, MD, a cardiologist and professor at Harvard Medical School, Boston. “These data have been known for quite some time, but this analysis was done in a more rigorous way.” The finding of “a small increase in risk for diabetes is really because diabetes has a biochemical threshold and statin treatment nudges some people a little past a line that is semi-arbitrary. It’s important to be cognizant of this, but it in no way dissuades me from treating patients aggressively with statins to reduce their ASCVD risk. I would monitor their A1c levels, and if they go higher and can’t be controlled with lifestyle we have plenty of medications that can control it,” he said in an interview.
 

No difference by statin type

The meta-analysis used data from 13 placebo-controlled statin trials that together involved 123,940 participants and had an average 4.3 years of follow-up, and four trials that compared one statin with another and collectively involved 30,734 participants with an average 4.9 years of follow-up.

The analyses showed that high-intensity statin treatment increased the rate of incident diabetes by a significant 36% relative to controls and increased the rate of worsening glycemia by a significant 24% compared with controls. Low- or moderate-intensity statin regimens increased incident diabetes by a significant 10% and raised the incidence of worsening glycemia by a significant 10% compared with controls, Dr. Preiss reported.

These effects did not significantly differ by type of statin (the study included people treated with atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), nor across a variety of subgroups based on age, sex, race, body mass index, diabetes risk, renal function, cholesterol levels, or cardiovascular disease. The effect was also consistent regardless of the duration of treatment.

Dr. Preiss also downplayed the magnitude of the apparent difference in risk posed by high-intensity and less intense statin regimens. “I suspect the apparent heterogeneity is true, but not quite as big as what we see,” he said.

The mechanisms by which statins have this effect remain unclear, but evidence suggests that it may be a direct effect of the main action of statins, inhibition of the HMG-CoA reductase enzyme.

The study received no commercial funding. Dr. Preiss and Dr. Stone had no disclosures. Dr. Everett has been a consultant to Eli Lilly, Gilead, Ipsen, Janssen, and Provention. Dr. Sabatine has been a consultant to Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.

CHICAGO – A new, expanded meta-analysis confirmed the long-known effect that statin treatment has on raising blood glucose levels and causing incident diabetes, but it also documented that these effects are small and any risk they pose to statin users is dwarfed by the cholesterol-lowering effect of statins and their ability to reduce risk for atherosclerotic cardiovascular disease (ASCVD).

Mitchel L. Zoler/MDedge

This meta-analysis of 23 trials with a total of more than 150,000 participants showed that statin therapy significantly increased the risk for new-onset diabetes and worsening glycemia, driven by a “very small but generalized increase in glucose,” with a greater effect from high-intensity statin regimens and a similar but somewhat more muted effect from low- and moderate-intensity statin treatment, David Preiss, MBChB, PhD, reported at the American Heart Association scientific sessions.

Dr. Preiss also stressed that despite this, “the cardiovascular benefits of statin therapy remain substantial and profound” in people regardless of whether they have diabetes, prediabetes, or normoglycemia when they start statin treatment, noting that the impact of even high-intensity statin treatment is “absolutely tiny” increases in hemoglobin A1c and blood glucose.

“This does not detract from the substantial benefit of statin treatment,” declared Dr. Preiss, a metabolic medicine specialist and endocrinologist at Oxford (England) University.
 

Small glycemia increases ‘nudge’ some into diabetes

The data Dr. Preiss reported showed that high-intensity statin treatment (atorvastatin at a daily dose of at least 40 mg, or rosuvastatin at a daily dose of at least 20 mg) led to an average increase in A1c levels of 0.08 percentage points among people without diabetes when their treatment began and 0.24 percentage points among people already diagnosed with diabetes. Blood glucose levels rose by an average of 0.04 mmol/L (less than 1 mg/d) in those without diabetes, and by an average 0.22 mmol/L (about 4 mg/dL) in those with diabetes. People who received low- or moderate-intensity statin regimens had significant but smaller increases.

“We’re not talking about people going from no diabetes to frank diabetes. We’re talking about [statins] nudging a very small number of people across a diabetes threshold,” an A1c of 6.5% that is set somewhat arbitrarily based on an increased risk for developing retinopathy, Dr. Preiss said. ”A person just needs to lose a [daily] can of Coke’s worth of weight to eliminate any apparent diabetes risk,” he noted.
 

Benefit outweighs risks by three- to sevenfold

Dr. Preiss presented two other examples of what his findings showed to illustrate the relatively small risk posed by statin therapy compared with its potential benefits. Treating 10,000 people for 5 years with a high-intensity statin regimen in those with established ASCVD (secondary prevention) would result in an increment of 150 extra people developing diabetes because of the hyperglycemic effect of statins, compared with an expected prevention of 1,000 ASCVD events. Among 10,000 people at high ASCVD risk and taking a high-intensity statin regimen for primary prevention 5 years of treatment would result in roughly 130 extra cases of incident diabetes while preventing about 500 ASCVD events.

In addition, applying the new risk estimates to the people included in the UK Biobank database, whose median A1c is 5.5%, showed that a high-intensity statin regimen could be expected to raise the prevalence of those with an A1c of 6.5% or greater from 4.5% to 5.7%.

Several preventive cardiologists who heard the report and were not involved with the analysis agreed with Dr. Preiss that the benefits of statin treatment substantially offset this confirmed hyperglycemic effect.
 

Risk ‘more than counterbalanced by benefit’

“He clearly showed that the small hyperglycemia risk posed by statin use is more than counterbalanced by its benefit for reducing ASCVD events,” commented Neil J. Stone, MD, a cardiologist and professor of medicine at Northwestern University, Chicago. “I agree that, for those with prediabetes who are on the road to diabetes with or without a statin, the small increase in glucose with a statin should not dissuade statin usage because the benefit is so large. Rather, it should focus efforts to improve diet, increase physical activity, and keep weight controlled.”

Dr. Stone also noted in an interview that in the JUPITER trial, which examined the effects of a daily 20-mg dose of rosuvastatin (Crestor), a high-intensity regimen, study participants with diabetes risk factors who were assigned to rosuvastatin had an onset of diabetes that was earlier than people assigned to placebo by only about 5.4 weeks, yet this group had evidence of significant benefit.

Mitchel L. Zoler/MDedge News

“I agree with Dr. Preiss that the benefits of statins in reducing heart attack, stroke, and cardiovascular death far outweigh their modest effects on glycemia,” commented Brendan M. Everett, MD, a cardiologist and preventive medicine specialist at Brigham and Women’s Hospital in Boston. “This is particularly true for those with preexisting prediabetes or diabetes, who have an elevated risk of atherosclerotic events and thus stand to derive more significant benefit from statins. The benefits of lowering LDL cholesterol with a statin for preventing seriously morbid, and potentially fatal, cardiovascular events far outweigh the extremely modest, or even negligible, increases in the risk of diabetes that could be seen with the extremely small increases in A1c,” Dr. Everett said in an interview.

The new findings “reaffirm that there is a increased risk [from statins] but the most important point is that it is a very, very tiny difference in A1c,” commented Marc S. Sabatine, MD, a cardiologist and professor at Harvard Medical School, Boston. “These data have been known for quite some time, but this analysis was done in a more rigorous way.” The finding of “a small increase in risk for diabetes is really because diabetes has a biochemical threshold and statin treatment nudges some people a little past a line that is semi-arbitrary. It’s important to be cognizant of this, but it in no way dissuades me from treating patients aggressively with statins to reduce their ASCVD risk. I would monitor their A1c levels, and if they go higher and can’t be controlled with lifestyle we have plenty of medications that can control it,” he said in an interview.
 

No difference by statin type

The meta-analysis used data from 13 placebo-controlled statin trials that together involved 123,940 participants and had an average 4.3 years of follow-up, and four trials that compared one statin with another and collectively involved 30,734 participants with an average 4.9 years of follow-up.

The analyses showed that high-intensity statin treatment increased the rate of incident diabetes by a significant 36% relative to controls and increased the rate of worsening glycemia by a significant 24% compared with controls. Low- or moderate-intensity statin regimens increased incident diabetes by a significant 10% and raised the incidence of worsening glycemia by a significant 10% compared with controls, Dr. Preiss reported.

These effects did not significantly differ by type of statin (the study included people treated with atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), nor across a variety of subgroups based on age, sex, race, body mass index, diabetes risk, renal function, cholesterol levels, or cardiovascular disease. The effect was also consistent regardless of the duration of treatment.

Dr. Preiss also downplayed the magnitude of the apparent difference in risk posed by high-intensity and less intense statin regimens. “I suspect the apparent heterogeneity is true, but not quite as big as what we see,” he said.

The mechanisms by which statins have this effect remain unclear, but evidence suggests that it may be a direct effect of the main action of statins, inhibition of the HMG-CoA reductase enzyme.

The study received no commercial funding. Dr. Preiss and Dr. Stone had no disclosures. Dr. Everett has been a consultant to Eli Lilly, Gilead, Ipsen, Janssen, and Provention. Dr. Sabatine has been a consultant to Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

CHICAGO – The traditional Chinese herbal medicine tongxinluo added to guideline-directed therapy improves clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the CTS-AMI study suggests.

Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.

Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.

The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.

He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”

Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.

The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.

In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.

The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).

Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).

Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.

The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.

At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.

At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).

In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).

Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.

“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.

Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”

Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”

Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.

“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”

He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.

“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.

Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”

The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.

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

CHICAGO – The traditional Chinese herbal medicine tongxinluo added to guideline-directed therapy improves clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the CTS-AMI study suggests.

Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.

Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.

The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.

He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”

Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.

The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.

In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.

The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).

Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).

Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.

The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.

At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.

At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).

In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).

Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.

“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.

Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”

Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”

Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.

“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”

He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.

“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.

Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”

The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.

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

CHICAGO – The traditional Chinese herbal medicine tongxinluo added to guideline-directed therapy improves clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the CTS-AMI study suggests.

Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.

Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.

The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.

He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”

Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.

The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.

In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.

The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).

Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).

Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.

The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.

At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.

At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).

In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).

Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.

“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.

Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”

Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”

Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.

“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”

He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.

“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.

Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”

The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.

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

CHICAGO – A stepwise care pathway was associated with a substantial reduction in the number of invasive tests performed and a major improvement in outcomes, relative to usual management, in patients suspected of coronary artery disease (CAD), according to 1-year results of the multinational, randomized PRECISE trial.

The care pathway is appropriate for patients with nonacute chest pain or equivalent complaints that have raised suspicion of CAD, and it is extremely simple, according to the description from the principal investigator, Pamela S. Douglas, MD, given in her presentation at the annual scientific sessions of the American Heart Association.

Ted Bosworth/MDedge News

Unlike the highly complex diagnostic algorithms shunting suspected CAD patients to the vast array of potential evaluations, the newly tested protocol, characterized as a “precision strategy,” divides patients into those who are immediate candidates for invasive testing and those who are not. The discriminator is the PROMISE minimal risk assessment score, a tool already validated.

Those deemed candidates for testing on the basis of an elevated score undergo computed coronary CT angiography (cCTA). In those who are not, testing is deferred.
 

Strategy is simple but effective

Although simple, this pathway is highly effective, judging by the results of the PRECISE trial, which tested the strategy in 2,103 patients at 65 sites in North America and Europe. The primary outcome was a composite of major adverse cardiovascular events (MACE) that included death, nonfatal MI, and catheterization without observed CAD.

After a median follow-up of 11.8 months, the primary MACE endpoint was reached in about 11.3% of those in the usual-care group, which was more than twofold higher than the 4.2% in the precision strategy group. The unadjusted risk reduction was 65% but rose to more than 70% (hazard ratio, 0.29; P < .001) after adjustment for gender and baseline characteristics.

In the arm randomized to the precision strategy, 16% were characterized as low risk and received no further testing. Almost all the others underwent cCTA alone (48%) or cCTA with fractional flow reserve (FFR) (31%). Stress echocardiography, treadmill electrocardiography, and other functional studies were performed in the small proportion of remaining patients.
 

cCTA performed in just 15% of usual care

In the usual-care arm, cCTA with or without FFR was only performed in 15%. More than 80% of patients underwent evaluations with one or more of an array of functional tests. For example, one-third were evaluated with single photon emission CT/PET and nearly as many underwent stress echocardiography testing. Only 7% in usual care underwent no testing after referral.

Within the MACE composite endpoint, almost all the relative benefit in the precision strategy arm was derived from the endpoint of angiography performed without evidence of obstructive CAD (2.6% vs. 10.2%). Rates of all-cause mortality and MI were not significantly different.

Important for the safety and utility of the precision strategy, there “were no deaths or MI events among those assigned deferred testing ” in that experimental arm, according to Dr. Douglas, professor of research in cardiovascular diseases at Duke University, Durham, N.C.

Instead, those in the precision strategy arm were far less likely to undergo catheterization without finding CAD (20% vs. 60%) and far less likely to undergo catheterization without revascularization (28% vs. 70%).

In addition, the group randomized to the precision strategy were more likely to be placed on risk reducing therapies following testing. Although the higher proportion of patients placed on antihypertensive therapy did not reach statistical significance (P = .1), the increased proportions placed on lipid therapy (P < .001) and antiplatelet therapy (P < .001) did.

Citing a study in JAMA Cardiology that found that more than 25% of patients presenting with stable chest pain have normal coronary arteries, Dr. Douglas said that the precision strategy as shown in the PRECISE trial addresses several agreed-upon goals in guidelines from the AHA, the European Society of Cardiology and the U.K.’s National Institute for Health and Care Excellence. These goals include reducing unnecessary testing by risk stratification, improving diagnostic yield of the testing that is performed, and avoiding the costs and complications of unneeded invasive testing.

New protocol called preferred approach

On the basis of these results, Dr. Douglas called the precision strategy “a preferred approach in evaluating patients with stable symptoms and suspected coronary disease.”

Julie Indik, MD, PhD, a professor of medicine at the University of Arizona, Tuscon, said that application of this approach in routine care could have “a major impact on care” by avoiding unnecessary tests with no apparent adverse effect on outcomes.

Although not demonstrated in this study, Dr. Indik suggested that the large number of patients tested for CAD each year – she estimated 4 million visits – means that less testing is likely to have a major impact on the costs of care, and she praised “the practical, efficient” approach of the precision strategy.

Ted Bosworth/MDedge News

Ron Blankstein, MD, director of cardiac computed tomography, Brigham and Women’s Hospital, Boston, also said these data “have both economic and safety implications.” As an AHA-invited discussant of this study, he emphasized that this is a strategy that should only be applied to lower risk patients with no prior history of CAD, but, in this group, he believes these data “will inform future guidelines.”

Dr. Douglas declined to speculate on whether the precision strategy will be incorporated into future guidelines, but she did say that the PRECISE data demonstrate that this approach improves quality of care.

In an interview, Dr. Douglas suggested that this care pathway could provide a basis on which to demonstrate improved outcomes with more efficient use of resources, a common definition of quality care delivery.

Dr. Douglas reported financial relationships with Caption Health, Kowa, and Heartflow, which provided funding for the PRECISE trial. Dr. Indik reported no potential conflicts of interest. Dr. Blankstein reported financial relationships with Amgen, Caristo Diagnostics, and Novartis.

CHICAGO – A stepwise care pathway was associated with a substantial reduction in the number of invasive tests performed and a major improvement in outcomes, relative to usual management, in patients suspected of coronary artery disease (CAD), according to 1-year results of the multinational, randomized PRECISE trial.

The care pathway is appropriate for patients with nonacute chest pain or equivalent complaints that have raised suspicion of CAD, and it is extremely simple, according to the description from the principal investigator, Pamela S. Douglas, MD, given in her presentation at the annual scientific sessions of the American Heart Association.

Ted Bosworth/MDedge News

Unlike the highly complex diagnostic algorithms shunting suspected CAD patients to the vast array of potential evaluations, the newly tested protocol, characterized as a “precision strategy,” divides patients into those who are immediate candidates for invasive testing and those who are not. The discriminator is the PROMISE minimal risk assessment score, a tool already validated.

Those deemed candidates for testing on the basis of an elevated score undergo computed coronary CT angiography (cCTA). In those who are not, testing is deferred.
 

Strategy is simple but effective

Although simple, this pathway is highly effective, judging by the results of the PRECISE trial, which tested the strategy in 2,103 patients at 65 sites in North America and Europe. The primary outcome was a composite of major adverse cardiovascular events (MACE) that included death, nonfatal MI, and catheterization without observed CAD.

After a median follow-up of 11.8 months, the primary MACE endpoint was reached in about 11.3% of those in the usual-care group, which was more than twofold higher than the 4.2% in the precision strategy group. The unadjusted risk reduction was 65% but rose to more than 70% (hazard ratio, 0.29; P < .001) after adjustment for gender and baseline characteristics.

In the arm randomized to the precision strategy, 16% were characterized as low risk and received no further testing. Almost all the others underwent cCTA alone (48%) or cCTA with fractional flow reserve (FFR) (31%). Stress echocardiography, treadmill electrocardiography, and other functional studies were performed in the small proportion of remaining patients.
 

cCTA performed in just 15% of usual care

In the usual-care arm, cCTA with or without FFR was only performed in 15%. More than 80% of patients underwent evaluations with one or more of an array of functional tests. For example, one-third were evaluated with single photon emission CT/PET and nearly as many underwent stress echocardiography testing. Only 7% in usual care underwent no testing after referral.

Within the MACE composite endpoint, almost all the relative benefit in the precision strategy arm was derived from the endpoint of angiography performed without evidence of obstructive CAD (2.6% vs. 10.2%). Rates of all-cause mortality and MI were not significantly different.

Important for the safety and utility of the precision strategy, there “were no deaths or MI events among those assigned deferred testing ” in that experimental arm, according to Dr. Douglas, professor of research in cardiovascular diseases at Duke University, Durham, N.C.

Instead, those in the precision strategy arm were far less likely to undergo catheterization without finding CAD (20% vs. 60%) and far less likely to undergo catheterization without revascularization (28% vs. 70%).

In addition, the group randomized to the precision strategy were more likely to be placed on risk reducing therapies following testing. Although the higher proportion of patients placed on antihypertensive therapy did not reach statistical significance (P = .1), the increased proportions placed on lipid therapy (P < .001) and antiplatelet therapy (P < .001) did.

Citing a study in JAMA Cardiology that found that more than 25% of patients presenting with stable chest pain have normal coronary arteries, Dr. Douglas said that the precision strategy as shown in the PRECISE trial addresses several agreed-upon goals in guidelines from the AHA, the European Society of Cardiology and the U.K.’s National Institute for Health and Care Excellence. These goals include reducing unnecessary testing by risk stratification, improving diagnostic yield of the testing that is performed, and avoiding the costs and complications of unneeded invasive testing.

New protocol called preferred approach

On the basis of these results, Dr. Douglas called the precision strategy “a preferred approach in evaluating patients with stable symptoms and suspected coronary disease.”

Julie Indik, MD, PhD, a professor of medicine at the University of Arizona, Tuscon, said that application of this approach in routine care could have “a major impact on care” by avoiding unnecessary tests with no apparent adverse effect on outcomes.

Although not demonstrated in this study, Dr. Indik suggested that the large number of patients tested for CAD each year – she estimated 4 million visits – means that less testing is likely to have a major impact on the costs of care, and she praised “the practical, efficient” approach of the precision strategy.

Ted Bosworth/MDedge News

Ron Blankstein, MD, director of cardiac computed tomography, Brigham and Women’s Hospital, Boston, also said these data “have both economic and safety implications.” As an AHA-invited discussant of this study, he emphasized that this is a strategy that should only be applied to lower risk patients with no prior history of CAD, but, in this group, he believes these data “will inform future guidelines.”

Dr. Douglas declined to speculate on whether the precision strategy will be incorporated into future guidelines, but she did say that the PRECISE data demonstrate that this approach improves quality of care.

In an interview, Dr. Douglas suggested that this care pathway could provide a basis on which to demonstrate improved outcomes with more efficient use of resources, a common definition of quality care delivery.

Dr. Douglas reported financial relationships with Caption Health, Kowa, and Heartflow, which provided funding for the PRECISE trial. Dr. Indik reported no potential conflicts of interest. Dr. Blankstein reported financial relationships with Amgen, Caristo Diagnostics, and Novartis.

CHICAGO – A stepwise care pathway was associated with a substantial reduction in the number of invasive tests performed and a major improvement in outcomes, relative to usual management, in patients suspected of coronary artery disease (CAD), according to 1-year results of the multinational, randomized PRECISE trial.

The care pathway is appropriate for patients with nonacute chest pain or equivalent complaints that have raised suspicion of CAD, and it is extremely simple, according to the description from the principal investigator, Pamela S. Douglas, MD, given in her presentation at the annual scientific sessions of the American Heart Association.

Ted Bosworth/MDedge News

Unlike the highly complex diagnostic algorithms shunting suspected CAD patients to the vast array of potential evaluations, the newly tested protocol, characterized as a “precision strategy,” divides patients into those who are immediate candidates for invasive testing and those who are not. The discriminator is the PROMISE minimal risk assessment score, a tool already validated.

Those deemed candidates for testing on the basis of an elevated score undergo computed coronary CT angiography (cCTA). In those who are not, testing is deferred.
 

Strategy is simple but effective

Although simple, this pathway is highly effective, judging by the results of the PRECISE trial, which tested the strategy in 2,103 patients at 65 sites in North America and Europe. The primary outcome was a composite of major adverse cardiovascular events (MACE) that included death, nonfatal MI, and catheterization without observed CAD.

After a median follow-up of 11.8 months, the primary MACE endpoint was reached in about 11.3% of those in the usual-care group, which was more than twofold higher than the 4.2% in the precision strategy group. The unadjusted risk reduction was 65% but rose to more than 70% (hazard ratio, 0.29; P < .001) after adjustment for gender and baseline characteristics.

In the arm randomized to the precision strategy, 16% were characterized as low risk and received no further testing. Almost all the others underwent cCTA alone (48%) or cCTA with fractional flow reserve (FFR) (31%). Stress echocardiography, treadmill electrocardiography, and other functional studies were performed in the small proportion of remaining patients.
 

cCTA performed in just 15% of usual care

In the usual-care arm, cCTA with or without FFR was only performed in 15%. More than 80% of patients underwent evaluations with one or more of an array of functional tests. For example, one-third were evaluated with single photon emission CT/PET and nearly as many underwent stress echocardiography testing. Only 7% in usual care underwent no testing after referral.

Within the MACE composite endpoint, almost all the relative benefit in the precision strategy arm was derived from the endpoint of angiography performed without evidence of obstructive CAD (2.6% vs. 10.2%). Rates of all-cause mortality and MI were not significantly different.

Important for the safety and utility of the precision strategy, there “were no deaths or MI events among those assigned deferred testing ” in that experimental arm, according to Dr. Douglas, professor of research in cardiovascular diseases at Duke University, Durham, N.C.

Instead, those in the precision strategy arm were far less likely to undergo catheterization without finding CAD (20% vs. 60%) and far less likely to undergo catheterization without revascularization (28% vs. 70%).

In addition, the group randomized to the precision strategy were more likely to be placed on risk reducing therapies following testing. Although the higher proportion of patients placed on antihypertensive therapy did not reach statistical significance (P = .1), the increased proportions placed on lipid therapy (P < .001) and antiplatelet therapy (P < .001) did.

Citing a study in JAMA Cardiology that found that more than 25% of patients presenting with stable chest pain have normal coronary arteries, Dr. Douglas said that the precision strategy as shown in the PRECISE trial addresses several agreed-upon goals in guidelines from the AHA, the European Society of Cardiology and the U.K.’s National Institute for Health and Care Excellence. These goals include reducing unnecessary testing by risk stratification, improving diagnostic yield of the testing that is performed, and avoiding the costs and complications of unneeded invasive testing.

New protocol called preferred approach

On the basis of these results, Dr. Douglas called the precision strategy “a preferred approach in evaluating patients with stable symptoms and suspected coronary disease.”

Julie Indik, MD, PhD, a professor of medicine at the University of Arizona, Tuscon, said that application of this approach in routine care could have “a major impact on care” by avoiding unnecessary tests with no apparent adverse effect on outcomes.

Although not demonstrated in this study, Dr. Indik suggested that the large number of patients tested for CAD each year – she estimated 4 million visits – means that less testing is likely to have a major impact on the costs of care, and she praised “the practical, efficient” approach of the precision strategy.

Ted Bosworth/MDedge News

Ron Blankstein, MD, director of cardiac computed tomography, Brigham and Women’s Hospital, Boston, also said these data “have both economic and safety implications.” As an AHA-invited discussant of this study, he emphasized that this is a strategy that should only be applied to lower risk patients with no prior history of CAD, but, in this group, he believes these data “will inform future guidelines.”

Dr. Douglas declined to speculate on whether the precision strategy will be incorporated into future guidelines, but she did say that the PRECISE data demonstrate that this approach improves quality of care.

In an interview, Dr. Douglas suggested that this care pathway could provide a basis on which to demonstrate improved outcomes with more efficient use of resources, a common definition of quality care delivery.

Dr. Douglas reported financial relationships with Caption Health, Kowa, and Heartflow, which provided funding for the PRECISE trial. Dr. Indik reported no potential conflicts of interest. Dr. Blankstein reported financial relationships with Amgen, Caristo Diagnostics, and Novartis.

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

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

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

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

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

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

CHICAGO – Despite a 25% reduction in triglycerides (TGs) along with similar reductions in very-low-density lipoprotein (VLDL), and remnant cholesterol, a novel agent failed to provide any protection in a multinational trial against a composite endpoint of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.

“Our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy,” reported Aruna Das Pradhan, MD, of Harvard Medical School, Boston, and Queen Mary University, London.

Ted Bosworth/MDedge News

No benefit from fibrates seen in statin era

“We have not seen a significant cardiovascular event reduction with a fibrate in the statin era,” according to Karol Watson, MD, PhD, director of the UCLA Women’s Cardiovascular Health Center, Los Angeles.

Ted Bosworth/MDedge News

Lipid profile improved as predicted

Yet, in regard to an improvement in the lipid profile, pemafibrate performed as predicted. When compared to placebo 4 months into the trial, pemafibrate was associated with median reductions of 26.2% in TGs, 25.8% in VLDL, and 25.6% in remnant cholesterol, which is cholesterol transported in TG-rich lipoproteins after lipolysis and lipoprotein remodeling.

Furthermore, pemafibrate was associated with a median 27.6% reduction relative to placebo in apolipoprotein C-III and a median 4.8% reduction in apolipoprotein E, all of which would be expected to reduce CV risk.

The findings of PROMINENT were published online in the New England Journal of Medicine immediately after their presentation.

The findings of this study do not eliminate any hope for lowering residual CV risk with TG reductions, but they do suggest the relationship with other lipid subfractions is complex, according to Salim S. Virani, MD, PhD, a professor of cardiology at Baylor College of Medicine, Houston.

“I think that the lack of efficacy despite TG lowering may be largely due to a lack of an overall decrease in the apolipoprotein B level,” speculated Dr. Virani, who wrote an editorial that accompanied publication of the PROMINENT results.

He noted that pemafibrate is implicated in converting remnant cholesterol to LDL cholesterol, which might be one reason for a counterproductive effect on CV risk.

“In order for therapies that lower TG levels to be effective, they probably have to have mechanisms to increase clearance of TG-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL,” Dr. Virani explained in an attempt to unravel the interplay of these variables.

Although this study enrolled patients “who would be predicted to have the most benefit from a TG-lowering strategy,” Dr. Watson agreed that these results do not necessarily extend to other means of lowering TG. However, it might draw into question the value of pemafibrate and perhaps other drugs in this class for treatment of hypertriglyceridemia. In addition to a lack of CV benefit, treatment was not without risks, including a higher rate of thromboembolism and adverse renal events.

Dr. Das Pradhan reported financial relationships with Denka, Medtelligence, Optum, Novo Nordisk, and Kowa, which provided funding for this trial. Dr. Watson reported financial relationships with Amarin, Amgen, Boehringer-Ingelheim, and Esperion.

CHICAGO – Despite a 25% reduction in triglycerides (TGs) along with similar reductions in very-low-density lipoprotein (VLDL), and remnant cholesterol, a novel agent failed to provide any protection in a multinational trial against a composite endpoint of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.

“Our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy,” reported Aruna Das Pradhan, MD, of Harvard Medical School, Boston, and Queen Mary University, London.

Ted Bosworth/MDedge News

No benefit from fibrates seen in statin era

“We have not seen a significant cardiovascular event reduction with a fibrate in the statin era,” according to Karol Watson, MD, PhD, director of the UCLA Women’s Cardiovascular Health Center, Los Angeles.

Ted Bosworth/MDedge News

Lipid profile improved as predicted

Yet, in regard to an improvement in the lipid profile, pemafibrate performed as predicted. When compared to placebo 4 months into the trial, pemafibrate was associated with median reductions of 26.2% in TGs, 25.8% in VLDL, and 25.6% in remnant cholesterol, which is cholesterol transported in TG-rich lipoproteins after lipolysis and lipoprotein remodeling.

Furthermore, pemafibrate was associated with a median 27.6% reduction relative to placebo in apolipoprotein C-III and a median 4.8% reduction in apolipoprotein E, all of which would be expected to reduce CV risk.

The findings of PROMINENT were published online in the New England Journal of Medicine immediately after their presentation.

The findings of this study do not eliminate any hope for lowering residual CV risk with TG reductions, but they do suggest the relationship with other lipid subfractions is complex, according to Salim S. Virani, MD, PhD, a professor of cardiology at Baylor College of Medicine, Houston.

“I think that the lack of efficacy despite TG lowering may be largely due to a lack of an overall decrease in the apolipoprotein B level,” speculated Dr. Virani, who wrote an editorial that accompanied publication of the PROMINENT results.

He noted that pemafibrate is implicated in converting remnant cholesterol to LDL cholesterol, which might be one reason for a counterproductive effect on CV risk.

“In order for therapies that lower TG levels to be effective, they probably have to have mechanisms to increase clearance of TG-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL,” Dr. Virani explained in an attempt to unravel the interplay of these variables.

Although this study enrolled patients “who would be predicted to have the most benefit from a TG-lowering strategy,” Dr. Watson agreed that these results do not necessarily extend to other means of lowering TG. However, it might draw into question the value of pemafibrate and perhaps other drugs in this class for treatment of hypertriglyceridemia. In addition to a lack of CV benefit, treatment was not without risks, including a higher rate of thromboembolism and adverse renal events.

Dr. Das Pradhan reported financial relationships with Denka, Medtelligence, Optum, Novo Nordisk, and Kowa, which provided funding for this trial. Dr. Watson reported financial relationships with Amarin, Amgen, Boehringer-Ingelheim, and Esperion.

CHICAGO – Despite a 25% reduction in triglycerides (TGs) along with similar reductions in very-low-density lipoprotein (VLDL), and remnant cholesterol, a novel agent failed to provide any protection in a multinational trial against a composite endpoint of major adverse cardiovascular events (MACE) in patients with type 2 diabetes.

“Our data further highlight the complexity of lipid mediators of residual risk among patients with insulin resistance who are receiving statin therapy,” reported Aruna Das Pradhan, MD, of Harvard Medical School, Boston, and Queen Mary University, London.

Ted Bosworth/MDedge News

No benefit from fibrates seen in statin era

“We have not seen a significant cardiovascular event reduction with a fibrate in the statin era,” according to Karol Watson, MD, PhD, director of the UCLA Women’s Cardiovascular Health Center, Los Angeles.

Ted Bosworth/MDedge News

Lipid profile improved as predicted

Yet, in regard to an improvement in the lipid profile, pemafibrate performed as predicted. When compared to placebo 4 months into the trial, pemafibrate was associated with median reductions of 26.2% in TGs, 25.8% in VLDL, and 25.6% in remnant cholesterol, which is cholesterol transported in TG-rich lipoproteins after lipolysis and lipoprotein remodeling.

Furthermore, pemafibrate was associated with a median 27.6% reduction relative to placebo in apolipoprotein C-III and a median 4.8% reduction in apolipoprotein E, all of which would be expected to reduce CV risk.

The findings of PROMINENT were published online in the New England Journal of Medicine immediately after their presentation.

The findings of this study do not eliminate any hope for lowering residual CV risk with TG reductions, but they do suggest the relationship with other lipid subfractions is complex, according to Salim S. Virani, MD, PhD, a professor of cardiology at Baylor College of Medicine, Houston.

“I think that the lack of efficacy despite TG lowering may be largely due to a lack of an overall decrease in the apolipoprotein B level,” speculated Dr. Virani, who wrote an editorial that accompanied publication of the PROMINENT results.

He noted that pemafibrate is implicated in converting remnant cholesterol to LDL cholesterol, which might be one reason for a counterproductive effect on CV risk.

“In order for therapies that lower TG levels to be effective, they probably have to have mechanisms to increase clearance of TG-rich remnant lipoprotein cholesterol particles rather than just converting remnant lipoproteins to LDL,” Dr. Virani explained in an attempt to unravel the interplay of these variables.

Although this study enrolled patients “who would be predicted to have the most benefit from a TG-lowering strategy,” Dr. Watson agreed that these results do not necessarily extend to other means of lowering TG. However, it might draw into question the value of pemafibrate and perhaps other drugs in this class for treatment of hypertriglyceridemia. In addition to a lack of CV benefit, treatment was not without risks, including a higher rate of thromboembolism and adverse renal events.

Dr. Das Pradhan reported financial relationships with Denka, Medtelligence, Optum, Novo Nordisk, and Kowa, which provided funding for this trial. Dr. Watson reported financial relationships with Amarin, Amgen, Boehringer-Ingelheim, and Esperion.

Severe marital stress was associated with worse recovery after myocardial infarction in a large U.S. cohort of married/partnered patients aged 55 years or younger.

Compared with patients who reported no or mild marital stress a month after their MI, patients who reported severe marital stress had worse physical and mental health, worse generic and cardiovascular quality of life, more frequent angina symptoms, and a greater likelihood of having a hospital readmission a year later.

These findings held true after adjusting for gender, age, race/ethnicity, and baseline health status (model 1) and after further adjusting for education and income levels and employment and insurance status (model 2).

A greater percentage of women than men reported having severe marital stress (39% vs. 30%; P = .001).

Cenjing Zhu, MPhil, a PhD candidate at Yale University, New Haven, Conn., and colleagues will present this study at the American Heart Association scientific sessions.

The results show that “both patients and care providers should be aware that stress experienced in one’s everyday life, such as marital stress, can affect AMI [acute MI] recovery,” Ms. Zhu said in an email.

Health care providers should consider incorporating screening for everyday stress during follow-up patient visits to better spot people at high risk of a poor recovery and further hospitalizations, she added. When possible, they could guide patients to resources to help them manage and reduce their stress levels.

According to Ms. Zhu, the findings suggest that “managing personal stress may be as important as managing other clinical risk factors during the recovery process.”

This study in younger patients with MI “shows that high levels of marital stress impair heart attack recovery, and women have greater impairment in their heart attack recovery compared to men,” AHA spokesperson Nieca Goldberg, MD, who was not involved with this research, told this news organization.

The study shows that “clinicians have to incorporate mental health as part of their assessment of all patients,” said Dr. Goldberg, a clinical associate professor of medicine at New York University and medical director of Atria New York City.

“Our mental health impacts our physical health,” she noted. “Questions about marital stress should be included as part of an overall assessment of mental health. This means assessing all patients for stress, anxiety, and depression.”

Patients who are experiencing marital stress should share the information with their doctor and discuss ways to be referred to therapists and cardiac rehabilitation providers, she said. “My final thought is, women have often been told that their cardiac symptoms are due to stress by doctors. Now we know stress impacts physical health and [is] no longer an excuse but a contributing factor to our physical health.”
 

Does marital stress affect young MI recovery?

Previous literature has linked psychological stress with worse cardiovascular outcomes, Ms. Zhu noted.

However, little is known about the prognostic impact of marital stress on 1-year health outcomes for younger people who survive an MI.

To investigate this, the researchers analyzed data from participants in the Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study.

The current study comprised 1,593 adults, including 1,020 female participants (64%), who were treated for MI at 103 hospitals in 30 U.S. states.

VIRGO enrolled participants in a 2:1 female-to-male ratio so as to enrich the inclusion of women, Ms. Zhu explained.

In the study, “partnered” participants were individuals who self-reported as “living as married/living with a partner.” There were 126 such patients (8%) in the current study.

The mean age of the patients was 47, and about 90% were 40-55 years old. Three quarters were White, 13% were Black, and 7% were Hispanic.

Marital stress was assessed on the basis of patients’ replies to 17 questions in the Stockholm Marital Stress Scale regarding the quality of their emotional and sexual relationships with their spouses/partners.

The researchers divided patients into three groups on the basis of their marital stress: mild or absent (lowest quartile), moderate (second quartile), and severe (upper two quartiles).

At 1 year after their MI, patients replied to questionnaires that assessed their health, quality of life, and depressive and angina symptoms. Hospital readmissions were determined on the basis of self-reports and medical records.

Compared to participants who reported no or mild marital stress, those who reported severe mental stress had significantly worse scores for physical and mental health and generic and cardiovascular quality of life, after adjusting for baseline health and demographics. They had worse scores for mental health and quality of life, after further adjusting for socioeconomic status.

In the fully adjusted model, patients who reported severe marital stress were significantly more likely to report more frequent chest pain/angina (odds ratio, 1.49; 95% confidence interval, 1.06-2.10; P = .023) and to have been readmitted to hospital for any cause (OR, 1.45; 95% CI, 1.04-2.00; P = .006), compared with the patients who reported no or mild marital stress.

Study limitations include the fact that the findings are based on self-reported questionnaire replies; they may not be generalizable to patients in other countries; and they do not extend beyond a period of 1 year.

The researchers call for further research “to understand this complex relationship and potential causal pathway associated with these findings.”

“Additional stressors beyond marital stress, such as financial strain or work stress, may also play a role in young adults’ recovery, and the interaction between these factors require further research,” Ms. Zhu noted in a press release from the AHA.

The study was funded by Canadian Institutes of Health Research. The VIRGO study was funded by the National Heart, Lung, and Blood Institute. Ms. Zhu and Dr. Goldberg have disclosed no relevant financial relationships.

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

Severe marital stress was associated with worse recovery after myocardial infarction in a large U.S. cohort of married/partnered patients aged 55 years or younger.

Compared with patients who reported no or mild marital stress a month after their MI, patients who reported severe marital stress had worse physical and mental health, worse generic and cardiovascular quality of life, more frequent angina symptoms, and a greater likelihood of having a hospital readmission a year later.

These findings held true after adjusting for gender, age, race/ethnicity, and baseline health status (model 1) and after further adjusting for education and income levels and employment and insurance status (model 2).

A greater percentage of women than men reported having severe marital stress (39% vs. 30%; P = .001).

Cenjing Zhu, MPhil, a PhD candidate at Yale University, New Haven, Conn., and colleagues will present this study at the American Heart Association scientific sessions.

The results show that “both patients and care providers should be aware that stress experienced in one’s everyday life, such as marital stress, can affect AMI [acute MI] recovery,” Ms. Zhu said in an email.

Health care providers should consider incorporating screening for everyday stress during follow-up patient visits to better spot people at high risk of a poor recovery and further hospitalizations, she added. When possible, they could guide patients to resources to help them manage and reduce their stress levels.

According to Ms. Zhu, the findings suggest that “managing personal stress may be as important as managing other clinical risk factors during the recovery process.”

This study in younger patients with MI “shows that high levels of marital stress impair heart attack recovery, and women have greater impairment in their heart attack recovery compared to men,” AHA spokesperson Nieca Goldberg, MD, who was not involved with this research, told this news organization.

The study shows that “clinicians have to incorporate mental health as part of their assessment of all patients,” said Dr. Goldberg, a clinical associate professor of medicine at New York University and medical director of Atria New York City.

“Our mental health impacts our physical health,” she noted. “Questions about marital stress should be included as part of an overall assessment of mental health. This means assessing all patients for stress, anxiety, and depression.”

Patients who are experiencing marital stress should share the information with their doctor and discuss ways to be referred to therapists and cardiac rehabilitation providers, she said. “My final thought is, women have often been told that their cardiac symptoms are due to stress by doctors. Now we know stress impacts physical health and [is] no longer an excuse but a contributing factor to our physical health.”
 

Does marital stress affect young MI recovery?

Previous literature has linked psychological stress with worse cardiovascular outcomes, Ms. Zhu noted.

However, little is known about the prognostic impact of marital stress on 1-year health outcomes for younger people who survive an MI.

To investigate this, the researchers analyzed data from participants in the Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study.

The current study comprised 1,593 adults, including 1,020 female participants (64%), who were treated for MI at 103 hospitals in 30 U.S. states.

VIRGO enrolled participants in a 2:1 female-to-male ratio so as to enrich the inclusion of women, Ms. Zhu explained.

In the study, “partnered” participants were individuals who self-reported as “living as married/living with a partner.” There were 126 such patients (8%) in the current study.

The mean age of the patients was 47, and about 90% were 40-55 years old. Three quarters were White, 13% were Black, and 7% were Hispanic.

Marital stress was assessed on the basis of patients’ replies to 17 questions in the Stockholm Marital Stress Scale regarding the quality of their emotional and sexual relationships with their spouses/partners.

The researchers divided patients into three groups on the basis of their marital stress: mild or absent (lowest quartile), moderate (second quartile), and severe (upper two quartiles).

At 1 year after their MI, patients replied to questionnaires that assessed their health, quality of life, and depressive and angina symptoms. Hospital readmissions were determined on the basis of self-reports and medical records.

Compared to participants who reported no or mild marital stress, those who reported severe mental stress had significantly worse scores for physical and mental health and generic and cardiovascular quality of life, after adjusting for baseline health and demographics. They had worse scores for mental health and quality of life, after further adjusting for socioeconomic status.

In the fully adjusted model, patients who reported severe marital stress were significantly more likely to report more frequent chest pain/angina (odds ratio, 1.49; 95% confidence interval, 1.06-2.10; P = .023) and to have been readmitted to hospital for any cause (OR, 1.45; 95% CI, 1.04-2.00; P = .006), compared with the patients who reported no or mild marital stress.

Study limitations include the fact that the findings are based on self-reported questionnaire replies; they may not be generalizable to patients in other countries; and they do not extend beyond a period of 1 year.

The researchers call for further research “to understand this complex relationship and potential causal pathway associated with these findings.”

“Additional stressors beyond marital stress, such as financial strain or work stress, may also play a role in young adults’ recovery, and the interaction between these factors require further research,” Ms. Zhu noted in a press release from the AHA.

The study was funded by Canadian Institutes of Health Research. The VIRGO study was funded by the National Heart, Lung, and Blood Institute. Ms. Zhu and Dr. Goldberg have disclosed no relevant financial relationships.

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

Severe marital stress was associated with worse recovery after myocardial infarction in a large U.S. cohort of married/partnered patients aged 55 years or younger.

Compared with patients who reported no or mild marital stress a month after their MI, patients who reported severe marital stress had worse physical and mental health, worse generic and cardiovascular quality of life, more frequent angina symptoms, and a greater likelihood of having a hospital readmission a year later.

These findings held true after adjusting for gender, age, race/ethnicity, and baseline health status (model 1) and after further adjusting for education and income levels and employment and insurance status (model 2).

A greater percentage of women than men reported having severe marital stress (39% vs. 30%; P = .001).

Cenjing Zhu, MPhil, a PhD candidate at Yale University, New Haven, Conn., and colleagues will present this study at the American Heart Association scientific sessions.

The results show that “both patients and care providers should be aware that stress experienced in one’s everyday life, such as marital stress, can affect AMI [acute MI] recovery,” Ms. Zhu said in an email.

Health care providers should consider incorporating screening for everyday stress during follow-up patient visits to better spot people at high risk of a poor recovery and further hospitalizations, she added. When possible, they could guide patients to resources to help them manage and reduce their stress levels.

According to Ms. Zhu, the findings suggest that “managing personal stress may be as important as managing other clinical risk factors during the recovery process.”

This study in younger patients with MI “shows that high levels of marital stress impair heart attack recovery, and women have greater impairment in their heart attack recovery compared to men,” AHA spokesperson Nieca Goldberg, MD, who was not involved with this research, told this news organization.

The study shows that “clinicians have to incorporate mental health as part of their assessment of all patients,” said Dr. Goldberg, a clinical associate professor of medicine at New York University and medical director of Atria New York City.

“Our mental health impacts our physical health,” she noted. “Questions about marital stress should be included as part of an overall assessment of mental health. This means assessing all patients for stress, anxiety, and depression.”

Patients who are experiencing marital stress should share the information with their doctor and discuss ways to be referred to therapists and cardiac rehabilitation providers, she said. “My final thought is, women have often been told that their cardiac symptoms are due to stress by doctors. Now we know stress impacts physical health and [is] no longer an excuse but a contributing factor to our physical health.”
 

Does marital stress affect young MI recovery?

Previous literature has linked psychological stress with worse cardiovascular outcomes, Ms. Zhu noted.

However, little is known about the prognostic impact of marital stress on 1-year health outcomes for younger people who survive an MI.

To investigate this, the researchers analyzed data from participants in the Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study.

The current study comprised 1,593 adults, including 1,020 female participants (64%), who were treated for MI at 103 hospitals in 30 U.S. states.

VIRGO enrolled participants in a 2:1 female-to-male ratio so as to enrich the inclusion of women, Ms. Zhu explained.

In the study, “partnered” participants were individuals who self-reported as “living as married/living with a partner.” There were 126 such patients (8%) in the current study.

The mean age of the patients was 47, and about 90% were 40-55 years old. Three quarters were White, 13% were Black, and 7% were Hispanic.

Marital stress was assessed on the basis of patients’ replies to 17 questions in the Stockholm Marital Stress Scale regarding the quality of their emotional and sexual relationships with their spouses/partners.

The researchers divided patients into three groups on the basis of their marital stress: mild or absent (lowest quartile), moderate (second quartile), and severe (upper two quartiles).

At 1 year after their MI, patients replied to questionnaires that assessed their health, quality of life, and depressive and angina symptoms. Hospital readmissions were determined on the basis of self-reports and medical records.

Compared to participants who reported no or mild marital stress, those who reported severe mental stress had significantly worse scores for physical and mental health and generic and cardiovascular quality of life, after adjusting for baseline health and demographics. They had worse scores for mental health and quality of life, after further adjusting for socioeconomic status.

In the fully adjusted model, patients who reported severe marital stress were significantly more likely to report more frequent chest pain/angina (odds ratio, 1.49; 95% confidence interval, 1.06-2.10; P = .023) and to have been readmitted to hospital for any cause (OR, 1.45; 95% CI, 1.04-2.00; P = .006), compared with the patients who reported no or mild marital stress.

Study limitations include the fact that the findings are based on self-reported questionnaire replies; they may not be generalizable to patients in other countries; and they do not extend beyond a period of 1 year.

The researchers call for further research “to understand this complex relationship and potential causal pathway associated with these findings.”

“Additional stressors beyond marital stress, such as financial strain or work stress, may also play a role in young adults’ recovery, and the interaction between these factors require further research,” Ms. Zhu noted in a press release from the AHA.

The study was funded by Canadian Institutes of Health Research. The VIRGO study was funded by the National Heart, Lung, and Blood Institute. Ms. Zhu and Dr. Goldberg have disclosed no relevant financial relationships.

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