CAD & Atherosclerosis

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

dbrunk@mdedge.com

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

dbrunk@mdedge.com

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

dbrunk@mdedge.com

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

People who frequently alter the amount of sleep and time they go to bed each night are twofold more likely to develop cardiovascular disease, independent of traditional CVD risk factors, new research suggests.

Prior studies have focused on shift workers because night shift work will influence circadian rhythm and increase CVD risk. But it is increasingly recognized that circadian disruption may occur outside of shift work and accumulate over time, particularly given modern lifestyle factors such as increased use of mobile devices and television at night, said study coauthor Tianyi Huang, ScD, MSc, of Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts.

“Even if they tend to go to sleep at certain times, by following that lifestyle or behavior, it can interfere with their planned sleep timing,” he said.

“One thing that surprised me in this sample is that about one third of participants have irregular sleep patterns that can put them at increased risk of cardiovascular disease. So I think the prevalence is higher than expected,” Huang added.

As reported today in the Journal of the American College of Cardiology, the investigators used data from 7-day wrist actigraphy, 1 night of at-home polysomnography, and sleep questionnaires to assess sleep duration and sleep-onset timing among 1,992 Multi-Ethnic Study of Atherosclerosis () participants, aged 45 to 84 years, who were free of CVD and prospectively followed for a me MESA dian of 4.9 years.

A total of 786 patients (39.5%) had sleep duration standard deviation (SD) > 90 minutes and 510 (25.6%) had sleep-onset timing SD > 90 minutes.

During follow-up, there were 111 incident CVD events, including myocardial infarction, coronary heart disease death, stroke, and other coronary events.

Compared with people who had less than 1 hour of variation in sleep duration, the risk for incident CVD was 9% higher for people whose sleep duration varied 61 to 90 minutes (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.62 - 1.92), even after controlling for a variety of cardiovascular and sleep-related risk factors such as body mass index, systolic blood pressure, smoking status, total cholesterol, average sleep duration, insomnia symptoms, and sleep apnea.

Moreover, the adjusted CVD risk was substantially increased with 91 to 120 minutes of variation (HR, 1.59; 95% CI, 0.91 - 2.76) and more than 120 minutes of variation in sleep duration (HR, 2.14; 95% CI, 1.24 - 3.68).

Every 1-hour increase in sleep duration SD was associated with 36% higher CVD risk (95% CI; 1.07 - 1.73).

Compared with people with no more than a half hour of variation in nightly bedtimes, the adjusted hazard ratios for CVD were 1.16 (95% CI, 0.64 - 2.13), 1.52 (95% CI, 0.81 - 2.88), and 2.11 (95% CI, 1.13 - 3.91) when bedtimes varied by 31 to 60 minutes, 61 to 90 minutes, and more than 90 minutes.

For every 1-hour increase in sleep-onset timing SD, the risk of CVD was 18% higher (95% CI; 1.06 - 1.31).

“The results are similar for the regularity of sleep timing and the regularity of sleep duration, which means that both can contribute to circadian disruption and then lead to development of cardiovascular disease,” Huang said.

This is an important article and signals how sleep is an important marker and possibly a mediator of cardiovascular risk, said Harlan Krumholz, MD, of Yale School of Medicine in New Haven, Connecticut, who was not involved with the study.

“What I like about this is it’s a nice longitudinal, epidemiologic study with not just self-report, but sensor-detected sleep, that has been correlated with well-curated and adjudicated outcomes to give us a strong sense of this association,” he told theheart.org/Medscape Cardiology. “And also, that it goes beyond just the duration — they combine the duration and timing in order to give a fuller picture of sleep.”

Nevertheless, Krumholz said researchers are only at the beginning of being able to quantify the various dimensions of sleep and the degree to which sleep is a reflection of underlying physiologic issues, or whether patients are having erratic sleep patterns that are having a toxic effect on their overall health.

Questions also remain about the mechanism behind the association, whether the increased risk is universal or more harmful for some people, and the best way to measure factors during sleep that can most comprehensively and precisely predict risk.

“As we get more information flowing in from sensors, I think we will begin to develop more sophisticated approaches toward understanding risk, and it will be accompanied by other studies that will help us understand whether, again, this is a reflection of other processes that we should be paying attention to or whether it is a cause of disease and risk,” Krumholz said.

Subgroup analyses suggested positive associations between irregular sleep and CVD in African Americans, Hispanics, and Chinese Americans but not in whites. This could be because sleep irregularity, both timing and duration, was substantially higher in minorities, especially African Americans, but may also be as a result of chance because the study sample is relatively small, Huang explained.

The authors note that the overall findings are biologically plausible because of their previous work linking sleep irregularity with metabolic risk factors that predispose to atherosclerosis, such as obesity, diabetes, and hypertension. Participants with irregular sleep tended to have worse baseline cardiometabolic profiles, but this only explained a small portion of the associations between sleep irregularity and CVD, they note.

Other possible explanations include circadian clock genes, such as clock, per2 and bmal1, which have been shown experimentally to control a broad range of cardiovascular functions, from blood pressure and endothelial functions to vascular thrombosis and cardiac remodeling.

Irregular sleep may also influence the rhythms of the autonomic nervous system, and behavioral rhythms with regard to timing and/or amount of eating or exercise.

Further research is needed to understand the mechanisms driving the associations, the impact of sleep irregularity on individual CVD outcomes, and to determine whether a 7-day SD of more than 90 minutes for either sleep duration or sleep-onset timing can be used clinically as a threshold target for promoting cardiometabolically healthy sleep, Huang said.

“When providers communicate with their patients regarding strategies for CVD prevention, usually they focus on healthy diet and physical activity; and even when they talk about sleep, they talk about whether they have good sleep quality or sufficient sleep,” he said. “But one thing they should provide is advice regarding sleep regularity and [they should] recommend their patients follow a regular sleep pattern for the purpose of cardiovascular prevention.”

In a related editorial, Olaf Oldenburg, MD, Luderus-Kliniken Münster, Clemenshospital, Münster, Germany, and Jens Spiesshoefer, MD, Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy, write that the observed independent association between sleep irregularity and CVD “is a particularly striking finding given that impaired circadian rhythm is likely to be much more prevalent than the extreme example of shift work.”

They call on researchers to utilize big data to facilitate understanding of the association and say it is essential to test whether experimental data support the hypothesis that altered circadian rhythms would translate into unfavorable changes in 24-hour sympathovagal and neurohormonal balance, and ultimately CVD.

The present study “will, and should, stimulate much needed additional research on the association between sleep and CVD that may offer novel approaches to help improve the prognosis and daily symptom burden of patients with CVD, and might make sleep itself a therapeutic target in CVD,” the editorialists conclude.

This research was supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI), and by grants from the National Center for Advancing Translational Sciences. The MESA Sleep Study was supported by an NHLBI grant. Huang was supported by a career development grant from the National Institutes of Health.

Krumholz and Oldenburg have disclosed no relevant financial relationships. Spiesshoefer is supported by grants from the Else-Kröner-Fresenius Stiftung, the Innovative Medical Research program at the University of Münster, and Deutsche Herzstiftung; and by young investigator research support from Scuola Superiore Sant’Anna Pisa. He also has received travel grants and lecture honoraria from Boehringer Ingelheim and Chiesi.
 

Source: J Am Coll Cardiol. 2020 Mar 2. doi: 10.1016/j.jacc.2019.12.054.

This article first appeared on Medscape.com.

People who frequently alter the amount of sleep and time they go to bed each night are twofold more likely to develop cardiovascular disease, independent of traditional CVD risk factors, new research suggests.

Prior studies have focused on shift workers because night shift work will influence circadian rhythm and increase CVD risk. But it is increasingly recognized that circadian disruption may occur outside of shift work and accumulate over time, particularly given modern lifestyle factors such as increased use of mobile devices and television at night, said study coauthor Tianyi Huang, ScD, MSc, of Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts.

“Even if they tend to go to sleep at certain times, by following that lifestyle or behavior, it can interfere with their planned sleep timing,” he said.

“One thing that surprised me in this sample is that about one third of participants have irregular sleep patterns that can put them at increased risk of cardiovascular disease. So I think the prevalence is higher than expected,” Huang added.

As reported today in the Journal of the American College of Cardiology, the investigators used data from 7-day wrist actigraphy, 1 night of at-home polysomnography, and sleep questionnaires to assess sleep duration and sleep-onset timing among 1,992 Multi-Ethnic Study of Atherosclerosis () participants, aged 45 to 84 years, who were free of CVD and prospectively followed for a me MESA dian of 4.9 years.

A total of 786 patients (39.5%) had sleep duration standard deviation (SD) > 90 minutes and 510 (25.6%) had sleep-onset timing SD > 90 minutes.

During follow-up, there were 111 incident CVD events, including myocardial infarction, coronary heart disease death, stroke, and other coronary events.

Compared with people who had less than 1 hour of variation in sleep duration, the risk for incident CVD was 9% higher for people whose sleep duration varied 61 to 90 minutes (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.62 - 1.92), even after controlling for a variety of cardiovascular and sleep-related risk factors such as body mass index, systolic blood pressure, smoking status, total cholesterol, average sleep duration, insomnia symptoms, and sleep apnea.

Moreover, the adjusted CVD risk was substantially increased with 91 to 120 minutes of variation (HR, 1.59; 95% CI, 0.91 - 2.76) and more than 120 minutes of variation in sleep duration (HR, 2.14; 95% CI, 1.24 - 3.68).

Every 1-hour increase in sleep duration SD was associated with 36% higher CVD risk (95% CI; 1.07 - 1.73).

Compared with people with no more than a half hour of variation in nightly bedtimes, the adjusted hazard ratios for CVD were 1.16 (95% CI, 0.64 - 2.13), 1.52 (95% CI, 0.81 - 2.88), and 2.11 (95% CI, 1.13 - 3.91) when bedtimes varied by 31 to 60 minutes, 61 to 90 minutes, and more than 90 minutes.

For every 1-hour increase in sleep-onset timing SD, the risk of CVD was 18% higher (95% CI; 1.06 - 1.31).

“The results are similar for the regularity of sleep timing and the regularity of sleep duration, which means that both can contribute to circadian disruption and then lead to development of cardiovascular disease,” Huang said.

This is an important article and signals how sleep is an important marker and possibly a mediator of cardiovascular risk, said Harlan Krumholz, MD, of Yale School of Medicine in New Haven, Connecticut, who was not involved with the study.

“What I like about this is it’s a nice longitudinal, epidemiologic study with not just self-report, but sensor-detected sleep, that has been correlated with well-curated and adjudicated outcomes to give us a strong sense of this association,” he told theheart.org/Medscape Cardiology. “And also, that it goes beyond just the duration — they combine the duration and timing in order to give a fuller picture of sleep.”

Nevertheless, Krumholz said researchers are only at the beginning of being able to quantify the various dimensions of sleep and the degree to which sleep is a reflection of underlying physiologic issues, or whether patients are having erratic sleep patterns that are having a toxic effect on their overall health.

Questions also remain about the mechanism behind the association, whether the increased risk is universal or more harmful for some people, and the best way to measure factors during sleep that can most comprehensively and precisely predict risk.

“As we get more information flowing in from sensors, I think we will begin to develop more sophisticated approaches toward understanding risk, and it will be accompanied by other studies that will help us understand whether, again, this is a reflection of other processes that we should be paying attention to or whether it is a cause of disease and risk,” Krumholz said.

Subgroup analyses suggested positive associations between irregular sleep and CVD in African Americans, Hispanics, and Chinese Americans but not in whites. This could be because sleep irregularity, both timing and duration, was substantially higher in minorities, especially African Americans, but may also be as a result of chance because the study sample is relatively small, Huang explained.

The authors note that the overall findings are biologically plausible because of their previous work linking sleep irregularity with metabolic risk factors that predispose to atherosclerosis, such as obesity, diabetes, and hypertension. Participants with irregular sleep tended to have worse baseline cardiometabolic profiles, but this only explained a small portion of the associations between sleep irregularity and CVD, they note.

Other possible explanations include circadian clock genes, such as clock, per2 and bmal1, which have been shown experimentally to control a broad range of cardiovascular functions, from blood pressure and endothelial functions to vascular thrombosis and cardiac remodeling.

Irregular sleep may also influence the rhythms of the autonomic nervous system, and behavioral rhythms with regard to timing and/or amount of eating or exercise.

Further research is needed to understand the mechanisms driving the associations, the impact of sleep irregularity on individual CVD outcomes, and to determine whether a 7-day SD of more than 90 minutes for either sleep duration or sleep-onset timing can be used clinically as a threshold target for promoting cardiometabolically healthy sleep, Huang said.

“When providers communicate with their patients regarding strategies for CVD prevention, usually they focus on healthy diet and physical activity; and even when they talk about sleep, they talk about whether they have good sleep quality or sufficient sleep,” he said. “But one thing they should provide is advice regarding sleep regularity and [they should] recommend their patients follow a regular sleep pattern for the purpose of cardiovascular prevention.”

In a related editorial, Olaf Oldenburg, MD, Luderus-Kliniken Münster, Clemenshospital, Münster, Germany, and Jens Spiesshoefer, MD, Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy, write that the observed independent association between sleep irregularity and CVD “is a particularly striking finding given that impaired circadian rhythm is likely to be much more prevalent than the extreme example of shift work.”

They call on researchers to utilize big data to facilitate understanding of the association and say it is essential to test whether experimental data support the hypothesis that altered circadian rhythms would translate into unfavorable changes in 24-hour sympathovagal and neurohormonal balance, and ultimately CVD.

The present study “will, and should, stimulate much needed additional research on the association between sleep and CVD that may offer novel approaches to help improve the prognosis and daily symptom burden of patients with CVD, and might make sleep itself a therapeutic target in CVD,” the editorialists conclude.

This research was supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI), and by grants from the National Center for Advancing Translational Sciences. The MESA Sleep Study was supported by an NHLBI grant. Huang was supported by a career development grant from the National Institutes of Health.

Krumholz and Oldenburg have disclosed no relevant financial relationships. Spiesshoefer is supported by grants from the Else-Kröner-Fresenius Stiftung, the Innovative Medical Research program at the University of Münster, and Deutsche Herzstiftung; and by young investigator research support from Scuola Superiore Sant’Anna Pisa. He also has received travel grants and lecture honoraria from Boehringer Ingelheim and Chiesi.
 

Source: J Am Coll Cardiol. 2020 Mar 2. doi: 10.1016/j.jacc.2019.12.054.

This article first appeared on Medscape.com.

People who frequently alter the amount of sleep and time they go to bed each night are twofold more likely to develop cardiovascular disease, independent of traditional CVD risk factors, new research suggests.

Prior studies have focused on shift workers because night shift work will influence circadian rhythm and increase CVD risk. But it is increasingly recognized that circadian disruption may occur outside of shift work and accumulate over time, particularly given modern lifestyle factors such as increased use of mobile devices and television at night, said study coauthor Tianyi Huang, ScD, MSc, of Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts.

“Even if they tend to go to sleep at certain times, by following that lifestyle or behavior, it can interfere with their planned sleep timing,” he said.

“One thing that surprised me in this sample is that about one third of participants have irregular sleep patterns that can put them at increased risk of cardiovascular disease. So I think the prevalence is higher than expected,” Huang added.

As reported today in the Journal of the American College of Cardiology, the investigators used data from 7-day wrist actigraphy, 1 night of at-home polysomnography, and sleep questionnaires to assess sleep duration and sleep-onset timing among 1,992 Multi-Ethnic Study of Atherosclerosis () participants, aged 45 to 84 years, who were free of CVD and prospectively followed for a me MESA dian of 4.9 years.

A total of 786 patients (39.5%) had sleep duration standard deviation (SD) > 90 minutes and 510 (25.6%) had sleep-onset timing SD > 90 minutes.

During follow-up, there were 111 incident CVD events, including myocardial infarction, coronary heart disease death, stroke, and other coronary events.

Compared with people who had less than 1 hour of variation in sleep duration, the risk for incident CVD was 9% higher for people whose sleep duration varied 61 to 90 minutes (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.62 - 1.92), even after controlling for a variety of cardiovascular and sleep-related risk factors such as body mass index, systolic blood pressure, smoking status, total cholesterol, average sleep duration, insomnia symptoms, and sleep apnea.

Moreover, the adjusted CVD risk was substantially increased with 91 to 120 minutes of variation (HR, 1.59; 95% CI, 0.91 - 2.76) and more than 120 minutes of variation in sleep duration (HR, 2.14; 95% CI, 1.24 - 3.68).

Every 1-hour increase in sleep duration SD was associated with 36% higher CVD risk (95% CI; 1.07 - 1.73).

Compared with people with no more than a half hour of variation in nightly bedtimes, the adjusted hazard ratios for CVD were 1.16 (95% CI, 0.64 - 2.13), 1.52 (95% CI, 0.81 - 2.88), and 2.11 (95% CI, 1.13 - 3.91) when bedtimes varied by 31 to 60 minutes, 61 to 90 minutes, and more than 90 minutes.

For every 1-hour increase in sleep-onset timing SD, the risk of CVD was 18% higher (95% CI; 1.06 - 1.31).

“The results are similar for the regularity of sleep timing and the regularity of sleep duration, which means that both can contribute to circadian disruption and then lead to development of cardiovascular disease,” Huang said.

This is an important article and signals how sleep is an important marker and possibly a mediator of cardiovascular risk, said Harlan Krumholz, MD, of Yale School of Medicine in New Haven, Connecticut, who was not involved with the study.

“What I like about this is it’s a nice longitudinal, epidemiologic study with not just self-report, but sensor-detected sleep, that has been correlated with well-curated and adjudicated outcomes to give us a strong sense of this association,” he told theheart.org/Medscape Cardiology. “And also, that it goes beyond just the duration — they combine the duration and timing in order to give a fuller picture of sleep.”

Nevertheless, Krumholz said researchers are only at the beginning of being able to quantify the various dimensions of sleep and the degree to which sleep is a reflection of underlying physiologic issues, or whether patients are having erratic sleep patterns that are having a toxic effect on their overall health.

Questions also remain about the mechanism behind the association, whether the increased risk is universal or more harmful for some people, and the best way to measure factors during sleep that can most comprehensively and precisely predict risk.

“As we get more information flowing in from sensors, I think we will begin to develop more sophisticated approaches toward understanding risk, and it will be accompanied by other studies that will help us understand whether, again, this is a reflection of other processes that we should be paying attention to or whether it is a cause of disease and risk,” Krumholz said.

Subgroup analyses suggested positive associations between irregular sleep and CVD in African Americans, Hispanics, and Chinese Americans but not in whites. This could be because sleep irregularity, both timing and duration, was substantially higher in minorities, especially African Americans, but may also be as a result of chance because the study sample is relatively small, Huang explained.

The authors note that the overall findings are biologically plausible because of their previous work linking sleep irregularity with metabolic risk factors that predispose to atherosclerosis, such as obesity, diabetes, and hypertension. Participants with irregular sleep tended to have worse baseline cardiometabolic profiles, but this only explained a small portion of the associations between sleep irregularity and CVD, they note.

Other possible explanations include circadian clock genes, such as clock, per2 and bmal1, which have been shown experimentally to control a broad range of cardiovascular functions, from blood pressure and endothelial functions to vascular thrombosis and cardiac remodeling.

Irregular sleep may also influence the rhythms of the autonomic nervous system, and behavioral rhythms with regard to timing and/or amount of eating or exercise.

Further research is needed to understand the mechanisms driving the associations, the impact of sleep irregularity on individual CVD outcomes, and to determine whether a 7-day SD of more than 90 minutes for either sleep duration or sleep-onset timing can be used clinically as a threshold target for promoting cardiometabolically healthy sleep, Huang said.

“When providers communicate with their patients regarding strategies for CVD prevention, usually they focus on healthy diet and physical activity; and even when they talk about sleep, they talk about whether they have good sleep quality or sufficient sleep,” he said. “But one thing they should provide is advice regarding sleep regularity and [they should] recommend their patients follow a regular sleep pattern for the purpose of cardiovascular prevention.”

In a related editorial, Olaf Oldenburg, MD, Luderus-Kliniken Münster, Clemenshospital, Münster, Germany, and Jens Spiesshoefer, MD, Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy, write that the observed independent association between sleep irregularity and CVD “is a particularly striking finding given that impaired circadian rhythm is likely to be much more prevalent than the extreme example of shift work.”

They call on researchers to utilize big data to facilitate understanding of the association and say it is essential to test whether experimental data support the hypothesis that altered circadian rhythms would translate into unfavorable changes in 24-hour sympathovagal and neurohormonal balance, and ultimately CVD.

The present study “will, and should, stimulate much needed additional research on the association between sleep and CVD that may offer novel approaches to help improve the prognosis and daily symptom burden of patients with CVD, and might make sleep itself a therapeutic target in CVD,” the editorialists conclude.

This research was supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI), and by grants from the National Center for Advancing Translational Sciences. The MESA Sleep Study was supported by an NHLBI grant. Huang was supported by a career development grant from the National Institutes of Health.

Krumholz and Oldenburg have disclosed no relevant financial relationships. Spiesshoefer is supported by grants from the Else-Kröner-Fresenius Stiftung, the Innovative Medical Research program at the University of Münster, and Deutsche Herzstiftung; and by young investigator research support from Scuola Superiore Sant’Anna Pisa. He also has received travel grants and lecture honoraria from Boehringer Ingelheim and Chiesi.
 

Source: J Am Coll Cardiol. 2020 Mar 2. doi: 10.1016/j.jacc.2019.12.054.

This article first appeared on Medscape.com.

NATIONAL HARBOR, MD. – If positive, a major ongoing phase 3 trial of CSL112, an agent designed to promote efflux of cholesterol from macrophages, is positioned to prove the HDL hypothesis, according to an outline of the rationale of the trial at CRT 2020 sponsored by MedStar Heart & Vascular Institute.

“Twenty papers now show better efflux means better outcomes independent of standard risk factors” and “we know this drug improves efflux,” explained C. Michael Gibson, MD, an interventional cardiologist at Beth Israel Deaconess Hospital, Boston.

The HDL hypothesis was derived from the Framingham Heart Study, which correlated high levels of HDL cholesterol with a reduced risk of adverse cardiovascular (CV) outcomes, according to Dr. Gibson. Just as elevated LDL proved to be a treatable risk factor for CV events, reduced HDL was the target of numerous trials to achieve the same types of benefits.

All have failed.

The problem has been in seeing HDL as a number without addressing its function, Dr. Gibson said. In essence, he believes “the HDL hypothesis not been really tested to date.”

CSL112 is a novel formulation of apolipoprotein A-1 (apoA-1) that has been purified from human plasma and reconstituted to form HDL. In the experimental and clinical setting, including the AEGIS I pilot study, weekly infusions of CSL112 have been associated with a degree of cholesterol efflux that predicts major CV risk reductions.

At the same time that the multinational event-driven AEGIS II trial will determine whether cholesterol efflux with CSL112 does translate into protection from CV events, it will also examine the HDL side of the lipid equation. Dr. Gibson said that it is specifically designed to circumvent the weaknesses of previous efforts to target HDL for reducing CV risk.

“The previous studies were conducted in the wrong patients with the wrong drugs given in the wrong doses at the wrong times,” said Dr. Gibson, who is also professor of medicine at Harvard Medical School, Boston.

One major difference from previous trials is that AEGIS II is enrolling patients with an acute coronary syndrome rather than stable atherosclerosis. Many of those being enrolled have had a recent event. Also, rather than raising HDL, the goal of CSL112 is to increase cholesterol efflux, which is now considered to be the key function of HDL. Furthermore, the time frame for the primary outcome, which is a composite of major adverse cardiac outcomes (MACE), is 90 days rather than several years.

In patients with ACS, “it is the early period of vulnerability where efflux of cholesterol really appears to have the greatest influence on outcomes,” Dr. Gibson explained.

The failure of previous efforts to treat HDL now appears to be based on an incomplete understanding of the goals, according to Dr. Gibson. The doomed cholesteryl ester transfer protein (CETP) drugs, for example, effectively increased HDL levels, but generated a form of HDL that “was not all that functional.”

He noted that niacin raises HDL but has off-target effects. Apo-A1 Milano, a mutant variation of apo-A1, is now understood to reduce the endogenous form, which Dr. Gibson said might explain its counterproductive effect on CV protection.

Using a garbage truck analogy to explain the growing appreciation of factors involved in cholesterol accumulation in the macrophage, Dr. Gibson characterized ABCA1, a transporter protein sitting on the surface of the macrophage, as the loader. He described LCAT (lecithin-cholesterol acyltransferase), an enzyme that converts cholesterol into cholesteryl ester, as the compactor. He sees CRL112 as an empty garbage truck sent into the macrophage to reverse the process.

“We are moving beyond thinking of HDL as a number to try to better appreciate its function,” Dr. Gibson said.

The AEGIS II trial was opened in March of 2018. It has a planned enrollment of 17,400 patients, with an estimated completion date of October 2021.

Dr. Gibson reports financial relationships with Bayer, Janssen, Johnson & Johnson, and CSL Behring, the sponsor of the AEGIS II trial.

NATIONAL HARBOR, MD. – If positive, a major ongoing phase 3 trial of CSL112, an agent designed to promote efflux of cholesterol from macrophages, is positioned to prove the HDL hypothesis, according to an outline of the rationale of the trial at CRT 2020 sponsored by MedStar Heart & Vascular Institute.

“Twenty papers now show better efflux means better outcomes independent of standard risk factors” and “we know this drug improves efflux,” explained C. Michael Gibson, MD, an interventional cardiologist at Beth Israel Deaconess Hospital, Boston.

The HDL hypothesis was derived from the Framingham Heart Study, which correlated high levels of HDL cholesterol with a reduced risk of adverse cardiovascular (CV) outcomes, according to Dr. Gibson. Just as elevated LDL proved to be a treatable risk factor for CV events, reduced HDL was the target of numerous trials to achieve the same types of benefits.

All have failed.

The problem has been in seeing HDL as a number without addressing its function, Dr. Gibson said. In essence, he believes “the HDL hypothesis not been really tested to date.”

CSL112 is a novel formulation of apolipoprotein A-1 (apoA-1) that has been purified from human plasma and reconstituted to form HDL. In the experimental and clinical setting, including the AEGIS I pilot study, weekly infusions of CSL112 have been associated with a degree of cholesterol efflux that predicts major CV risk reductions.

At the same time that the multinational event-driven AEGIS II trial will determine whether cholesterol efflux with CSL112 does translate into protection from CV events, it will also examine the HDL side of the lipid equation. Dr. Gibson said that it is specifically designed to circumvent the weaknesses of previous efforts to target HDL for reducing CV risk.

“The previous studies were conducted in the wrong patients with the wrong drugs given in the wrong doses at the wrong times,” said Dr. Gibson, who is also professor of medicine at Harvard Medical School, Boston.

One major difference from previous trials is that AEGIS II is enrolling patients with an acute coronary syndrome rather than stable atherosclerosis. Many of those being enrolled have had a recent event. Also, rather than raising HDL, the goal of CSL112 is to increase cholesterol efflux, which is now considered to be the key function of HDL. Furthermore, the time frame for the primary outcome, which is a composite of major adverse cardiac outcomes (MACE), is 90 days rather than several years.

In patients with ACS, “it is the early period of vulnerability where efflux of cholesterol really appears to have the greatest influence on outcomes,” Dr. Gibson explained.

The failure of previous efforts to treat HDL now appears to be based on an incomplete understanding of the goals, according to Dr. Gibson. The doomed cholesteryl ester transfer protein (CETP) drugs, for example, effectively increased HDL levels, but generated a form of HDL that “was not all that functional.”

He noted that niacin raises HDL but has off-target effects. Apo-A1 Milano, a mutant variation of apo-A1, is now understood to reduce the endogenous form, which Dr. Gibson said might explain its counterproductive effect on CV protection.

Using a garbage truck analogy to explain the growing appreciation of factors involved in cholesterol accumulation in the macrophage, Dr. Gibson characterized ABCA1, a transporter protein sitting on the surface of the macrophage, as the loader. He described LCAT (lecithin-cholesterol acyltransferase), an enzyme that converts cholesterol into cholesteryl ester, as the compactor. He sees CRL112 as an empty garbage truck sent into the macrophage to reverse the process.

“We are moving beyond thinking of HDL as a number to try to better appreciate its function,” Dr. Gibson said.

The AEGIS II trial was opened in March of 2018. It has a planned enrollment of 17,400 patients, with an estimated completion date of October 2021.

Dr. Gibson reports financial relationships with Bayer, Janssen, Johnson & Johnson, and CSL Behring, the sponsor of the AEGIS II trial.

NATIONAL HARBOR, MD. – If positive, a major ongoing phase 3 trial of CSL112, an agent designed to promote efflux of cholesterol from macrophages, is positioned to prove the HDL hypothesis, according to an outline of the rationale of the trial at CRT 2020 sponsored by MedStar Heart & Vascular Institute.

“Twenty papers now show better efflux means better outcomes independent of standard risk factors” and “we know this drug improves efflux,” explained C. Michael Gibson, MD, an interventional cardiologist at Beth Israel Deaconess Hospital, Boston.

The HDL hypothesis was derived from the Framingham Heart Study, which correlated high levels of HDL cholesterol with a reduced risk of adverse cardiovascular (CV) outcomes, according to Dr. Gibson. Just as elevated LDL proved to be a treatable risk factor for CV events, reduced HDL was the target of numerous trials to achieve the same types of benefits.

All have failed.

The problem has been in seeing HDL as a number without addressing its function, Dr. Gibson said. In essence, he believes “the HDL hypothesis not been really tested to date.”

CSL112 is a novel formulation of apolipoprotein A-1 (apoA-1) that has been purified from human plasma and reconstituted to form HDL. In the experimental and clinical setting, including the AEGIS I pilot study, weekly infusions of CSL112 have been associated with a degree of cholesterol efflux that predicts major CV risk reductions.

At the same time that the multinational event-driven AEGIS II trial will determine whether cholesterol efflux with CSL112 does translate into protection from CV events, it will also examine the HDL side of the lipid equation. Dr. Gibson said that it is specifically designed to circumvent the weaknesses of previous efforts to target HDL for reducing CV risk.

“The previous studies were conducted in the wrong patients with the wrong drugs given in the wrong doses at the wrong times,” said Dr. Gibson, who is also professor of medicine at Harvard Medical School, Boston.

One major difference from previous trials is that AEGIS II is enrolling patients with an acute coronary syndrome rather than stable atherosclerosis. Many of those being enrolled have had a recent event. Also, rather than raising HDL, the goal of CSL112 is to increase cholesterol efflux, which is now considered to be the key function of HDL. Furthermore, the time frame for the primary outcome, which is a composite of major adverse cardiac outcomes (MACE), is 90 days rather than several years.

In patients with ACS, “it is the early period of vulnerability where efflux of cholesterol really appears to have the greatest influence on outcomes,” Dr. Gibson explained.

The failure of previous efforts to treat HDL now appears to be based on an incomplete understanding of the goals, according to Dr. Gibson. The doomed cholesteryl ester transfer protein (CETP) drugs, for example, effectively increased HDL levels, but generated a form of HDL that “was not all that functional.”

He noted that niacin raises HDL but has off-target effects. Apo-A1 Milano, a mutant variation of apo-A1, is now understood to reduce the endogenous form, which Dr. Gibson said might explain its counterproductive effect on CV protection.

Using a garbage truck analogy to explain the growing appreciation of factors involved in cholesterol accumulation in the macrophage, Dr. Gibson characterized ABCA1, a transporter protein sitting on the surface of the macrophage, as the loader. He described LCAT (lecithin-cholesterol acyltransferase), an enzyme that converts cholesterol into cholesteryl ester, as the compactor. He sees CRL112 as an empty garbage truck sent into the macrophage to reverse the process.

“We are moving beyond thinking of HDL as a number to try to better appreciate its function,” Dr. Gibson said.

The AEGIS II trial was opened in March of 2018. It has a planned enrollment of 17,400 patients, with an estimated completion date of October 2021.

Dr. Gibson reports financial relationships with Bayer, Janssen, Johnson & Johnson, and CSL Behring, the sponsor of the AEGIS II trial.

Bempedoic acid, the first agent in a new class of drugs that reduce LDL cholesterol, received Food and Drug Administration approval on Feb. 21 for treating selected hypercholesterolemic patients and is a welcome addition to the medicine cabinet, say lipid experts.

MDedge News

However, it is a tertiary option at least until results from a 14,000 patient clinical-outcome trial of bempedoic acid come out, likely in 2022, they agreed.

“I’m excited to have a new tool in the toolkit for treating high-risk patients, but I will always reach first for the drugs proven to reduce clinical outcomes,” said Erin D. Michos, MD, director of Women’s Cardiovascular Health and associate director of Preventive Cardiology at Johns Hopkins Medicine in Baltimore. That sentiment, shared by other experts, should for the time being relegate bempedoic acid (Nexletol) to a backup role behind statins, ezetimibe, and the PCSK9 inhibitor antibodies that are all now on the U.S. market and all buttressed with evidence of their ability to cut cardiovascular disease death and other CVD outcomes from large outcome studies.

The existing evidence base for bempedoic acid rests primarily two multicenter, randomized, placebo-controlled clinical trials of bempedoic acid in patients with LDL levels above 70 mg/dL while on maximally tolerated lipid-lowering therapy. In CLEAR Harmony, results showed that treatment with bempedoic acid cut LDL-cholesterol levels by an average of 18% more compared with placebo (N Engl J Med 2019;380:1022-32). In CLEAR Wisdom, bempedoic acid reduced LDL cholesterol levels by 17% (JAMA. 2019;322[18]:1780-8).

While those two trials proved the drug’s ability to lower levels of LDL cholesterol, they lacked the power to address whether this effect cut the incidence of CVD events, a question that the CLEAR Outcomes trial aims to answer.

“I believe in the lipid hypothesis, but the main thing we need to see is whether bempedoic acid leads to a meaningful reduction in CVD events. The window for bempedoic acid will remain narrow until we see the outcomes results,” Dr. Michos said in an interview.

Bempedoic acid is a prodrug that’s activated in liver and targets the same cholesterol synthesis pathway as statins by inhibition of ATP-citrate lyase, an enzyme that’s upstream of HMG-CoA reductase, thereby enhancing LDL cholesterol clearance via up-regulation of LDL receptors

.

Combined treatment with bempedoic acid and ezetimibe “may be successful in avoiding [using] a PCSK9 inhibitor in some patients, and in particular patients with HeFH or those who are statin intolerant.” But like his colleagues, Dr. Eckel agreed that, for the moment, ezetimibe has an edge over bempedoic acid because of its more extensive evidence base. “If the combination of bempedoic acid and ezetimibe is not needed, the decision [of which one of these to use] needs to depend on the outcome trial results for ezetimibe,” he said. Other factors clinicians could apply if faced with choosing between these two agents include the significant reduction in high-sensitivity C-reactive protein that bempedoic acid produces; the downside that bempedoic acid can cause in some patients an early and persistent rise in serum uric acid levels that can trigger gout flares in patients with a history of gout or at risk for gout; and cost, he said.

Cost is the room-dwelling elephant that colors many decisions about which lipid-lowering drug to use for patients, with options running the price gamut from the generic and uniformly affordable statins and ezetimibe, to the notoriously pricey PCSK9 inhibitors that remain for many patients either prohibitively expensive or hard to get covered by some insurers. Bempedoic acid seems on track to fall somewhere between these two poles, although staff members from Esperion, the company that developed and will market bempedoic acid as Nexletol starting on March 30, declared in a conference call on Feb. 24 that “cost will not be an issue,” for indicated patients prescribed the drug. Company representatives cited a program of coupons, discounts, and rebates they have planned that they anticipate will allow patients who meet the labeled indications to have an out-of-pocket cost for bempedoic acid of “as low as” $10 for a 90-pill supply. They also noted their goal of getting bempedoic acid onto the lowest tier of the Medicare formulary.

How these steps actually play out in the fun house of U.S. prescription drug pricing and preauthorizations remains to be seen. “Out-of-pocket costs are not the real drivers” of drug access, noted Dr. Robinson. “Insurers will likely start with restricted access and prior authorization requirements, just as they did with ezetimibe when it was on patent and prior to having the results from a CVD outcomes trial.” For the time being, bempedoic acid can generally be seen as “expensive ezetimibe,” summed up Dr. Robinson.

Despite that somewhat dismissive characterization, experts are intrigued by the possibility of combining two moderately potent, oral, and safe lipid-lowering drugs in selected patients as a potential alternative to the still financially challenging PCSK9 inhibitors. Combining bempedoic acid and ezetimibe “has a lot of appeal,” said Dr. Michos. “Even though preauthorization has gotten better, it’s still a challenge to get a PCSK9 inhibitor approved.”

Much of her enthusiasm stems from a study reported last year that randomized 301 patients to treatment with bempedoic acid, ezetimibe, or both. The results showed that combined treatment has a similar safety profile to treatment with either drug alone, and produced a cut in LDL cholesterol that was roughly additive for the reductions produced by each drug by itself: Ezetimibe alone cut LDL by about 23%, bempedoic acid alone by about 17%, and the two dosed together once daily resulted in an average 36% drop (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864671). The results showed that, “in patients requiring intensive LDL cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention,” wrote Dr. Michos and a coauthor in a commentary that appeared with the study results (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864672).

The concept of combined bempedoic acid and ezetimibe treatment is so appealing that the bempedoic acid manufacturer, Esperion, has already developed a single-pill formulation of the two drugs that received FDA marketing approval on February 26. A company statement said that marketing of this combined formulation, Nexlizet, will start in July 2020.

Although interest in bempedoic acid seems running high for patients included in the new FDA indication, Dr. Michos and others see possibly greater potential for what would now be off-label use for primary prevention in high-risk patients without HeFH, patients who generally don’t qualify for insurance coverage of a PCSK9 inhibitor.

“Use in primary prevention in [non-HeFH] patients with insufficient lowering of LDL cholesterol wouldn’t surprise me,” but a big concern will be out-of-pocket cost when off-label use precludes insurance coverage or discount eligibility, noted Dr. Eckel. An Esperion spokesperson said that the undiscounted, wholesale acquisition cost for bempedoic acid is expected to be roughly $10/pill, or about $300 for a 30-day supply, positioning it more or less midway between generic statins and ezetimibe and the list price for a PCSk9 inhibitor of roughly $500/month.

“I’m most excited about bempedoic acid in the off-label space, for patients who can’t get approved for a PCSK9 inhibitor, for treating patients with subclinical ASCVD, or really high-risk patients with multiple risk factors including diabetes,” especially when these patients are intolerant of a high-intensity statin regimen, said Dr. Michos. “I have a clinic full of patients” who can’t take their full, indicated dosage of a high-intensity statin, and when those patients also can’t get on treatment with a PCSK9 inhibitor then bempedoic acid will be an important part of their alternative regimen, she explained.

Dr. Michos had no disclosures. Dr. Robinson has received research funding from Esperion and from several other companies, and she has been a consultant to Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. Dr. Eckel has received honoraria from Kowa, Merck, Novo Nordisk, and Sanofi/Regeneron.

This article was updated 2/27/20.

mzoler@mdedge.com

Bempedoic acid, the first agent in a new class of drugs that reduce LDL cholesterol, received Food and Drug Administration approval on Feb. 21 for treating selected hypercholesterolemic patients and is a welcome addition to the medicine cabinet, say lipid experts.

MDedge News

However, it is a tertiary option at least until results from a 14,000 patient clinical-outcome trial of bempedoic acid come out, likely in 2022, they agreed.

“I’m excited to have a new tool in the toolkit for treating high-risk patients, but I will always reach first for the drugs proven to reduce clinical outcomes,” said Erin D. Michos, MD, director of Women’s Cardiovascular Health and associate director of Preventive Cardiology at Johns Hopkins Medicine in Baltimore. That sentiment, shared by other experts, should for the time being relegate bempedoic acid (Nexletol) to a backup role behind statins, ezetimibe, and the PCSK9 inhibitor antibodies that are all now on the U.S. market and all buttressed with evidence of their ability to cut cardiovascular disease death and other CVD outcomes from large outcome studies.

The existing evidence base for bempedoic acid rests primarily two multicenter, randomized, placebo-controlled clinical trials of bempedoic acid in patients with LDL levels above 70 mg/dL while on maximally tolerated lipid-lowering therapy. In CLEAR Harmony, results showed that treatment with bempedoic acid cut LDL-cholesterol levels by an average of 18% more compared with placebo (N Engl J Med 2019;380:1022-32). In CLEAR Wisdom, bempedoic acid reduced LDL cholesterol levels by 17% (JAMA. 2019;322[18]:1780-8).

While those two trials proved the drug’s ability to lower levels of LDL cholesterol, they lacked the power to address whether this effect cut the incidence of CVD events, a question that the CLEAR Outcomes trial aims to answer.

“I believe in the lipid hypothesis, but the main thing we need to see is whether bempedoic acid leads to a meaningful reduction in CVD events. The window for bempedoic acid will remain narrow until we see the outcomes results,” Dr. Michos said in an interview.

Bempedoic acid is a prodrug that’s activated in liver and targets the same cholesterol synthesis pathway as statins by inhibition of ATP-citrate lyase, an enzyme that’s upstream of HMG-CoA reductase, thereby enhancing LDL cholesterol clearance via up-regulation of LDL receptors

.

Combined treatment with bempedoic acid and ezetimibe “may be successful in avoiding [using] a PCSK9 inhibitor in some patients, and in particular patients with HeFH or those who are statin intolerant.” But like his colleagues, Dr. Eckel agreed that, for the moment, ezetimibe has an edge over bempedoic acid because of its more extensive evidence base. “If the combination of bempedoic acid and ezetimibe is not needed, the decision [of which one of these to use] needs to depend on the outcome trial results for ezetimibe,” he said. Other factors clinicians could apply if faced with choosing between these two agents include the significant reduction in high-sensitivity C-reactive protein that bempedoic acid produces; the downside that bempedoic acid can cause in some patients an early and persistent rise in serum uric acid levels that can trigger gout flares in patients with a history of gout or at risk for gout; and cost, he said.

Cost is the room-dwelling elephant that colors many decisions about which lipid-lowering drug to use for patients, with options running the price gamut from the generic and uniformly affordable statins and ezetimibe, to the notoriously pricey PCSK9 inhibitors that remain for many patients either prohibitively expensive or hard to get covered by some insurers. Bempedoic acid seems on track to fall somewhere between these two poles, although staff members from Esperion, the company that developed and will market bempedoic acid as Nexletol starting on March 30, declared in a conference call on Feb. 24 that “cost will not be an issue,” for indicated patients prescribed the drug. Company representatives cited a program of coupons, discounts, and rebates they have planned that they anticipate will allow patients who meet the labeled indications to have an out-of-pocket cost for bempedoic acid of “as low as” $10 for a 90-pill supply. They also noted their goal of getting bempedoic acid onto the lowest tier of the Medicare formulary.

How these steps actually play out in the fun house of U.S. prescription drug pricing and preauthorizations remains to be seen. “Out-of-pocket costs are not the real drivers” of drug access, noted Dr. Robinson. “Insurers will likely start with restricted access and prior authorization requirements, just as they did with ezetimibe when it was on patent and prior to having the results from a CVD outcomes trial.” For the time being, bempedoic acid can generally be seen as “expensive ezetimibe,” summed up Dr. Robinson.

Despite that somewhat dismissive characterization, experts are intrigued by the possibility of combining two moderately potent, oral, and safe lipid-lowering drugs in selected patients as a potential alternative to the still financially challenging PCSK9 inhibitors. Combining bempedoic acid and ezetimibe “has a lot of appeal,” said Dr. Michos. “Even though preauthorization has gotten better, it’s still a challenge to get a PCSK9 inhibitor approved.”

Much of her enthusiasm stems from a study reported last year that randomized 301 patients to treatment with bempedoic acid, ezetimibe, or both. The results showed that combined treatment has a similar safety profile to treatment with either drug alone, and produced a cut in LDL cholesterol that was roughly additive for the reductions produced by each drug by itself: Ezetimibe alone cut LDL by about 23%, bempedoic acid alone by about 17%, and the two dosed together once daily resulted in an average 36% drop (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864671). The results showed that, “in patients requiring intensive LDL cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention,” wrote Dr. Michos and a coauthor in a commentary that appeared with the study results (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864672).

The concept of combined bempedoic acid and ezetimibe treatment is so appealing that the bempedoic acid manufacturer, Esperion, has already developed a single-pill formulation of the two drugs that received FDA marketing approval on February 26. A company statement said that marketing of this combined formulation, Nexlizet, will start in July 2020.

Although interest in bempedoic acid seems running high for patients included in the new FDA indication, Dr. Michos and others see possibly greater potential for what would now be off-label use for primary prevention in high-risk patients without HeFH, patients who generally don’t qualify for insurance coverage of a PCSK9 inhibitor.

“Use in primary prevention in [non-HeFH] patients with insufficient lowering of LDL cholesterol wouldn’t surprise me,” but a big concern will be out-of-pocket cost when off-label use precludes insurance coverage or discount eligibility, noted Dr. Eckel. An Esperion spokesperson said that the undiscounted, wholesale acquisition cost for bempedoic acid is expected to be roughly $10/pill, or about $300 for a 30-day supply, positioning it more or less midway between generic statins and ezetimibe and the list price for a PCSk9 inhibitor of roughly $500/month.

“I’m most excited about bempedoic acid in the off-label space, for patients who can’t get approved for a PCSK9 inhibitor, for treating patients with subclinical ASCVD, or really high-risk patients with multiple risk factors including diabetes,” especially when these patients are intolerant of a high-intensity statin regimen, said Dr. Michos. “I have a clinic full of patients” who can’t take their full, indicated dosage of a high-intensity statin, and when those patients also can’t get on treatment with a PCSK9 inhibitor then bempedoic acid will be an important part of their alternative regimen, she explained.

Dr. Michos had no disclosures. Dr. Robinson has received research funding from Esperion and from several other companies, and she has been a consultant to Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. Dr. Eckel has received honoraria from Kowa, Merck, Novo Nordisk, and Sanofi/Regeneron.

This article was updated 2/27/20.

mzoler@mdedge.com

Bempedoic acid, the first agent in a new class of drugs that reduce LDL cholesterol, received Food and Drug Administration approval on Feb. 21 for treating selected hypercholesterolemic patients and is a welcome addition to the medicine cabinet, say lipid experts.

MDedge News

However, it is a tertiary option at least until results from a 14,000 patient clinical-outcome trial of bempedoic acid come out, likely in 2022, they agreed.

“I’m excited to have a new tool in the toolkit for treating high-risk patients, but I will always reach first for the drugs proven to reduce clinical outcomes,” said Erin D. Michos, MD, director of Women’s Cardiovascular Health and associate director of Preventive Cardiology at Johns Hopkins Medicine in Baltimore. That sentiment, shared by other experts, should for the time being relegate bempedoic acid (Nexletol) to a backup role behind statins, ezetimibe, and the PCSK9 inhibitor antibodies that are all now on the U.S. market and all buttressed with evidence of their ability to cut cardiovascular disease death and other CVD outcomes from large outcome studies.

The existing evidence base for bempedoic acid rests primarily two multicenter, randomized, placebo-controlled clinical trials of bempedoic acid in patients with LDL levels above 70 mg/dL while on maximally tolerated lipid-lowering therapy. In CLEAR Harmony, results showed that treatment with bempedoic acid cut LDL-cholesterol levels by an average of 18% more compared with placebo (N Engl J Med 2019;380:1022-32). In CLEAR Wisdom, bempedoic acid reduced LDL cholesterol levels by 17% (JAMA. 2019;322[18]:1780-8).

While those two trials proved the drug’s ability to lower levels of LDL cholesterol, they lacked the power to address whether this effect cut the incidence of CVD events, a question that the CLEAR Outcomes trial aims to answer.

“I believe in the lipid hypothesis, but the main thing we need to see is whether bempedoic acid leads to a meaningful reduction in CVD events. The window for bempedoic acid will remain narrow until we see the outcomes results,” Dr. Michos said in an interview.

Bempedoic acid is a prodrug that’s activated in liver and targets the same cholesterol synthesis pathway as statins by inhibition of ATP-citrate lyase, an enzyme that’s upstream of HMG-CoA reductase, thereby enhancing LDL cholesterol clearance via up-regulation of LDL receptors

.

Combined treatment with bempedoic acid and ezetimibe “may be successful in avoiding [using] a PCSK9 inhibitor in some patients, and in particular patients with HeFH or those who are statin intolerant.” But like his colleagues, Dr. Eckel agreed that, for the moment, ezetimibe has an edge over bempedoic acid because of its more extensive evidence base. “If the combination of bempedoic acid and ezetimibe is not needed, the decision [of which one of these to use] needs to depend on the outcome trial results for ezetimibe,” he said. Other factors clinicians could apply if faced with choosing between these two agents include the significant reduction in high-sensitivity C-reactive protein that bempedoic acid produces; the downside that bempedoic acid can cause in some patients an early and persistent rise in serum uric acid levels that can trigger gout flares in patients with a history of gout or at risk for gout; and cost, he said.

Cost is the room-dwelling elephant that colors many decisions about which lipid-lowering drug to use for patients, with options running the price gamut from the generic and uniformly affordable statins and ezetimibe, to the notoriously pricey PCSK9 inhibitors that remain for many patients either prohibitively expensive or hard to get covered by some insurers. Bempedoic acid seems on track to fall somewhere between these two poles, although staff members from Esperion, the company that developed and will market bempedoic acid as Nexletol starting on March 30, declared in a conference call on Feb. 24 that “cost will not be an issue,” for indicated patients prescribed the drug. Company representatives cited a program of coupons, discounts, and rebates they have planned that they anticipate will allow patients who meet the labeled indications to have an out-of-pocket cost for bempedoic acid of “as low as” $10 for a 90-pill supply. They also noted their goal of getting bempedoic acid onto the lowest tier of the Medicare formulary.

How these steps actually play out in the fun house of U.S. prescription drug pricing and preauthorizations remains to be seen. “Out-of-pocket costs are not the real drivers” of drug access, noted Dr. Robinson. “Insurers will likely start with restricted access and prior authorization requirements, just as they did with ezetimibe when it was on patent and prior to having the results from a CVD outcomes trial.” For the time being, bempedoic acid can generally be seen as “expensive ezetimibe,” summed up Dr. Robinson.

Despite that somewhat dismissive characterization, experts are intrigued by the possibility of combining two moderately potent, oral, and safe lipid-lowering drugs in selected patients as a potential alternative to the still financially challenging PCSK9 inhibitors. Combining bempedoic acid and ezetimibe “has a lot of appeal,” said Dr. Michos. “Even though preauthorization has gotten better, it’s still a challenge to get a PCSK9 inhibitor approved.”

Much of her enthusiasm stems from a study reported last year that randomized 301 patients to treatment with bempedoic acid, ezetimibe, or both. The results showed that combined treatment has a similar safety profile to treatment with either drug alone, and produced a cut in LDL cholesterol that was roughly additive for the reductions produced by each drug by itself: Ezetimibe alone cut LDL by about 23%, bempedoic acid alone by about 17%, and the two dosed together once daily resulted in an average 36% drop (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864671). The results showed that, “in patients requiring intensive LDL cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention,” wrote Dr. Michos and a coauthor in a commentary that appeared with the study results (Eur J Prev Cardiol. 2019 Jul 29. doi: 10.1177/2047487319864672).

The concept of combined bempedoic acid and ezetimibe treatment is so appealing that the bempedoic acid manufacturer, Esperion, has already developed a single-pill formulation of the two drugs that received FDA marketing approval on February 26. A company statement said that marketing of this combined formulation, Nexlizet, will start in July 2020.

Although interest in bempedoic acid seems running high for patients included in the new FDA indication, Dr. Michos and others see possibly greater potential for what would now be off-label use for primary prevention in high-risk patients without HeFH, patients who generally don’t qualify for insurance coverage of a PCSK9 inhibitor.

“Use in primary prevention in [non-HeFH] patients with insufficient lowering of LDL cholesterol wouldn’t surprise me,” but a big concern will be out-of-pocket cost when off-label use precludes insurance coverage or discount eligibility, noted Dr. Eckel. An Esperion spokesperson said that the undiscounted, wholesale acquisition cost for bempedoic acid is expected to be roughly $10/pill, or about $300 for a 30-day supply, positioning it more or less midway between generic statins and ezetimibe and the list price for a PCSk9 inhibitor of roughly $500/month.

“I’m most excited about bempedoic acid in the off-label space, for patients who can’t get approved for a PCSK9 inhibitor, for treating patients with subclinical ASCVD, or really high-risk patients with multiple risk factors including diabetes,” especially when these patients are intolerant of a high-intensity statin regimen, said Dr. Michos. “I have a clinic full of patients” who can’t take their full, indicated dosage of a high-intensity statin, and when those patients also can’t get on treatment with a PCSK9 inhibitor then bempedoic acid will be an important part of their alternative regimen, she explained.

Dr. Michos had no disclosures. Dr. Robinson has received research funding from Esperion and from several other companies, and she has been a consultant to Amgen, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi. Dr. Eckel has received honoraria from Kowa, Merck, Novo Nordisk, and Sanofi/Regeneron.

This article was updated 2/27/20.

mzoler@mdedge.com

The Food and Drug Administration has approved bempedoic acid (Nexletol) for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional LDL cholesterol lowering.

The oral adenosine triphosphate–citrate lyase (ACL) inhibitor is indicated as an adjunct to diet and maximally tolerated statin therapy in these patients, and approved at the 180 mg once daily dose, the agency announced today.

The safety and efficacy of bempedoic acid were demonstrated over 52 weeks in two multicenter randomized, clinical trials involving 3,009 adults with HeFH or established ASCVD on maximally tolerated statin therapy.

The difference between bempedoic acid and placebo for the primary outcome of change in LDL cholesterol from baseline to week 12 was –18% in the first trial, CLEAR Harmony (95% confidence interval, –20% to –16%; P less than .001), and –17% in the second trial, CLEAR Wisdom (95% CI, –21% to –14%; P less than .001).

The label notes that the effect on cardiovascular morbidity and mortality has not been determined. The label also includes warnings stating that bempedoic acid may increase blood uric acid levels and is associated with an increased risk of tendon rupture or injury.

In clinical trials, 26% of bempedoic acid–treated patients with normal baseline uric acid values versus 9.5% of placebo-treated patients experienced hyperuricemia one or more times, and 3.5% of patients experienced clinically significant hyperuricemia reported as an adverse reaction versus 1.1% with placebo, according to the label. Gout was reported in 1.5% of patients treated with bempedoic acid and 0.4% of those treated with placebo.

Also in clinical trials, the risk of tendon rupture was 0.5% with bempedoic acid and 0% with placebo. Tendon rupture involved the rotator cuff, biceps tendon, or Achilles tendon, and occurred within weeks to months of starting the drug. Rupture may “occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders,” the label states.

The label also advises that patients avoid concomitant use of bempedoic acid with simvastatin greater than 20 mg or pravastatin greater than 40 mg because it causes an increase in statin concentrations and may increase the risk of related myopathy.

A decision is expected shortly on a new drug application submitted by Esperion for an LDL cholesterol–lowering indication for bempedoic acid 180 mg/ezetimibe 10 mg combination tablet.

Full prescribing information is available online.

This article first appeared on Medscape.com.

The Food and Drug Administration has approved bempedoic acid (Nexletol) for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional LDL cholesterol lowering.

The oral adenosine triphosphate–citrate lyase (ACL) inhibitor is indicated as an adjunct to diet and maximally tolerated statin therapy in these patients, and approved at the 180 mg once daily dose, the agency announced today.

The safety and efficacy of bempedoic acid were demonstrated over 52 weeks in two multicenter randomized, clinical trials involving 3,009 adults with HeFH or established ASCVD on maximally tolerated statin therapy.

The difference between bempedoic acid and placebo for the primary outcome of change in LDL cholesterol from baseline to week 12 was –18% in the first trial, CLEAR Harmony (95% confidence interval, –20% to –16%; P less than .001), and –17% in the second trial, CLEAR Wisdom (95% CI, –21% to –14%; P less than .001).

The label notes that the effect on cardiovascular morbidity and mortality has not been determined. The label also includes warnings stating that bempedoic acid may increase blood uric acid levels and is associated with an increased risk of tendon rupture or injury.

In clinical trials, 26% of bempedoic acid–treated patients with normal baseline uric acid values versus 9.5% of placebo-treated patients experienced hyperuricemia one or more times, and 3.5% of patients experienced clinically significant hyperuricemia reported as an adverse reaction versus 1.1% with placebo, according to the label. Gout was reported in 1.5% of patients treated with bempedoic acid and 0.4% of those treated with placebo.

Also in clinical trials, the risk of tendon rupture was 0.5% with bempedoic acid and 0% with placebo. Tendon rupture involved the rotator cuff, biceps tendon, or Achilles tendon, and occurred within weeks to months of starting the drug. Rupture may “occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders,” the label states.

The label also advises that patients avoid concomitant use of bempedoic acid with simvastatin greater than 20 mg or pravastatin greater than 40 mg because it causes an increase in statin concentrations and may increase the risk of related myopathy.

A decision is expected shortly on a new drug application submitted by Esperion for an LDL cholesterol–lowering indication for bempedoic acid 180 mg/ezetimibe 10 mg combination tablet.

Full prescribing information is available online.

This article first appeared on Medscape.com.

The Food and Drug Administration has approved bempedoic acid (Nexletol) for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional LDL cholesterol lowering.

The oral adenosine triphosphate–citrate lyase (ACL) inhibitor is indicated as an adjunct to diet and maximally tolerated statin therapy in these patients, and approved at the 180 mg once daily dose, the agency announced today.

The safety and efficacy of bempedoic acid were demonstrated over 52 weeks in two multicenter randomized, clinical trials involving 3,009 adults with HeFH or established ASCVD on maximally tolerated statin therapy.

The difference between bempedoic acid and placebo for the primary outcome of change in LDL cholesterol from baseline to week 12 was –18% in the first trial, CLEAR Harmony (95% confidence interval, –20% to –16%; P less than .001), and –17% in the second trial, CLEAR Wisdom (95% CI, –21% to –14%; P less than .001).

The label notes that the effect on cardiovascular morbidity and mortality has not been determined. The label also includes warnings stating that bempedoic acid may increase blood uric acid levels and is associated with an increased risk of tendon rupture or injury.

In clinical trials, 26% of bempedoic acid–treated patients with normal baseline uric acid values versus 9.5% of placebo-treated patients experienced hyperuricemia one or more times, and 3.5% of patients experienced clinically significant hyperuricemia reported as an adverse reaction versus 1.1% with placebo, according to the label. Gout was reported in 1.5% of patients treated with bempedoic acid and 0.4% of those treated with placebo.

Also in clinical trials, the risk of tendon rupture was 0.5% with bempedoic acid and 0% with placebo. Tendon rupture involved the rotator cuff, biceps tendon, or Achilles tendon, and occurred within weeks to months of starting the drug. Rupture may “occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders,” the label states.

The label also advises that patients avoid concomitant use of bempedoic acid with simvastatin greater than 20 mg or pravastatin greater than 40 mg because it causes an increase in statin concentrations and may increase the risk of related myopathy.

A decision is expected shortly on a new drug application submitted by Esperion for an LDL cholesterol–lowering indication for bempedoic acid 180 mg/ezetimibe 10 mg combination tablet.

Full prescribing information is available online.

This article first appeared on Medscape.com.

Changes in gut microbiota linked to red meat intake over time were significantly associated with increased risk of coronary heart disease, regardless of baseline microbiota measures, based on data from 760 participants in the Nurses’ Health Study.

“A gut microbiota–related metabolite, trimethylamine N-oxide (TMAO), has been related to risks of major adverse cardiovascular events including myocardial infarction and coronary heart disease (CHD) in epidemiological studies,” but previous studies have not examined the impact of long-term changes in TMAO on CHD risk, wrote Yoriko Heianza, RD, PhD, of Tulane University, New Orleans, and colleagues.

Red meat has been shown to increase TMAO levels, whereas discontinuation of red meat intake reduced plasma TMAO levels (Eur Heart J 2019;40:583-94), the investigators wrote.

In their study, published in the Journal of the American College of Cardiology, the researchers evaluated blood samples from 760 women who were participants in the Nurses’ Health Study. The samples were collected at two time points: 1989-1990 and 2000-2002. The researchers identified 360 incident cases of CHD over the study period and compared them with matched controls.

Over roughly 10 years, increases in TMAO over time were significantly associated with increased CHD risk, with a relative risk of 1.58 for the top tertile and a relative risk of 1.33 per each standard deviation.

Women with elevated levels of TMAO both at baseline and at the 10-year point had the highest CHD risk (relative risk 1.79), compared with women with low TMAO levels at baseline and 10 years later.

The researchers also found an impact of diet on the TMAO-CHD relationship. Individuals with unhealthy eating patterns based on the Alternate Healthy Eating Index showed greater increases in TMAO and greater CHD risk. By contrast, greater adherence to healthy eating habits attenuated the impact of TMAO and CHD.

The study findings were limited by several factors, including the inability to assess the timing of the changes in the metabolites that contributed to CHD, the reliance on self-reports for dietary patterns and other variables, and the inclusion only of women health professionals in the study population, the researchers noted. However, the results were strengthened by the availability of long-term blood samples and a patient population free of disease at baseline.

In addition, “adherence to healthy dietary patterns may modulate the adverse relationship between TMAO changes and CHD, suggesting that TMAO as a potential intermediate endpoint of interventions focusing on dietary modifications for CHD prevention,” the researchers wrote.

“The findings of the study provide further evidence for the role of TMAO as a predictive biomarker for atherosclerotic heart disease and strengthen the case for TMAO as a potential intervention target in CV [cardiovascular] disease prevention,” wrote Paul A. Heidenreich, MD, and Petra Mamic, MD, of Stanford (Calif.) University, in an accompanying editorial.

In addition, “It is increasingly clear that GMB [gut microbiota] metabolites have biological activity, and that dietary changes alter the GMB and its metabolic output, with subsequent modulation of downstream host effects,” they wrote.

“While acknowledging the limitations of self-reported dietary pattern assessment, this is an important finding because it suggests that healthy dietary patterns may in some ways neutralize TMAO’s harmful effects on the CV system, potentially through other identified and unidentified GMB-mediated pathways,” they added.

The study was sponsored in part by the National Institutes of Health, the Boston Obesity Nutrition Research Center, and the United States–Israel Binational Science Foundation. Neither the researchers nor the editorialists had any financial conflicts to disclose.

SOURCES: Heianza Y et al. J Am Coll Cardiol. 2020 Feb 17. doi: 0.1016/j.jacc.2019.11.060; Heidenreich PA, Mamic P. J Am Coll Cardiol. 2020 Feb 17. doi: 10.1016/j.jacc.2019.12.023.

Changes in gut microbiota linked to red meat intake over time were significantly associated with increased risk of coronary heart disease, regardless of baseline microbiota measures, based on data from 760 participants in the Nurses’ Health Study.

“A gut microbiota–related metabolite, trimethylamine N-oxide (TMAO), has been related to risks of major adverse cardiovascular events including myocardial infarction and coronary heart disease (CHD) in epidemiological studies,” but previous studies have not examined the impact of long-term changes in TMAO on CHD risk, wrote Yoriko Heianza, RD, PhD, of Tulane University, New Orleans, and colleagues.

Red meat has been shown to increase TMAO levels, whereas discontinuation of red meat intake reduced plasma TMAO levels (Eur Heart J 2019;40:583-94), the investigators wrote.

In their study, published in the Journal of the American College of Cardiology, the researchers evaluated blood samples from 760 women who were participants in the Nurses’ Health Study. The samples were collected at two time points: 1989-1990 and 2000-2002. The researchers identified 360 incident cases of CHD over the study period and compared them with matched controls.

Over roughly 10 years, increases in TMAO over time were significantly associated with increased CHD risk, with a relative risk of 1.58 for the top tertile and a relative risk of 1.33 per each standard deviation.

Women with elevated levels of TMAO both at baseline and at the 10-year point had the highest CHD risk (relative risk 1.79), compared with women with low TMAO levels at baseline and 10 years later.

The researchers also found an impact of diet on the TMAO-CHD relationship. Individuals with unhealthy eating patterns based on the Alternate Healthy Eating Index showed greater increases in TMAO and greater CHD risk. By contrast, greater adherence to healthy eating habits attenuated the impact of TMAO and CHD.

The study findings were limited by several factors, including the inability to assess the timing of the changes in the metabolites that contributed to CHD, the reliance on self-reports for dietary patterns and other variables, and the inclusion only of women health professionals in the study population, the researchers noted. However, the results were strengthened by the availability of long-term blood samples and a patient population free of disease at baseline.

In addition, “adherence to healthy dietary patterns may modulate the adverse relationship between TMAO changes and CHD, suggesting that TMAO as a potential intermediate endpoint of interventions focusing on dietary modifications for CHD prevention,” the researchers wrote.

“The findings of the study provide further evidence for the role of TMAO as a predictive biomarker for atherosclerotic heart disease and strengthen the case for TMAO as a potential intervention target in CV [cardiovascular] disease prevention,” wrote Paul A. Heidenreich, MD, and Petra Mamic, MD, of Stanford (Calif.) University, in an accompanying editorial.

In addition, “It is increasingly clear that GMB [gut microbiota] metabolites have biological activity, and that dietary changes alter the GMB and its metabolic output, with subsequent modulation of downstream host effects,” they wrote.

“While acknowledging the limitations of self-reported dietary pattern assessment, this is an important finding because it suggests that healthy dietary patterns may in some ways neutralize TMAO’s harmful effects on the CV system, potentially through other identified and unidentified GMB-mediated pathways,” they added.

The study was sponsored in part by the National Institutes of Health, the Boston Obesity Nutrition Research Center, and the United States–Israel Binational Science Foundation. Neither the researchers nor the editorialists had any financial conflicts to disclose.

SOURCES: Heianza Y et al. J Am Coll Cardiol. 2020 Feb 17. doi: 0.1016/j.jacc.2019.11.060; Heidenreich PA, Mamic P. J Am Coll Cardiol. 2020 Feb 17. doi: 10.1016/j.jacc.2019.12.023.

Changes in gut microbiota linked to red meat intake over time were significantly associated with increased risk of coronary heart disease, regardless of baseline microbiota measures, based on data from 760 participants in the Nurses’ Health Study.

“A gut microbiota–related metabolite, trimethylamine N-oxide (TMAO), has been related to risks of major adverse cardiovascular events including myocardial infarction and coronary heart disease (CHD) in epidemiological studies,” but previous studies have not examined the impact of long-term changes in TMAO on CHD risk, wrote Yoriko Heianza, RD, PhD, of Tulane University, New Orleans, and colleagues.

Red meat has been shown to increase TMAO levels, whereas discontinuation of red meat intake reduced plasma TMAO levels (Eur Heart J 2019;40:583-94), the investigators wrote.

In their study, published in the Journal of the American College of Cardiology, the researchers evaluated blood samples from 760 women who were participants in the Nurses’ Health Study. The samples were collected at two time points: 1989-1990 and 2000-2002. The researchers identified 360 incident cases of CHD over the study period and compared them with matched controls.

Over roughly 10 years, increases in TMAO over time were significantly associated with increased CHD risk, with a relative risk of 1.58 for the top tertile and a relative risk of 1.33 per each standard deviation.

Women with elevated levels of TMAO both at baseline and at the 10-year point had the highest CHD risk (relative risk 1.79), compared with women with low TMAO levels at baseline and 10 years later.

The researchers also found an impact of diet on the TMAO-CHD relationship. Individuals with unhealthy eating patterns based on the Alternate Healthy Eating Index showed greater increases in TMAO and greater CHD risk. By contrast, greater adherence to healthy eating habits attenuated the impact of TMAO and CHD.

The study findings were limited by several factors, including the inability to assess the timing of the changes in the metabolites that contributed to CHD, the reliance on self-reports for dietary patterns and other variables, and the inclusion only of women health professionals in the study population, the researchers noted. However, the results were strengthened by the availability of long-term blood samples and a patient population free of disease at baseline.

In addition, “adherence to healthy dietary patterns may modulate the adverse relationship between TMAO changes and CHD, suggesting that TMAO as a potential intermediate endpoint of interventions focusing on dietary modifications for CHD prevention,” the researchers wrote.

“The findings of the study provide further evidence for the role of TMAO as a predictive biomarker for atherosclerotic heart disease and strengthen the case for TMAO as a potential intervention target in CV [cardiovascular] disease prevention,” wrote Paul A. Heidenreich, MD, and Petra Mamic, MD, of Stanford (Calif.) University, in an accompanying editorial.

In addition, “It is increasingly clear that GMB [gut microbiota] metabolites have biological activity, and that dietary changes alter the GMB and its metabolic output, with subsequent modulation of downstream host effects,” they wrote.

“While acknowledging the limitations of self-reported dietary pattern assessment, this is an important finding because it suggests that healthy dietary patterns may in some ways neutralize TMAO’s harmful effects on the CV system, potentially through other identified and unidentified GMB-mediated pathways,” they added.

The study was sponsored in part by the National Institutes of Health, the Boston Obesity Nutrition Research Center, and the United States–Israel Binational Science Foundation. Neither the researchers nor the editorialists had any financial conflicts to disclose.

SOURCES: Heianza Y et al. J Am Coll Cardiol. 2020 Feb 17. doi: 0.1016/j.jacc.2019.11.060; Heidenreich PA, Mamic P. J Am Coll Cardiol. 2020 Feb 17. doi: 10.1016/j.jacc.2019.12.023.

The controversy regarding the safety of treating peripheral artery disease (PAD) with paclitaxel-coated devices has only deepened in the new year, with two recent studies suggesting opposite safety findings.
 

The debate began with a 2018 meta-analysis showing a late mortality signal associated with paclitaxel drug-coated balloons (DCBs) that sent reverberations through the interventional cardiology community (J Am Heart Assoc. 2018 Dec 18;7[24]:e011245).

Now, in a new meta-analysis involving eight randomized controlled trials (RCTs) and more than 1,400 patients with critical limb ischemia (CLI), the same researchers found significantly more early amputations and deaths in those treated with DCB below the knee, compared with conventional balloon angioplasty.

“The findings of our latest report add to previous evidence underpinning major safety concerns around use of paclitaxel in lower limb angioplasties – increased long-term patient mortality in cases of intermittent claudication,” lead author Konstantinos Katsanos MD, MSc, PhD, Patras University Hospital, Greece, said in an interview.

By contrast, a retrospective study of insurance claims in Germany showed no heightened mortality with paclitaxel-coated balloons and stents, compared with uncoated devices, in close to 38,000 patients with PAD.

On the contrary, use of paclitaxel-coated devices was associated with higher long-term survival, better amputation-free survival (AFS), and lower rates of major cardiovascular events in the treatment of chronic limb-threatening ischemia (CLTI).

These findings “emphasize the difference between population-based evidence and randomized trials,” lead author Christian-Alexander Behrendt, MD, University Medical Center Hamburg-Eppendorf, Germany, said in an interview.

Downstream “showers”

In the new meta-analysis led by Dr. Katsanos, published online Jan. 15, the 1,420 patients were treated with five different DCBs and 97% had CLI (J Vasc Intervent Radiol 2020 Feb;31[2]:202-12).

In up to 1-year follow-up, the paclitaxel DCB group had fewer target lesion revascularizations (TLR) than those of the uncoated device group (11.8% vs. 25.6%; risk ratio, 0.53; 95% confidence interval, 0.35-0.81) but worse AFS (13.7% vs. 9.4%; hazard ratio [HR], 1.52; 95% CI, 1.12-2.07).

The latter finding was driven by nonsignificant increased risks for all-cause death (odds ratio [OR], 1.39; 95% CI, 0.94-2.07) and major amputations (OR, 1.63; 95% CI, 0.92-2.90).

In dose-subgroup analyses, AFS was significantly worse in cases with high-dose (3.0-3.5 mcg/mm²) devices, but not in the single trial with a low-dose DCB (2.0 mcg/mm²).

“Considering the well-described downstream ‘showers’ of paclitaxel particles with current drug-coated balloons, we hypothesize that nontarget paclitaxel embolization is a plausible mechanism for distal foot and systemic toxicity,” Dr. Katsanos said.

Short time frame

Eric Secemsky, MD, of Harvard Medical School, and director of vascular intervention at Beth Israel Deaconess Medical Center, Boston, suggested in an interview that this theorized mechanism of harm in below-the-knee procedures could potentially shed light on a similar mechanism at play in above-the-knee procedures.

“We didn’t understand why people could potentially be dying in above-the-knee [procedures], and the suggestion here is that these devices might perhaps be causing particular embolization or maybe delayed wound healing,” Dr. Secemsky speculated.

However, “I don’t know that this is true, so I am cautious to say this is true,” he emphasized.

Dr. Secemsky said a strength of the Katsanos analysis is that the RCTs included more than 1,000 patients, but noted that it is hard to vet the quality and rigor of the data, as some of the studies have not yet been published. He also noted that paclitaxel-coated devices are not approved by the Food and Drug Administration in the United States for below-the-knee procedures.

Moreover, he continued, “two studies were driving the signal of harm: the IN.PACT DEEP, which included an iteration of their DCB that is no longer being tested; and the unpublished SINGA-PACLI trial. Those studies contributed most of the adverse events seen in this meta-analysis.”

In addition, the trials had different lengths of follow-up (6-12 months), he said. “Thus, the five trials with data available to 12 months are driving the 1-year findings, whereas three RCTs, including the primary RCT showing safety [Lutonix-BTK trial], only contribute data to 6 months.”

For this reason, “we are not too excited about this meta-analysis as of now, [because] all it tells us is that we need more data to support the safety of drug-coated devices in this population,” Dr. Secemsky said.

Dr. Katsanos explained that, “to address the differences in follow-up period and number of cases lost to follow-up, the primary endpoint was calculated on the log-hazard scale and expressed as a hazard ratio, as recommended for time-to-event outcomes.”

He highlighted that a short-term time frame of 6 months to 1 year was chosen “because it is clinically relevant to limb-threatening CLI.”

Sensitivity tests also “showed consistent direction and magnitude of the summary treatment effects in case of both AFS and freedom from TLR,” Dr. Katsanos emphasized.

Lower mortality, fewer amputations

The second study, published online Jan. 8, drew on health insurance claims in the German BARMER database to analyze 37,914 patients (mean age, 73.3 years, 49% female) and 21,546 propensity-score-matched patients with symptomatic CLTI or intermittent claudication (IC) with an index revascularization during 2010-2018 (Eur J Vasc Endovasc Surg. 2020 Jan 8. doi: 10.1016/j.ejvs.2019.12.034).

Patients were first stratified by CLTI or IC, and then by balloon vs. stent use. Paclitaxel-coated devices were then compared with uncoated devices within each stratum. The primary outcome was all-cause mortality at the end of follow-up.

From 2010 to 2018, the annual use of paclitaxel-coated devices increased dramatically from 3% to 39% in the CLTI group and from 4% to 48% in the IC group (P less than .001 for both).

A total of 2,454 deaths occurred within 5 years of follow-up (median, 2.7 years; longest, 8 years).

A Cox proportional hazards model (based on propensity-score-matched cohorts at 5 years) showed that, compared with uncoated devices, use of paclitaxel-coated devices in the CLTI group was associated with several improvements:

• Overall survival: HR, 0.83; 95% CI, 0.77-0.90.
• Amputation-free survival: HR, 0.85; 95% CI, 0.78-0.91.
• Major cardiovascular events: HR, 0.82; 95% CI, 0.77-0.88.

In the IC group, mortality was significantly better with DCB (HR, 0.87; 95% CI, 0.76-0.99) or a combination of DCB and drug-eluting stents (HR, 0.88; 95% CI, 0.80-0.98) than with uncoated devices, but similar for DES alone (HR, 0.91; 95% CI, 0.77-1.08).

No benefit was found for paclitaxel-coated devices in the IC group for AFS (HR, 0.91; 95% CI, 0.82-1.00) or major cardiovascular events (HR, 0.93; 95% CI, 0.87-1.00).

The authors acknowledge that “unmeasured confounding” may partly explain the results. It may be that patients revascularized with DCB or DES “are more likely to be treated in highly specialized trial centers with clear follow-up protocol.”

Moreover, these patients may have received “the best treatment,” including statin therapy, added Dr. Behrendt.

More evidence needed

Dr. Secemsky, who was not involved with either study, said the German investigators “did a wonderful job with this analysis in a large population of several thousand patients, showing nicely that after accounting for differences in comorbidities, the patients had no evidence of harm with [paclitaxel-coated] devices through 5 years.”

However, he cautioned, median follow-up time was just over 2 years. “Although the investigators had data all the way out to 5 years, over time, the number of patients contributing data became smaller, which results in more uncertainty with these longer-term findings,” he said. “As such, we still need to look at additional long-term data in this patient population to confirm the safety of these devices.”

At present, the “major consideration we want to address is whether it’s safe to use these devices, and we’re undertaking these analyses to examine safety, not to see if they improve mortality,” although the present study “has a suggestion of mortality benefit,” Dr. Secemsky said.

Dr. Katsanos added that paclitaxel-coated balloons “remain under investigation for below-knee arteries and critical limb ischemia,” with “a few randomized controlled trials on the way.”

“We need definitive evidence from high-quality multicenter controlled trials that these devices may improve wound healing and limb salvage without any systemic mortality risk,” he said.

Dr. Katsanos receives personal fees from Boston Scientific and Philips Healthcare. The study by Dr. Behrendt was part of the IDOMENEO project funded by the German Joint Federal Committee. Dr. Behrendt reports no relevant financial relationships. Dr. Secemsky reports institutional grants from Cook Medical, BD Bard, Medtronic, Beth Israel Deaconess Medical Center, and Boston Scientific, and reports consultancy for Cook Medical, BD Bard, and Medtronic.
 

This article first appeared on Medscape.com.

The controversy regarding the safety of treating peripheral artery disease (PAD) with paclitaxel-coated devices has only deepened in the new year, with two recent studies suggesting opposite safety findings.
 

The debate began with a 2018 meta-analysis showing a late mortality signal associated with paclitaxel drug-coated balloons (DCBs) that sent reverberations through the interventional cardiology community (J Am Heart Assoc. 2018 Dec 18;7[24]:e011245).

Now, in a new meta-analysis involving eight randomized controlled trials (RCTs) and more than 1,400 patients with critical limb ischemia (CLI), the same researchers found significantly more early amputations and deaths in those treated with DCB below the knee, compared with conventional balloon angioplasty.

“The findings of our latest report add to previous evidence underpinning major safety concerns around use of paclitaxel in lower limb angioplasties – increased long-term patient mortality in cases of intermittent claudication,” lead author Konstantinos Katsanos MD, MSc, PhD, Patras University Hospital, Greece, said in an interview.

By contrast, a retrospective study of insurance claims in Germany showed no heightened mortality with paclitaxel-coated balloons and stents, compared with uncoated devices, in close to 38,000 patients with PAD.

On the contrary, use of paclitaxel-coated devices was associated with higher long-term survival, better amputation-free survival (AFS), and lower rates of major cardiovascular events in the treatment of chronic limb-threatening ischemia (CLTI).

These findings “emphasize the difference between population-based evidence and randomized trials,” lead author Christian-Alexander Behrendt, MD, University Medical Center Hamburg-Eppendorf, Germany, said in an interview.

Downstream “showers”

In the new meta-analysis led by Dr. Katsanos, published online Jan. 15, the 1,420 patients were treated with five different DCBs and 97% had CLI (J Vasc Intervent Radiol 2020 Feb;31[2]:202-12).

In up to 1-year follow-up, the paclitaxel DCB group had fewer target lesion revascularizations (TLR) than those of the uncoated device group (11.8% vs. 25.6%; risk ratio, 0.53; 95% confidence interval, 0.35-0.81) but worse AFS (13.7% vs. 9.4%; hazard ratio [HR], 1.52; 95% CI, 1.12-2.07).

The latter finding was driven by nonsignificant increased risks for all-cause death (odds ratio [OR], 1.39; 95% CI, 0.94-2.07) and major amputations (OR, 1.63; 95% CI, 0.92-2.90).

In dose-subgroup analyses, AFS was significantly worse in cases with high-dose (3.0-3.5 mcg/mm²) devices, but not in the single trial with a low-dose DCB (2.0 mcg/mm²).

“Considering the well-described downstream ‘showers’ of paclitaxel particles with current drug-coated balloons, we hypothesize that nontarget paclitaxel embolization is a plausible mechanism for distal foot and systemic toxicity,” Dr. Katsanos said.

Short time frame

Eric Secemsky, MD, of Harvard Medical School, and director of vascular intervention at Beth Israel Deaconess Medical Center, Boston, suggested in an interview that this theorized mechanism of harm in below-the-knee procedures could potentially shed light on a similar mechanism at play in above-the-knee procedures.

“We didn’t understand why people could potentially be dying in above-the-knee [procedures], and the suggestion here is that these devices might perhaps be causing particular embolization or maybe delayed wound healing,” Dr. Secemsky speculated.

However, “I don’t know that this is true, so I am cautious to say this is true,” he emphasized.

Dr. Secemsky said a strength of the Katsanos analysis is that the RCTs included more than 1,000 patients, but noted that it is hard to vet the quality and rigor of the data, as some of the studies have not yet been published. He also noted that paclitaxel-coated devices are not approved by the Food and Drug Administration in the United States for below-the-knee procedures.

Moreover, he continued, “two studies were driving the signal of harm: the IN.PACT DEEP, which included an iteration of their DCB that is no longer being tested; and the unpublished SINGA-PACLI trial. Those studies contributed most of the adverse events seen in this meta-analysis.”

In addition, the trials had different lengths of follow-up (6-12 months), he said. “Thus, the five trials with data available to 12 months are driving the 1-year findings, whereas three RCTs, including the primary RCT showing safety [Lutonix-BTK trial], only contribute data to 6 months.”

For this reason, “we are not too excited about this meta-analysis as of now, [because] all it tells us is that we need more data to support the safety of drug-coated devices in this population,” Dr. Secemsky said.

Dr. Katsanos explained that, “to address the differences in follow-up period and number of cases lost to follow-up, the primary endpoint was calculated on the log-hazard scale and expressed as a hazard ratio, as recommended for time-to-event outcomes.”

He highlighted that a short-term time frame of 6 months to 1 year was chosen “because it is clinically relevant to limb-threatening CLI.”

Sensitivity tests also “showed consistent direction and magnitude of the summary treatment effects in case of both AFS and freedom from TLR,” Dr. Katsanos emphasized.

Lower mortality, fewer amputations

The second study, published online Jan. 8, drew on health insurance claims in the German BARMER database to analyze 37,914 patients (mean age, 73.3 years, 49% female) and 21,546 propensity-score-matched patients with symptomatic CLTI or intermittent claudication (IC) with an index revascularization during 2010-2018 (Eur J Vasc Endovasc Surg. 2020 Jan 8. doi: 10.1016/j.ejvs.2019.12.034).

Patients were first stratified by CLTI or IC, and then by balloon vs. stent use. Paclitaxel-coated devices were then compared with uncoated devices within each stratum. The primary outcome was all-cause mortality at the end of follow-up.

From 2010 to 2018, the annual use of paclitaxel-coated devices increased dramatically from 3% to 39% in the CLTI group and from 4% to 48% in the IC group (P less than .001 for both).

A total of 2,454 deaths occurred within 5 years of follow-up (median, 2.7 years; longest, 8 years).

A Cox proportional hazards model (based on propensity-score-matched cohorts at 5 years) showed that, compared with uncoated devices, use of paclitaxel-coated devices in the CLTI group was associated with several improvements:

• Overall survival: HR, 0.83; 95% CI, 0.77-0.90.
• Amputation-free survival: HR, 0.85; 95% CI, 0.78-0.91.
• Major cardiovascular events: HR, 0.82; 95% CI, 0.77-0.88.

In the IC group, mortality was significantly better with DCB (HR, 0.87; 95% CI, 0.76-0.99) or a combination of DCB and drug-eluting stents (HR, 0.88; 95% CI, 0.80-0.98) than with uncoated devices, but similar for DES alone (HR, 0.91; 95% CI, 0.77-1.08).

No benefit was found for paclitaxel-coated devices in the IC group for AFS (HR, 0.91; 95% CI, 0.82-1.00) or major cardiovascular events (HR, 0.93; 95% CI, 0.87-1.00).

The authors acknowledge that “unmeasured confounding” may partly explain the results. It may be that patients revascularized with DCB or DES “are more likely to be treated in highly specialized trial centers with clear follow-up protocol.”

Moreover, these patients may have received “the best treatment,” including statin therapy, added Dr. Behrendt.

More evidence needed

Dr. Secemsky, who was not involved with either study, said the German investigators “did a wonderful job with this analysis in a large population of several thousand patients, showing nicely that after accounting for differences in comorbidities, the patients had no evidence of harm with [paclitaxel-coated] devices through 5 years.”

However, he cautioned, median follow-up time was just over 2 years. “Although the investigators had data all the way out to 5 years, over time, the number of patients contributing data became smaller, which results in more uncertainty with these longer-term findings,” he said. “As such, we still need to look at additional long-term data in this patient population to confirm the safety of these devices.”

At present, the “major consideration we want to address is whether it’s safe to use these devices, and we’re undertaking these analyses to examine safety, not to see if they improve mortality,” although the present study “has a suggestion of mortality benefit,” Dr. Secemsky said.

Dr. Katsanos added that paclitaxel-coated balloons “remain under investigation for below-knee arteries and critical limb ischemia,” with “a few randomized controlled trials on the way.”

“We need definitive evidence from high-quality multicenter controlled trials that these devices may improve wound healing and limb salvage without any systemic mortality risk,” he said.

Dr. Katsanos receives personal fees from Boston Scientific and Philips Healthcare. The study by Dr. Behrendt was part of the IDOMENEO project funded by the German Joint Federal Committee. Dr. Behrendt reports no relevant financial relationships. Dr. Secemsky reports institutional grants from Cook Medical, BD Bard, Medtronic, Beth Israel Deaconess Medical Center, and Boston Scientific, and reports consultancy for Cook Medical, BD Bard, and Medtronic.
 

This article first appeared on Medscape.com.

The controversy regarding the safety of treating peripheral artery disease (PAD) with paclitaxel-coated devices has only deepened in the new year, with two recent studies suggesting opposite safety findings.
 

The debate began with a 2018 meta-analysis showing a late mortality signal associated with paclitaxel drug-coated balloons (DCBs) that sent reverberations through the interventional cardiology community (J Am Heart Assoc. 2018 Dec 18;7[24]:e011245).

Now, in a new meta-analysis involving eight randomized controlled trials (RCTs) and more than 1,400 patients with critical limb ischemia (CLI), the same researchers found significantly more early amputations and deaths in those treated with DCB below the knee, compared with conventional balloon angioplasty.

“The findings of our latest report add to previous evidence underpinning major safety concerns around use of paclitaxel in lower limb angioplasties – increased long-term patient mortality in cases of intermittent claudication,” lead author Konstantinos Katsanos MD, MSc, PhD, Patras University Hospital, Greece, said in an interview.

By contrast, a retrospective study of insurance claims in Germany showed no heightened mortality with paclitaxel-coated balloons and stents, compared with uncoated devices, in close to 38,000 patients with PAD.

On the contrary, use of paclitaxel-coated devices was associated with higher long-term survival, better amputation-free survival (AFS), and lower rates of major cardiovascular events in the treatment of chronic limb-threatening ischemia (CLTI).

These findings “emphasize the difference between population-based evidence and randomized trials,” lead author Christian-Alexander Behrendt, MD, University Medical Center Hamburg-Eppendorf, Germany, said in an interview.

Downstream “showers”

In the new meta-analysis led by Dr. Katsanos, published online Jan. 15, the 1,420 patients were treated with five different DCBs and 97% had CLI (J Vasc Intervent Radiol 2020 Feb;31[2]:202-12).

In up to 1-year follow-up, the paclitaxel DCB group had fewer target lesion revascularizations (TLR) than those of the uncoated device group (11.8% vs. 25.6%; risk ratio, 0.53; 95% confidence interval, 0.35-0.81) but worse AFS (13.7% vs. 9.4%; hazard ratio [HR], 1.52; 95% CI, 1.12-2.07).

The latter finding was driven by nonsignificant increased risks for all-cause death (odds ratio [OR], 1.39; 95% CI, 0.94-2.07) and major amputations (OR, 1.63; 95% CI, 0.92-2.90).

In dose-subgroup analyses, AFS was significantly worse in cases with high-dose (3.0-3.5 mcg/mm²) devices, but not in the single trial with a low-dose DCB (2.0 mcg/mm²).

“Considering the well-described downstream ‘showers’ of paclitaxel particles with current drug-coated balloons, we hypothesize that nontarget paclitaxel embolization is a plausible mechanism for distal foot and systemic toxicity,” Dr. Katsanos said.

Short time frame

Eric Secemsky, MD, of Harvard Medical School, and director of vascular intervention at Beth Israel Deaconess Medical Center, Boston, suggested in an interview that this theorized mechanism of harm in below-the-knee procedures could potentially shed light on a similar mechanism at play in above-the-knee procedures.

“We didn’t understand why people could potentially be dying in above-the-knee [procedures], and the suggestion here is that these devices might perhaps be causing particular embolization or maybe delayed wound healing,” Dr. Secemsky speculated.

However, “I don’t know that this is true, so I am cautious to say this is true,” he emphasized.

Dr. Secemsky said a strength of the Katsanos analysis is that the RCTs included more than 1,000 patients, but noted that it is hard to vet the quality and rigor of the data, as some of the studies have not yet been published. He also noted that paclitaxel-coated devices are not approved by the Food and Drug Administration in the United States for below-the-knee procedures.

Moreover, he continued, “two studies were driving the signal of harm: the IN.PACT DEEP, which included an iteration of their DCB that is no longer being tested; and the unpublished SINGA-PACLI trial. Those studies contributed most of the adverse events seen in this meta-analysis.”

In addition, the trials had different lengths of follow-up (6-12 months), he said. “Thus, the five trials with data available to 12 months are driving the 1-year findings, whereas three RCTs, including the primary RCT showing safety [Lutonix-BTK trial], only contribute data to 6 months.”

For this reason, “we are not too excited about this meta-analysis as of now, [because] all it tells us is that we need more data to support the safety of drug-coated devices in this population,” Dr. Secemsky said.

Dr. Katsanos explained that, “to address the differences in follow-up period and number of cases lost to follow-up, the primary endpoint was calculated on the log-hazard scale and expressed as a hazard ratio, as recommended for time-to-event outcomes.”

He highlighted that a short-term time frame of 6 months to 1 year was chosen “because it is clinically relevant to limb-threatening CLI.”

Sensitivity tests also “showed consistent direction and magnitude of the summary treatment effects in case of both AFS and freedom from TLR,” Dr. Katsanos emphasized.

Lower mortality, fewer amputations

The second study, published online Jan. 8, drew on health insurance claims in the German BARMER database to analyze 37,914 patients (mean age, 73.3 years, 49% female) and 21,546 propensity-score-matched patients with symptomatic CLTI or intermittent claudication (IC) with an index revascularization during 2010-2018 (Eur J Vasc Endovasc Surg. 2020 Jan 8. doi: 10.1016/j.ejvs.2019.12.034).

Patients were first stratified by CLTI or IC, and then by balloon vs. stent use. Paclitaxel-coated devices were then compared with uncoated devices within each stratum. The primary outcome was all-cause mortality at the end of follow-up.

From 2010 to 2018, the annual use of paclitaxel-coated devices increased dramatically from 3% to 39% in the CLTI group and from 4% to 48% in the IC group (P less than .001 for both).

A total of 2,454 deaths occurred within 5 years of follow-up (median, 2.7 years; longest, 8 years).

A Cox proportional hazards model (based on propensity-score-matched cohorts at 5 years) showed that, compared with uncoated devices, use of paclitaxel-coated devices in the CLTI group was associated with several improvements:

• Overall survival: HR, 0.83; 95% CI, 0.77-0.90.
• Amputation-free survival: HR, 0.85; 95% CI, 0.78-0.91.
• Major cardiovascular events: HR, 0.82; 95% CI, 0.77-0.88.

In the IC group, mortality was significantly better with DCB (HR, 0.87; 95% CI, 0.76-0.99) or a combination of DCB and drug-eluting stents (HR, 0.88; 95% CI, 0.80-0.98) than with uncoated devices, but similar for DES alone (HR, 0.91; 95% CI, 0.77-1.08).

No benefit was found for paclitaxel-coated devices in the IC group for AFS (HR, 0.91; 95% CI, 0.82-1.00) or major cardiovascular events (HR, 0.93; 95% CI, 0.87-1.00).

The authors acknowledge that “unmeasured confounding” may partly explain the results. It may be that patients revascularized with DCB or DES “are more likely to be treated in highly specialized trial centers with clear follow-up protocol.”

Moreover, these patients may have received “the best treatment,” including statin therapy, added Dr. Behrendt.

More evidence needed

Dr. Secemsky, who was not involved with either study, said the German investigators “did a wonderful job with this analysis in a large population of several thousand patients, showing nicely that after accounting for differences in comorbidities, the patients had no evidence of harm with [paclitaxel-coated] devices through 5 years.”

However, he cautioned, median follow-up time was just over 2 years. “Although the investigators had data all the way out to 5 years, over time, the number of patients contributing data became smaller, which results in more uncertainty with these longer-term findings,” he said. “As such, we still need to look at additional long-term data in this patient population to confirm the safety of these devices.”

At present, the “major consideration we want to address is whether it’s safe to use these devices, and we’re undertaking these analyses to examine safety, not to see if they improve mortality,” although the present study “has a suggestion of mortality benefit,” Dr. Secemsky said.

Dr. Katsanos added that paclitaxel-coated balloons “remain under investigation for below-knee arteries and critical limb ischemia,” with “a few randomized controlled trials on the way.”

“We need definitive evidence from high-quality multicenter controlled trials that these devices may improve wound healing and limb salvage without any systemic mortality risk,” he said.

Dr. Katsanos receives personal fees from Boston Scientific and Philips Healthcare. The study by Dr. Behrendt was part of the IDOMENEO project funded by the German Joint Federal Committee. Dr. Behrendt reports no relevant financial relationships. Dr. Secemsky reports institutional grants from Cook Medical, BD Bard, Medtronic, Beth Israel Deaconess Medical Center, and Boston Scientific, and reports consultancy for Cook Medical, BD Bard, and Medtronic.
 

This article first appeared on Medscape.com.

SNOWMASS, COLO. – Physical activity is potent medicine, and it doesn’t take all that much of it to derive the maximum cardiovascular benefit: namely, the equivalent of a brisk hour-long walk 5 days/week or jogging at a 10-minute-per-mile pace for half an hour twice weekly, Robert A. Vogel, MD, asserted at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

“I’m not telling you to run marathons. A message for your patients is, ‘You don’t have to do a lot, but you have to do something,’ ” said Dr. Vogel, a cardiologist at the University of Colorado at Denver, Aurora, with a longstanding interest in preventive cardiology.

He presented selected highlights from the massive evidence base underlying the recommendations put forth in the current comprehensive U.S. Department of Health & Human Services Physical Activity Guidelines for Americans.

One particularly compelling chunk of evidence comes from a Taiwanese government–funded prospective cohort study of more than 416,000 individuals followed for an average of 8 years. A key finding: 15 minutes of moderate-intensity physical activity daily was associated with a 14% reduction in the relative risk of all-cause mortality and a 19% reduction in death caused by cardiovascular disease, compared with that of inactive individuals. Moreover, each additional 15 minutes of daily moderate exercise further reduced mortality by 4%. These benefits extended across the full age spectrum of both sexes and applied to patients with cardiovascular disease (Lancet. 2011 Oct 1;378[9798]:1244-53).

“That’s a very impressive result for modest physical activity,” the cardiologist commented.

Data on more than 50,000 adult participants in the Aerobics Center Longitudinal Study based at the Cooper Clinic in Dallas show that vigorous exercise in the form of running at 6 mph for half an hour twice weekly, or a total of 10 metabolic equivalent of task hours (MET-HR) per week, was associated with a roughly 40% reduction in cardiovascular disease mortality. Importantly, 20, 40, or 50 MET-HR/week of vigorous exercise conferred no further survival benefit (J Am Coll Cardiol. 2014 Aug 5;64[5]:472-81). The same group showed that the sweet spot for moderate physical activity in terms of reduced cardiovascular mortality was brisk walking for an hour daily 5 days/week, for a total of 20 MET-HR, which was also associated with roughly a 40% risk reduction compared to inactivity. At that point the benefit plateaued, with no further mortality reduction noted with additional MET-HR of moderate exercise.

“For more than that, we have no evidence of additional cardiovascular benefit. It’s not going to get you to the Tokyo Olympics, but that’s what we need to be doing,” Dr. Vogel observed.

In another report from the Aerobics Center Longitudinal Study, investigators found that moderate-level cardiorespiratory fitness as defined by METs was associated with a 44% reduction in the risk of sudden cardiac death in men and women after adjustment for potential confounders, while high-level cardiorespiratory fitness was associated with a closely similar 48% reduction in risk. This applied to individuals who were hypertensive, overweight, and/or had poor health status, as well as to others (Mayo Clin Proc. 2016 Jul;91[7]:849-57).


 

All activity counts

Exercise physiologists speak of NEPA – nonexercise physical activity – such as taking out the garbage. Swedish investigators followed more than 4,200 individuals for an average of 12.5 years and found that high NEPA activity was independently associated with a 30% reduction in all-cause mortality and a 27% lower risk of a first cardiovascular disease event, compared with low NEPA. High NEPA in regular exercisers was associated with a lower rate of metabolic syndrome than in low-NEPA regular exercisers (Br J Sports Med. 2014 Feb;48[3]:233-8).

Don’t just sit there – stand!

The current federal physical activity guidelines place a new emphasis on the detrimental effects of sitting. A report on more than 221,000 participants in the Australian 45 and Up Study, with close to 1 million person-years of follow-up, demonstrated a linear inverse relationship between standing time per day and all-cause mortality. In a multivariate analysis adjusted for potential confounders, individuals who stood for 2-5 hours per day had a 10% lower risk of all-cause mortality than did those who stood for less than 2 hours. Standing for 5-8 hours was associated with a 15% relative risk reduction. And standing for more than 8 hours daily was linked to a 24% reduction in risk (Prev Med. 2014 Dec;69:187-91).

And it’s not just total daily sitting time that’s a risk factor. Prolonged, uninterrupted sedentary time was also associated with a dose-dependent increase in all-cause mortality in a prospective cohort study of nearly 8,000 U.S. adults (Ann Intern Med. 2017 Oct 3;167[7]:465-75).

“If you can’t walk around, talk to your patients standing up. That activity of getting out of your chair is lifesaving,” the cardiologist advised.
 

Get strong

Muscle-strengthening activity on at least 2 days/week is recommended in the federal guidelines because it’s independently associated with decreased all-cause mortality, even in individuals getting sufficient aerobic exercise, as shown in a large national study with 15-years’ follow-up (Prev Med. 2016 Jun;87:121-127).

“As we get older, we tend to forget about muscle. I work with the National Football League. These folks are pretty strong, but we never see diabetes in these very big players, who are often well over 300 lb. They’ve got a lot of muscle. If you want to prevent diabetes, be strong. It’s a very important factor,” Dr. Vogel said.
 

For the time constrained

Jogging is more time-efficient than brisk walking as a way to attain the maximum cardiovascular benefit of exercise. And the so-called “Weekend Warrior” study of nearly 64,000 U.K. adults showed that it’s okay to cram the full week’s worth of exercise into one or two sessions and be done with it. Compared with the inactive study participants, the weekend warriors had a 40% reduction in cardiovascular disease mortality, while individuals who split their physical activity up into three or more sessions per week had a nearly identical 41% relative risk reduction (JAMA Intern Med. 2017 Mar 1;177[3]:335-42).

Interval training is a standard way for athletes in training to improve their endurance by alternating short, intense exercise with brief recovery periods. It’s also a time saver: In one classic bicycling study, physically active men were randomized to standardized 2-week programs of sprint interval training or high-volume endurance training on the bike. The training time required to pass a rigorous cycling time trial test was 90% lower in the interval training group (J Physiol. 2006 Sep 15;575(Pt 3):901-11).

The same principle is applicable to the nonathlete interested in physical activity for heart health.

“When I run a couple of miles, I walk for 5 minutes, then maybe run for three-quarters of a mile, then walk again, then run. In interval training you get your heart rate up, and you drop it down. It’s a very good form of exercise. As a vascular biologist I know that if you put endothelial cells in a Petri dish and spin them real fast continuously, you will not get as good an improvement in endothelial function as if you spin the dish, stop it, spin it, stop it,” Dr. Vogel said.
 

High-volume exercise is safe, even with high coronary calcium

A clinically significant coronary artery calcification score of 100 Agatston units or more is no reason not to exercise. A Cooper Clinic report on nearly 22,000 middle-aged men without baseline cardiovascular disease who were followed for a mean of 10.4 years concluded that those in the highest-volume exercise group, many of whom were marathon runners and engaged in the equivalent of running for at least 5-6 hours/week at a pace of 10 minutes per mile, were 11% more likely to have an elevated baseline coronary artery calcification score than those who exercised less. But these highest-volume exercisers with elevated coronary calcium – their mean level was 807 Agatston units – had risks of all-cause and cardiovascular mortality that weren’t significantly different from those of men with elevated coronary calcium who exercised more moderately (JAMA Cardiol. 2019 Feb 1;4[2]:174-81).

Cardiac rehab

Dr. Vogel had harsh words for his physician colleagues with respect to the widespread underprescribing of cardiac rehabilitation programs.

“You guys are doing a crappy job with exercise in our most vulnerable patients: those who’ve had cardiovascular events,” he charged. “Cardiac rehabilitation is a Class I recommendation in our guidelines. And yet utilization in the United States is just 10%-20%. No other Class I recommendation is in that ballpark.”

A meta-analysis of 34 randomized trials totaling more than 6,000 post-MI patients concluded that those randomized to exercise-based cardiac rehabilitation had a 47% reduction in the risk of reinfarction, 36% lower cardiac mortality, and a 26% reduction in all-cause mortality (Am Heart J. 2011 Oct;162[4]:571-584.e2).

“The data show that cardiac rehabilitation is as effective as anything else we do in cardiovascular medicine. I understand that patients live far away, they don’t like to exercise – I’ve heard every excuse. But I am charging you with the responsibility of meeting a Class I recommendation that gets patients to live longer,” he declared.

Medicare now covers an enhanced, 72-session program called Intensive Cardiac Rehabilitation that teaches comprehensive lifestyle change and provides reasonable reimbursement. “It’s a good thing for our patients,” Dr. Vogel commented.
 

Yoga

For patients who are reluctant to pound the pavement, yoga may provide an alternative form of physical activity with tangible cardiovascular benefits. Dr. Vogel pointed to the Yoga-CaRe trial presented at the 2018 scientific sessions of the American Heart Association. Yoga-CaRe randomized 3,959 post-MI patients at 29 centers in India to a program of 13 supervised in-hospital yoga classes followed by yoga at home, or to a control group with three educational sessions. The rate of major adverse cardiovascular events over 42 months of follow-up was cut in half, compared with controls, in the 27% of participants who attended at least 10 of the 13 yoga classes. Their quality of life scores were higher, too.

Dr. Vogel reported serving as a paid consultant to the National Football League and the Pritikin Longevity Center. He is on the speaker’s bureau for Sanofi and Regeneron.

bjancin@mdedge.com

SNOWMASS, COLO. – Physical activity is potent medicine, and it doesn’t take all that much of it to derive the maximum cardiovascular benefit: namely, the equivalent of a brisk hour-long walk 5 days/week or jogging at a 10-minute-per-mile pace for half an hour twice weekly, Robert A. Vogel, MD, asserted at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

“I’m not telling you to run marathons. A message for your patients is, ‘You don’t have to do a lot, but you have to do something,’ ” said Dr. Vogel, a cardiologist at the University of Colorado at Denver, Aurora, with a longstanding interest in preventive cardiology.

He presented selected highlights from the massive evidence base underlying the recommendations put forth in the current comprehensive U.S. Department of Health & Human Services Physical Activity Guidelines for Americans.

One particularly compelling chunk of evidence comes from a Taiwanese government–funded prospective cohort study of more than 416,000 individuals followed for an average of 8 years. A key finding: 15 minutes of moderate-intensity physical activity daily was associated with a 14% reduction in the relative risk of all-cause mortality and a 19% reduction in death caused by cardiovascular disease, compared with that of inactive individuals. Moreover, each additional 15 minutes of daily moderate exercise further reduced mortality by 4%. These benefits extended across the full age spectrum of both sexes and applied to patients with cardiovascular disease (Lancet. 2011 Oct 1;378[9798]:1244-53).

“That’s a very impressive result for modest physical activity,” the cardiologist commented.

Data on more than 50,000 adult participants in the Aerobics Center Longitudinal Study based at the Cooper Clinic in Dallas show that vigorous exercise in the form of running at 6 mph for half an hour twice weekly, or a total of 10 metabolic equivalent of task hours (MET-HR) per week, was associated with a roughly 40% reduction in cardiovascular disease mortality. Importantly, 20, 40, or 50 MET-HR/week of vigorous exercise conferred no further survival benefit (J Am Coll Cardiol. 2014 Aug 5;64[5]:472-81). The same group showed that the sweet spot for moderate physical activity in terms of reduced cardiovascular mortality was brisk walking for an hour daily 5 days/week, for a total of 20 MET-HR, which was also associated with roughly a 40% risk reduction compared to inactivity. At that point the benefit plateaued, with no further mortality reduction noted with additional MET-HR of moderate exercise.

“For more than that, we have no evidence of additional cardiovascular benefit. It’s not going to get you to the Tokyo Olympics, but that’s what we need to be doing,” Dr. Vogel observed.

In another report from the Aerobics Center Longitudinal Study, investigators found that moderate-level cardiorespiratory fitness as defined by METs was associated with a 44% reduction in the risk of sudden cardiac death in men and women after adjustment for potential confounders, while high-level cardiorespiratory fitness was associated with a closely similar 48% reduction in risk. This applied to individuals who were hypertensive, overweight, and/or had poor health status, as well as to others (Mayo Clin Proc. 2016 Jul;91[7]:849-57).


 

All activity counts

Exercise physiologists speak of NEPA – nonexercise physical activity – such as taking out the garbage. Swedish investigators followed more than 4,200 individuals for an average of 12.5 years and found that high NEPA activity was independently associated with a 30% reduction in all-cause mortality and a 27% lower risk of a first cardiovascular disease event, compared with low NEPA. High NEPA in regular exercisers was associated with a lower rate of metabolic syndrome than in low-NEPA regular exercisers (Br J Sports Med. 2014 Feb;48[3]:233-8).

Don’t just sit there – stand!

The current federal physical activity guidelines place a new emphasis on the detrimental effects of sitting. A report on more than 221,000 participants in the Australian 45 and Up Study, with close to 1 million person-years of follow-up, demonstrated a linear inverse relationship between standing time per day and all-cause mortality. In a multivariate analysis adjusted for potential confounders, individuals who stood for 2-5 hours per day had a 10% lower risk of all-cause mortality than did those who stood for less than 2 hours. Standing for 5-8 hours was associated with a 15% relative risk reduction. And standing for more than 8 hours daily was linked to a 24% reduction in risk (Prev Med. 2014 Dec;69:187-91).

And it’s not just total daily sitting time that’s a risk factor. Prolonged, uninterrupted sedentary time was also associated with a dose-dependent increase in all-cause mortality in a prospective cohort study of nearly 8,000 U.S. adults (Ann Intern Med. 2017 Oct 3;167[7]:465-75).

“If you can’t walk around, talk to your patients standing up. That activity of getting out of your chair is lifesaving,” the cardiologist advised.
 

Get strong

Muscle-strengthening activity on at least 2 days/week is recommended in the federal guidelines because it’s independently associated with decreased all-cause mortality, even in individuals getting sufficient aerobic exercise, as shown in a large national study with 15-years’ follow-up (Prev Med. 2016 Jun;87:121-127).

“As we get older, we tend to forget about muscle. I work with the National Football League. These folks are pretty strong, but we never see diabetes in these very big players, who are often well over 300 lb. They’ve got a lot of muscle. If you want to prevent diabetes, be strong. It’s a very important factor,” Dr. Vogel said.
 

For the time constrained

Jogging is more time-efficient than brisk walking as a way to attain the maximum cardiovascular benefit of exercise. And the so-called “Weekend Warrior” study of nearly 64,000 U.K. adults showed that it’s okay to cram the full week’s worth of exercise into one or two sessions and be done with it. Compared with the inactive study participants, the weekend warriors had a 40% reduction in cardiovascular disease mortality, while individuals who split their physical activity up into three or more sessions per week had a nearly identical 41% relative risk reduction (JAMA Intern Med. 2017 Mar 1;177[3]:335-42).

Interval training is a standard way for athletes in training to improve their endurance by alternating short, intense exercise with brief recovery periods. It’s also a time saver: In one classic bicycling study, physically active men were randomized to standardized 2-week programs of sprint interval training or high-volume endurance training on the bike. The training time required to pass a rigorous cycling time trial test was 90% lower in the interval training group (J Physiol. 2006 Sep 15;575(Pt 3):901-11).

The same principle is applicable to the nonathlete interested in physical activity for heart health.

“When I run a couple of miles, I walk for 5 minutes, then maybe run for three-quarters of a mile, then walk again, then run. In interval training you get your heart rate up, and you drop it down. It’s a very good form of exercise. As a vascular biologist I know that if you put endothelial cells in a Petri dish and spin them real fast continuously, you will not get as good an improvement in endothelial function as if you spin the dish, stop it, spin it, stop it,” Dr. Vogel said.
 

High-volume exercise is safe, even with high coronary calcium

A clinically significant coronary artery calcification score of 100 Agatston units or more is no reason not to exercise. A Cooper Clinic report on nearly 22,000 middle-aged men without baseline cardiovascular disease who were followed for a mean of 10.4 years concluded that those in the highest-volume exercise group, many of whom were marathon runners and engaged in the equivalent of running for at least 5-6 hours/week at a pace of 10 minutes per mile, were 11% more likely to have an elevated baseline coronary artery calcification score than those who exercised less. But these highest-volume exercisers with elevated coronary calcium – their mean level was 807 Agatston units – had risks of all-cause and cardiovascular mortality that weren’t significantly different from those of men with elevated coronary calcium who exercised more moderately (JAMA Cardiol. 2019 Feb 1;4[2]:174-81).

Cardiac rehab

Dr. Vogel had harsh words for his physician colleagues with respect to the widespread underprescribing of cardiac rehabilitation programs.

“You guys are doing a crappy job with exercise in our most vulnerable patients: those who’ve had cardiovascular events,” he charged. “Cardiac rehabilitation is a Class I recommendation in our guidelines. And yet utilization in the United States is just 10%-20%. No other Class I recommendation is in that ballpark.”

A meta-analysis of 34 randomized trials totaling more than 6,000 post-MI patients concluded that those randomized to exercise-based cardiac rehabilitation had a 47% reduction in the risk of reinfarction, 36% lower cardiac mortality, and a 26% reduction in all-cause mortality (Am Heart J. 2011 Oct;162[4]:571-584.e2).

“The data show that cardiac rehabilitation is as effective as anything else we do in cardiovascular medicine. I understand that patients live far away, they don’t like to exercise – I’ve heard every excuse. But I am charging you with the responsibility of meeting a Class I recommendation that gets patients to live longer,” he declared.

Medicare now covers an enhanced, 72-session program called Intensive Cardiac Rehabilitation that teaches comprehensive lifestyle change and provides reasonable reimbursement. “It’s a good thing for our patients,” Dr. Vogel commented.
 

Yoga

For patients who are reluctant to pound the pavement, yoga may provide an alternative form of physical activity with tangible cardiovascular benefits. Dr. Vogel pointed to the Yoga-CaRe trial presented at the 2018 scientific sessions of the American Heart Association. Yoga-CaRe randomized 3,959 post-MI patients at 29 centers in India to a program of 13 supervised in-hospital yoga classes followed by yoga at home, or to a control group with three educational sessions. The rate of major adverse cardiovascular events over 42 months of follow-up was cut in half, compared with controls, in the 27% of participants who attended at least 10 of the 13 yoga classes. Their quality of life scores were higher, too.

Dr. Vogel reported serving as a paid consultant to the National Football League and the Pritikin Longevity Center. He is on the speaker’s bureau for Sanofi and Regeneron.

bjancin@mdedge.com

SNOWMASS, COLO. – Physical activity is potent medicine, and it doesn’t take all that much of it to derive the maximum cardiovascular benefit: namely, the equivalent of a brisk hour-long walk 5 days/week or jogging at a 10-minute-per-mile pace for half an hour twice weekly, Robert A. Vogel, MD, asserted at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

“I’m not telling you to run marathons. A message for your patients is, ‘You don’t have to do a lot, but you have to do something,’ ” said Dr. Vogel, a cardiologist at the University of Colorado at Denver, Aurora, with a longstanding interest in preventive cardiology.

He presented selected highlights from the massive evidence base underlying the recommendations put forth in the current comprehensive U.S. Department of Health & Human Services Physical Activity Guidelines for Americans.

One particularly compelling chunk of evidence comes from a Taiwanese government–funded prospective cohort study of more than 416,000 individuals followed for an average of 8 years. A key finding: 15 minutes of moderate-intensity physical activity daily was associated with a 14% reduction in the relative risk of all-cause mortality and a 19% reduction in death caused by cardiovascular disease, compared with that of inactive individuals. Moreover, each additional 15 minutes of daily moderate exercise further reduced mortality by 4%. These benefits extended across the full age spectrum of both sexes and applied to patients with cardiovascular disease (Lancet. 2011 Oct 1;378[9798]:1244-53).

“That’s a very impressive result for modest physical activity,” the cardiologist commented.

Data on more than 50,000 adult participants in the Aerobics Center Longitudinal Study based at the Cooper Clinic in Dallas show that vigorous exercise in the form of running at 6 mph for half an hour twice weekly, or a total of 10 metabolic equivalent of task hours (MET-HR) per week, was associated with a roughly 40% reduction in cardiovascular disease mortality. Importantly, 20, 40, or 50 MET-HR/week of vigorous exercise conferred no further survival benefit (J Am Coll Cardiol. 2014 Aug 5;64[5]:472-81). The same group showed that the sweet spot for moderate physical activity in terms of reduced cardiovascular mortality was brisk walking for an hour daily 5 days/week, for a total of 20 MET-HR, which was also associated with roughly a 40% risk reduction compared to inactivity. At that point the benefit plateaued, with no further mortality reduction noted with additional MET-HR of moderate exercise.

“For more than that, we have no evidence of additional cardiovascular benefit. It’s not going to get you to the Tokyo Olympics, but that’s what we need to be doing,” Dr. Vogel observed.

In another report from the Aerobics Center Longitudinal Study, investigators found that moderate-level cardiorespiratory fitness as defined by METs was associated with a 44% reduction in the risk of sudden cardiac death in men and women after adjustment for potential confounders, while high-level cardiorespiratory fitness was associated with a closely similar 48% reduction in risk. This applied to individuals who were hypertensive, overweight, and/or had poor health status, as well as to others (Mayo Clin Proc. 2016 Jul;91[7]:849-57).


 

All activity counts

Exercise physiologists speak of NEPA – nonexercise physical activity – such as taking out the garbage. Swedish investigators followed more than 4,200 individuals for an average of 12.5 years and found that high NEPA activity was independently associated with a 30% reduction in all-cause mortality and a 27% lower risk of a first cardiovascular disease event, compared with low NEPA. High NEPA in regular exercisers was associated with a lower rate of metabolic syndrome than in low-NEPA regular exercisers (Br J Sports Med. 2014 Feb;48[3]:233-8).

Don’t just sit there – stand!

The current federal physical activity guidelines place a new emphasis on the detrimental effects of sitting. A report on more than 221,000 participants in the Australian 45 and Up Study, with close to 1 million person-years of follow-up, demonstrated a linear inverse relationship between standing time per day and all-cause mortality. In a multivariate analysis adjusted for potential confounders, individuals who stood for 2-5 hours per day had a 10% lower risk of all-cause mortality than did those who stood for less than 2 hours. Standing for 5-8 hours was associated with a 15% relative risk reduction. And standing for more than 8 hours daily was linked to a 24% reduction in risk (Prev Med. 2014 Dec;69:187-91).

And it’s not just total daily sitting time that’s a risk factor. Prolonged, uninterrupted sedentary time was also associated with a dose-dependent increase in all-cause mortality in a prospective cohort study of nearly 8,000 U.S. adults (Ann Intern Med. 2017 Oct 3;167[7]:465-75).

“If you can’t walk around, talk to your patients standing up. That activity of getting out of your chair is lifesaving,” the cardiologist advised.
 

Get strong

Muscle-strengthening activity on at least 2 days/week is recommended in the federal guidelines because it’s independently associated with decreased all-cause mortality, even in individuals getting sufficient aerobic exercise, as shown in a large national study with 15-years’ follow-up (Prev Med. 2016 Jun;87:121-127).

“As we get older, we tend to forget about muscle. I work with the National Football League. These folks are pretty strong, but we never see diabetes in these very big players, who are often well over 300 lb. They’ve got a lot of muscle. If you want to prevent diabetes, be strong. It’s a very important factor,” Dr. Vogel said.
 

For the time constrained

Jogging is more time-efficient than brisk walking as a way to attain the maximum cardiovascular benefit of exercise. And the so-called “Weekend Warrior” study of nearly 64,000 U.K. adults showed that it’s okay to cram the full week’s worth of exercise into one or two sessions and be done with it. Compared with the inactive study participants, the weekend warriors had a 40% reduction in cardiovascular disease mortality, while individuals who split their physical activity up into three or more sessions per week had a nearly identical 41% relative risk reduction (JAMA Intern Med. 2017 Mar 1;177[3]:335-42).

Interval training is a standard way for athletes in training to improve their endurance by alternating short, intense exercise with brief recovery periods. It’s also a time saver: In one classic bicycling study, physically active men were randomized to standardized 2-week programs of sprint interval training or high-volume endurance training on the bike. The training time required to pass a rigorous cycling time trial test was 90% lower in the interval training group (J Physiol. 2006 Sep 15;575(Pt 3):901-11).

The same principle is applicable to the nonathlete interested in physical activity for heart health.

“When I run a couple of miles, I walk for 5 minutes, then maybe run for three-quarters of a mile, then walk again, then run. In interval training you get your heart rate up, and you drop it down. It’s a very good form of exercise. As a vascular biologist I know that if you put endothelial cells in a Petri dish and spin them real fast continuously, you will not get as good an improvement in endothelial function as if you spin the dish, stop it, spin it, stop it,” Dr. Vogel said.
 

High-volume exercise is safe, even with high coronary calcium

A clinically significant coronary artery calcification score of 100 Agatston units or more is no reason not to exercise. A Cooper Clinic report on nearly 22,000 middle-aged men without baseline cardiovascular disease who were followed for a mean of 10.4 years concluded that those in the highest-volume exercise group, many of whom were marathon runners and engaged in the equivalent of running for at least 5-6 hours/week at a pace of 10 minutes per mile, were 11% more likely to have an elevated baseline coronary artery calcification score than those who exercised less. But these highest-volume exercisers with elevated coronary calcium – their mean level was 807 Agatston units – had risks of all-cause and cardiovascular mortality that weren’t significantly different from those of men with elevated coronary calcium who exercised more moderately (JAMA Cardiol. 2019 Feb 1;4[2]:174-81).

Cardiac rehab

Dr. Vogel had harsh words for his physician colleagues with respect to the widespread underprescribing of cardiac rehabilitation programs.

“You guys are doing a crappy job with exercise in our most vulnerable patients: those who’ve had cardiovascular events,” he charged. “Cardiac rehabilitation is a Class I recommendation in our guidelines. And yet utilization in the United States is just 10%-20%. No other Class I recommendation is in that ballpark.”

A meta-analysis of 34 randomized trials totaling more than 6,000 post-MI patients concluded that those randomized to exercise-based cardiac rehabilitation had a 47% reduction in the risk of reinfarction, 36% lower cardiac mortality, and a 26% reduction in all-cause mortality (Am Heart J. 2011 Oct;162[4]:571-584.e2).

“The data show that cardiac rehabilitation is as effective as anything else we do in cardiovascular medicine. I understand that patients live far away, they don’t like to exercise – I’ve heard every excuse. But I am charging you with the responsibility of meeting a Class I recommendation that gets patients to live longer,” he declared.

Medicare now covers an enhanced, 72-session program called Intensive Cardiac Rehabilitation that teaches comprehensive lifestyle change and provides reasonable reimbursement. “It’s a good thing for our patients,” Dr. Vogel commented.
 

Yoga

For patients who are reluctant to pound the pavement, yoga may provide an alternative form of physical activity with tangible cardiovascular benefits. Dr. Vogel pointed to the Yoga-CaRe trial presented at the 2018 scientific sessions of the American Heart Association. Yoga-CaRe randomized 3,959 post-MI patients at 29 centers in India to a program of 13 supervised in-hospital yoga classes followed by yoga at home, or to a control group with three educational sessions. The rate of major adverse cardiovascular events over 42 months of follow-up was cut in half, compared with controls, in the 27% of participants who attended at least 10 of the 13 yoga classes. Their quality of life scores were higher, too.

Dr. Vogel reported serving as a paid consultant to the National Football League and the Pritikin Longevity Center. He is on the speaker’s bureau for Sanofi and Regeneron.

bjancin@mdedge.com

When people learn they have enough cardiovascular disease risk to start treatment with a statin or antihypertensive drug, the impact on their healthy-lifestyle choices seems to often be a wash, based on findings from more than 40,000 Finland residents followed for at least 4 years after starting their primary-prevention regimen.

American Heart Association

“Patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” wrote Maarit J. Korhonen, PhD, and associates in a report published in the Journal of the American Heart Association.

“Initiation of antihypertensive or statin therapy appears to be associated with lifestyle changes, some positive and others negative,” wrote Dr. Korhonen, a pharmacoepidemiologist at the University of Turku (Finland), and associates. This was the first reported study to assess a large-scale and prospectively followed cohort to look for associations between the use of medicines that prevent cardiovascular disease (CVD) and lifestyle changes. Most previous studies of these associations “have been cross sectional and provide no information on potential lifestyle changes during the time window around the initiation of medication use,” they added.

The new study specifically found that, on average, people who began treatment with at least one CVD-prevention medication for the first time were more likely to gain weight and more likely to become less active during the years following their treatment onset. But at the same time, these patients were also more likely to either quit or cut down on their smoking and alcohol consumption, the researchers found.

Their analysis used data from 41,225 people enrolled in the Finnish Public Sector Study, which prospectively began collecting data on a large number of Finland residents in the 1990s. They specifically focused on 81,772 completed questionnaires – collected at 4-year intervals – from people who completed at least two consecutive rounds of the survey during 2000-2013, and who were also at least 40 years old and free of prevalent CVD at the time of their first survey. The participants averaged nearly 53 years of age at their first survey, and 84% were women.

The researchers subdivided the survey responses into 8,837 (11%) people who began a statin, antihypertensive drug, or both during their participation; 26,914 (33%) already on a statin or antihypertensive drug when they completed their first questionnaire; and 46,021 response sets (56%) from people who never began treatment with either drug class. People who initiated a relevant drug began a median of 1.7 years following completion of their first survey, and a median of 2.4 years before their next survey. During follow-up, about 2% of all participants became newly diagnosed with some form of CVD.

The results showed that, after full adjustment for possible confounders, the mean increase in body mass index was larger among those who initiated a CVD-prevention drug, compared with those who did not. Among participants who were obese at entry, those who started a CVD drug had a statistically significant 37% increased rate of remaining obese, compared with those not starting these drugs. Among those who were not obese at baseline, those who began a CVD prevention drug had a statistically significant 82%% higher rate of becoming obese, compared with those not on a CVD-prevention drug. In addition, average daily energy expenditure, a measure of physical activity, showed a statistically significant decline among those who started a CVD drug, compared with those who did not. In contrast, CVD drug initiators had an average 1.85 gram/week decline in alcohol intake, compared with noninitiators, and those who were current smokers at the first survey and then started a CVD drug had a 26% relative drop in their smoking prevalence, compared with those who did not start a CVD drug, both statistically significant differences.

The findings suggest that “patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” the authors concluded. “This means that expansion of pharmacologic interventions toward populations at low CVD risk may not necessarily lead to expected benefits at the population level.”

The study received no commercial funding. Dr. Korhonen had no disclosures.

mzoler@mdedge.com

SOURCE: Korhonen MJ et al. J Am Heart Assoc. 2020 Feb 5. doi: 10.1161/JAHA.119.014.168.

When people learn they have enough cardiovascular disease risk to start treatment with a statin or antihypertensive drug, the impact on their healthy-lifestyle choices seems to often be a wash, based on findings from more than 40,000 Finland residents followed for at least 4 years after starting their primary-prevention regimen.

American Heart Association

“Patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” wrote Maarit J. Korhonen, PhD, and associates in a report published in the Journal of the American Heart Association.

“Initiation of antihypertensive or statin therapy appears to be associated with lifestyle changes, some positive and others negative,” wrote Dr. Korhonen, a pharmacoepidemiologist at the University of Turku (Finland), and associates. This was the first reported study to assess a large-scale and prospectively followed cohort to look for associations between the use of medicines that prevent cardiovascular disease (CVD) and lifestyle changes. Most previous studies of these associations “have been cross sectional and provide no information on potential lifestyle changes during the time window around the initiation of medication use,” they added.

The new study specifically found that, on average, people who began treatment with at least one CVD-prevention medication for the first time were more likely to gain weight and more likely to become less active during the years following their treatment onset. But at the same time, these patients were also more likely to either quit or cut down on their smoking and alcohol consumption, the researchers found.

Their analysis used data from 41,225 people enrolled in the Finnish Public Sector Study, which prospectively began collecting data on a large number of Finland residents in the 1990s. They specifically focused on 81,772 completed questionnaires – collected at 4-year intervals – from people who completed at least two consecutive rounds of the survey during 2000-2013, and who were also at least 40 years old and free of prevalent CVD at the time of their first survey. The participants averaged nearly 53 years of age at their first survey, and 84% were women.

The researchers subdivided the survey responses into 8,837 (11%) people who began a statin, antihypertensive drug, or both during their participation; 26,914 (33%) already on a statin or antihypertensive drug when they completed their first questionnaire; and 46,021 response sets (56%) from people who never began treatment with either drug class. People who initiated a relevant drug began a median of 1.7 years following completion of their first survey, and a median of 2.4 years before their next survey. During follow-up, about 2% of all participants became newly diagnosed with some form of CVD.

The results showed that, after full adjustment for possible confounders, the mean increase in body mass index was larger among those who initiated a CVD-prevention drug, compared with those who did not. Among participants who were obese at entry, those who started a CVD drug had a statistically significant 37% increased rate of remaining obese, compared with those not starting these drugs. Among those who were not obese at baseline, those who began a CVD prevention drug had a statistically significant 82%% higher rate of becoming obese, compared with those not on a CVD-prevention drug. In addition, average daily energy expenditure, a measure of physical activity, showed a statistically significant decline among those who started a CVD drug, compared with those who did not. In contrast, CVD drug initiators had an average 1.85 gram/week decline in alcohol intake, compared with noninitiators, and those who were current smokers at the first survey and then started a CVD drug had a 26% relative drop in their smoking prevalence, compared with those who did not start a CVD drug, both statistically significant differences.

The findings suggest that “patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” the authors concluded. “This means that expansion of pharmacologic interventions toward populations at low CVD risk may not necessarily lead to expected benefits at the population level.”

The study received no commercial funding. Dr. Korhonen had no disclosures.

mzoler@mdedge.com

SOURCE: Korhonen MJ et al. J Am Heart Assoc. 2020 Feb 5. doi: 10.1161/JAHA.119.014.168.

When people learn they have enough cardiovascular disease risk to start treatment with a statin or antihypertensive drug, the impact on their healthy-lifestyle choices seems to often be a wash, based on findings from more than 40,000 Finland residents followed for at least 4 years after starting their primary-prevention regimen.

American Heart Association

“Patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” wrote Maarit J. Korhonen, PhD, and associates in a report published in the Journal of the American Heart Association.

“Initiation of antihypertensive or statin therapy appears to be associated with lifestyle changes, some positive and others negative,” wrote Dr. Korhonen, a pharmacoepidemiologist at the University of Turku (Finland), and associates. This was the first reported study to assess a large-scale and prospectively followed cohort to look for associations between the use of medicines that prevent cardiovascular disease (CVD) and lifestyle changes. Most previous studies of these associations “have been cross sectional and provide no information on potential lifestyle changes during the time window around the initiation of medication use,” they added.

The new study specifically found that, on average, people who began treatment with at least one CVD-prevention medication for the first time were more likely to gain weight and more likely to become less active during the years following their treatment onset. But at the same time, these patients were also more likely to either quit or cut down on their smoking and alcohol consumption, the researchers found.

Their analysis used data from 41,225 people enrolled in the Finnish Public Sector Study, which prospectively began collecting data on a large number of Finland residents in the 1990s. They specifically focused on 81,772 completed questionnaires – collected at 4-year intervals – from people who completed at least two consecutive rounds of the survey during 2000-2013, and who were also at least 40 years old and free of prevalent CVD at the time of their first survey. The participants averaged nearly 53 years of age at their first survey, and 84% were women.

The researchers subdivided the survey responses into 8,837 (11%) people who began a statin, antihypertensive drug, or both during their participation; 26,914 (33%) already on a statin or antihypertensive drug when they completed their first questionnaire; and 46,021 response sets (56%) from people who never began treatment with either drug class. People who initiated a relevant drug began a median of 1.7 years following completion of their first survey, and a median of 2.4 years before their next survey. During follow-up, about 2% of all participants became newly diagnosed with some form of CVD.

The results showed that, after full adjustment for possible confounders, the mean increase in body mass index was larger among those who initiated a CVD-prevention drug, compared with those who did not. Among participants who were obese at entry, those who started a CVD drug had a statistically significant 37% increased rate of remaining obese, compared with those not starting these drugs. Among those who were not obese at baseline, those who began a CVD prevention drug had a statistically significant 82%% higher rate of becoming obese, compared with those not on a CVD-prevention drug. In addition, average daily energy expenditure, a measure of physical activity, showed a statistically significant decline among those who started a CVD drug, compared with those who did not. In contrast, CVD drug initiators had an average 1.85 gram/week decline in alcohol intake, compared with noninitiators, and those who were current smokers at the first survey and then started a CVD drug had a 26% relative drop in their smoking prevalence, compared with those who did not start a CVD drug, both statistically significant differences.

The findings suggest that “patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” the authors concluded. “This means that expansion of pharmacologic interventions toward populations at low CVD risk may not necessarily lead to expected benefits at the population level.”

The study received no commercial funding. Dr. Korhonen had no disclosures.

mzoler@mdedge.com

SOURCE: Korhonen MJ et al. J Am Heart Assoc. 2020 Feb 5. doi: 10.1161/JAHA.119.014.168.

SNOWMASS, COLO. – The concept that silent myocardial ischemia is clinically detrimental has fallen by the wayside, and routine screening for this phenomenon can no longer be recommended, Patrick T. O’Gara, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

What a difference a decade or 2 can make.

“Think about where we were 25 years ago, when we worried about people who had transient ST-segment depression without angina on Holter monitoring. We would wig out, chase them down the street, try to tackle them and load them up with medications and think about balloon [percutaneous transluminal coronary angioplasty]. And now we’re at the point where it doesn’t seem to help with respect to quality of life, let alone death or myocardial infarction,” observed Dr. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.

The end of the line for the now-discredited notion that silent ischemia carries clinical significance approaching that of ischemia plus angina pectoris was the landmark ISCHEMIA trial, reported in November 2019 at the annual scientific sessions of the American Heart Association. This randomized trial asked the question: Is there any high-risk subgroup of patients with stable ischemic heart disease not involving the left main coronary artery for whom a strategy of routine revascularization improves hard outcomes in the current era of highly effective, guideline-directed medical therapy?

The answer turned out to be no. At 5 years of follow-up of 5,179 randomized patients with baseline stable coronary artery disease (CAD) and rigorously determined baseline moderate or severe ischemia affecting more than 10% of the myocardium, there was no difference between patients randomized to routine revascularization plus optimal medical therapy versus those on optimal medical therapy alone in the primary combined outcome of cardiovascular death, MI, heart failure, cardiac arrest, or hospitalization for unstable angina.

Of note, 35% of participants in the ISCHEMIA trial had moderate or severe silent ischemia. Like those who had angina, they achieved no additional benefit from a strategy of routine revascularization in terms of the primary outcome. ISCHEMIA participants with angina did show significant and durable improvements in quality of life and angina control with routine revascularization; however, those with silent ischemia showed little or no such improvement with an invasive strategy.

That being said, Dr. O’Gara added that he supports the ISCHEMIA investigators’ efforts to obtain funding from the National Institutes of Health for another 5 years or so of follow-up in order to determine whether revascularization actually does lead to improvement in the hard outcomes.

“Remember, in the STICH trial it took 10 years to show superiority of CABG [coronary artery bypass surgery] versus medical therapy to treat ischemic cardiomyopathy [N Engl J Med 2016; 374:1511-20]. My own view is that it’s too premature to throw the baby out with the bathwater. I think shared decision making is still very important, and I think, for many of our patients, relief of angina and improved quality of life are legitimate reasons in a low-risk situation with a good interventionalist to proceed,” he said.

Dr. O’Gara traced the history of medical thinking about silent ischemia. The notion that silent ischemia carried a clinical significance comparable with ischemia with angina gained wide credence more than 30 years ago, when investigators from the National Institutes of Health–sponsored Coronary Artery Surgery Study registry reported: “Patients with either silent or symptomatic ischemia during exercise testing have a similar risk of developing an acute myocardial infarction or sudden death – except in the three-vessel CAD subgroup, where the risk is greater in silent ischemia” (Am J Cardiol. 1988 Dec 1;62[17]:1155-8).

“This was a very important observation and led to many, many recommendations about screening and making sure that you took the expression of ST-segment depression on exercise treadmill testing pretty seriously, even if your patient did not have angina,” Dr. O’Gara recalled.

The prevailing wisdom that silent ischemia was detrimental took a hit in the Detection of Ischemia in Asymptomatic Diabetics (DIAC) trial. DIAC was conducted at a time when it had become clear that type 2 diabetes was a condition associated with increased cardiovascular risk, and that various methods of imaging were more accurate than treadmill exercise testing for the detection of underlying CAD. But when 1,123 DIAC participants with type 2 diabetes were randomized to screening with adenosine-stress radionuclide myocardial perfusion imaging or not and prospectively followed for roughly 5 years, it turned out there was no between-group difference in cardiac death or MI (JAMA. 2009 Apr 15;301[15]:1547-55).

“This pretty much put the lid on going out of one’s way to do routine screening of this nature in persons with diabetes who were considered to be at higher than average risk for the development of coronary disease,” the cardiologist commented.

Another fissure in the idea that silent ischemia was worth searching for and treating came from CLARIFY, an observational international registry of more than 20,000 individuals with stable CAD, roughly 12% of whom had silent ischemia, a figure in line with the prevalence reported in other studies. The 2-year rate of cardiovascular death or MI in the group with silent ischemia didn’t differ from the rate in patients with neither angina nor provocable ischemia. In contrast, rates of cardiovascular death or MI were significantly higher in the groups with angina but no ischemia or angina with ischemia (JAMA Intern Med. 2014 Oct;174[10]:1651-9).

“There’s something about the expression of angina that’s a very key clinical marker,” Dr. O’Gara observed.

He noted that just a few months before the ISCHEMIA trial results were released, a report from the far-smaller, randomized second Medicine, Angioplasty, or Surgery Study “threw cold water” on the notion that stress-induced ischemia in patients with multivessel CAD is a bad thing. Over 10 years of follow-up, the risk of major adverse cardiovascular events or deterioration in left ventricular function was identical in patients with or without baseline ischemia on stress testing performed after percutaneous coronary intervention, CABG surgery, or initiation of medical therapy (JAMA Intern Med. 2019 Jul 22. doi: 10.1001/jamainternmed.2019.2227).
 

What the guidelines say

The 6-year-old U.S. guidelines on the diagnosis and management of patients with stable ischemic heart disease are clearly out of date on the topic of silent ischemia (Circulation. 2014 Nov 4;130[19]:1749-67). The recommendations are based on expert opinion formed prior to the massive amount of new evidence that has since become available. For example, the current guidelines state as a class IIa, level of evidence C recommendation that exercise or pharmacologic stress can be useful for follow-up assessment at 2-year or greater intervals in patients with stable ischemic heart disease with prior evidence of silent ischemia.

“This is a very weak recommendation. The class of recommendation says it would be reasonable, but in the absence of an evidence base and in light of newer information, I’m not sure that it approaches even a class IIa level of recommendation,” according to Dr. O’Gara.

The 2019 European Society of Cardiology guidelines on chronic coronary syndromes are similarly weak on silent ischemia. The European guidelines state that patients with diabetes or chronic kidney disease may have a higher burden of silent ischemia, might be at higher risk for atherosclerotic cardiovascular disease events, and that periodic ECGs and functional testing every 3-5 years might be considered.

“Obviously there’s a lot of leeway there in how you wish to interpret that,” Dr. O’Gara said. “And this did not rise to the level where they’d put it in the table of recommendations, but it’s simply included as part of the explanatory text.”
 

What’s coming next in stable ischemic heart disease

“Nowadays all the rage has to do with coronary microvascular dysfunction,” according to Dr. O’Gara. “I think all of the research interest currently is focused on the coronary microcirculation as perhaps the next frontier in our understanding of why it is that ischemia can occur in the absence of epicardial coronary disease.”

He highly recommended a review article entitled: “Reappraisal of Ischemic Heart Disease,” in which an international trio of prominent cardiologists asserted that coronary microvascular dysfunction not only plays a pivotal pathogenic role in angina pectoris, but also in a phenomenon known as microvascular angina – that is, angina in the absence of obstructive CAD. Microvascular angina may explain the roughly one-third of patients who experience acute coronary syndrome without epicardial coronary artery stenosis or thrombosis. The authors delved into the structural and functional mechanisms underlying coronary microvascular dysfunction, while noting that effective treatment of this common phenomenon remains a major unmet need (Circulation. 2018 Oct 2;138[14]:1463-80).

Dr. O’Gara reported receiving funding from the National Heart, Lung, and Blood Institute; from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial; from Edwards Lifesciences for the ongoing EARLY TAVR trial; and from Medtrace Pharma, a Danish company developing an innovative form of PET diagnostic imaging.

bjancin@mdedge.com

SNOWMASS, COLO. – The concept that silent myocardial ischemia is clinically detrimental has fallen by the wayside, and routine screening for this phenomenon can no longer be recommended, Patrick T. O’Gara, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

What a difference a decade or 2 can make.

“Think about where we were 25 years ago, when we worried about people who had transient ST-segment depression without angina on Holter monitoring. We would wig out, chase them down the street, try to tackle them and load them up with medications and think about balloon [percutaneous transluminal coronary angioplasty]. And now we’re at the point where it doesn’t seem to help with respect to quality of life, let alone death or myocardial infarction,” observed Dr. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.

The end of the line for the now-discredited notion that silent ischemia carries clinical significance approaching that of ischemia plus angina pectoris was the landmark ISCHEMIA trial, reported in November 2019 at the annual scientific sessions of the American Heart Association. This randomized trial asked the question: Is there any high-risk subgroup of patients with stable ischemic heart disease not involving the left main coronary artery for whom a strategy of routine revascularization improves hard outcomes in the current era of highly effective, guideline-directed medical therapy?

The answer turned out to be no. At 5 years of follow-up of 5,179 randomized patients with baseline stable coronary artery disease (CAD) and rigorously determined baseline moderate or severe ischemia affecting more than 10% of the myocardium, there was no difference between patients randomized to routine revascularization plus optimal medical therapy versus those on optimal medical therapy alone in the primary combined outcome of cardiovascular death, MI, heart failure, cardiac arrest, or hospitalization for unstable angina.

Of note, 35% of participants in the ISCHEMIA trial had moderate or severe silent ischemia. Like those who had angina, they achieved no additional benefit from a strategy of routine revascularization in terms of the primary outcome. ISCHEMIA participants with angina did show significant and durable improvements in quality of life and angina control with routine revascularization; however, those with silent ischemia showed little or no such improvement with an invasive strategy.

That being said, Dr. O’Gara added that he supports the ISCHEMIA investigators’ efforts to obtain funding from the National Institutes of Health for another 5 years or so of follow-up in order to determine whether revascularization actually does lead to improvement in the hard outcomes.

“Remember, in the STICH trial it took 10 years to show superiority of CABG [coronary artery bypass surgery] versus medical therapy to treat ischemic cardiomyopathy [N Engl J Med 2016; 374:1511-20]. My own view is that it’s too premature to throw the baby out with the bathwater. I think shared decision making is still very important, and I think, for many of our patients, relief of angina and improved quality of life are legitimate reasons in a low-risk situation with a good interventionalist to proceed,” he said.

Dr. O’Gara traced the history of medical thinking about silent ischemia. The notion that silent ischemia carried a clinical significance comparable with ischemia with angina gained wide credence more than 30 years ago, when investigators from the National Institutes of Health–sponsored Coronary Artery Surgery Study registry reported: “Patients with either silent or symptomatic ischemia during exercise testing have a similar risk of developing an acute myocardial infarction or sudden death – except in the three-vessel CAD subgroup, where the risk is greater in silent ischemia” (Am J Cardiol. 1988 Dec 1;62[17]:1155-8).

“This was a very important observation and led to many, many recommendations about screening and making sure that you took the expression of ST-segment depression on exercise treadmill testing pretty seriously, even if your patient did not have angina,” Dr. O’Gara recalled.

The prevailing wisdom that silent ischemia was detrimental took a hit in the Detection of Ischemia in Asymptomatic Diabetics (DIAC) trial. DIAC was conducted at a time when it had become clear that type 2 diabetes was a condition associated with increased cardiovascular risk, and that various methods of imaging were more accurate than treadmill exercise testing for the detection of underlying CAD. But when 1,123 DIAC participants with type 2 diabetes were randomized to screening with adenosine-stress radionuclide myocardial perfusion imaging or not and prospectively followed for roughly 5 years, it turned out there was no between-group difference in cardiac death or MI (JAMA. 2009 Apr 15;301[15]:1547-55).

“This pretty much put the lid on going out of one’s way to do routine screening of this nature in persons with diabetes who were considered to be at higher than average risk for the development of coronary disease,” the cardiologist commented.

Another fissure in the idea that silent ischemia was worth searching for and treating came from CLARIFY, an observational international registry of more than 20,000 individuals with stable CAD, roughly 12% of whom had silent ischemia, a figure in line with the prevalence reported in other studies. The 2-year rate of cardiovascular death or MI in the group with silent ischemia didn’t differ from the rate in patients with neither angina nor provocable ischemia. In contrast, rates of cardiovascular death or MI were significantly higher in the groups with angina but no ischemia or angina with ischemia (JAMA Intern Med. 2014 Oct;174[10]:1651-9).

“There’s something about the expression of angina that’s a very key clinical marker,” Dr. O’Gara observed.

He noted that just a few months before the ISCHEMIA trial results were released, a report from the far-smaller, randomized second Medicine, Angioplasty, or Surgery Study “threw cold water” on the notion that stress-induced ischemia in patients with multivessel CAD is a bad thing. Over 10 years of follow-up, the risk of major adverse cardiovascular events or deterioration in left ventricular function was identical in patients with or without baseline ischemia on stress testing performed after percutaneous coronary intervention, CABG surgery, or initiation of medical therapy (JAMA Intern Med. 2019 Jul 22. doi: 10.1001/jamainternmed.2019.2227).
 

What the guidelines say

The 6-year-old U.S. guidelines on the diagnosis and management of patients with stable ischemic heart disease are clearly out of date on the topic of silent ischemia (Circulation. 2014 Nov 4;130[19]:1749-67). The recommendations are based on expert opinion formed prior to the massive amount of new evidence that has since become available. For example, the current guidelines state as a class IIa, level of evidence C recommendation that exercise or pharmacologic stress can be useful for follow-up assessment at 2-year or greater intervals in patients with stable ischemic heart disease with prior evidence of silent ischemia.

“This is a very weak recommendation. The class of recommendation says it would be reasonable, but in the absence of an evidence base and in light of newer information, I’m not sure that it approaches even a class IIa level of recommendation,” according to Dr. O’Gara.

The 2019 European Society of Cardiology guidelines on chronic coronary syndromes are similarly weak on silent ischemia. The European guidelines state that patients with diabetes or chronic kidney disease may have a higher burden of silent ischemia, might be at higher risk for atherosclerotic cardiovascular disease events, and that periodic ECGs and functional testing every 3-5 years might be considered.

“Obviously there’s a lot of leeway there in how you wish to interpret that,” Dr. O’Gara said. “And this did not rise to the level where they’d put it in the table of recommendations, but it’s simply included as part of the explanatory text.”
 

What’s coming next in stable ischemic heart disease

“Nowadays all the rage has to do with coronary microvascular dysfunction,” according to Dr. O’Gara. “I think all of the research interest currently is focused on the coronary microcirculation as perhaps the next frontier in our understanding of why it is that ischemia can occur in the absence of epicardial coronary disease.”

He highly recommended a review article entitled: “Reappraisal of Ischemic Heart Disease,” in which an international trio of prominent cardiologists asserted that coronary microvascular dysfunction not only plays a pivotal pathogenic role in angina pectoris, but also in a phenomenon known as microvascular angina – that is, angina in the absence of obstructive CAD. Microvascular angina may explain the roughly one-third of patients who experience acute coronary syndrome without epicardial coronary artery stenosis or thrombosis. The authors delved into the structural and functional mechanisms underlying coronary microvascular dysfunction, while noting that effective treatment of this common phenomenon remains a major unmet need (Circulation. 2018 Oct 2;138[14]:1463-80).

Dr. O’Gara reported receiving funding from the National Heart, Lung, and Blood Institute; from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial; from Edwards Lifesciences for the ongoing EARLY TAVR trial; and from Medtrace Pharma, a Danish company developing an innovative form of PET diagnostic imaging.

bjancin@mdedge.com

SNOWMASS, COLO. – The concept that silent myocardial ischemia is clinically detrimental has fallen by the wayside, and routine screening for this phenomenon can no longer be recommended, Patrick T. O’Gara, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

What a difference a decade or 2 can make.

“Think about where we were 25 years ago, when we worried about people who had transient ST-segment depression without angina on Holter monitoring. We would wig out, chase them down the street, try to tackle them and load them up with medications and think about balloon [percutaneous transluminal coronary angioplasty]. And now we’re at the point where it doesn’t seem to help with respect to quality of life, let alone death or myocardial infarction,” observed Dr. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.

The end of the line for the now-discredited notion that silent ischemia carries clinical significance approaching that of ischemia plus angina pectoris was the landmark ISCHEMIA trial, reported in November 2019 at the annual scientific sessions of the American Heart Association. This randomized trial asked the question: Is there any high-risk subgroup of patients with stable ischemic heart disease not involving the left main coronary artery for whom a strategy of routine revascularization improves hard outcomes in the current era of highly effective, guideline-directed medical therapy?

The answer turned out to be no. At 5 years of follow-up of 5,179 randomized patients with baseline stable coronary artery disease (CAD) and rigorously determined baseline moderate or severe ischemia affecting more than 10% of the myocardium, there was no difference between patients randomized to routine revascularization plus optimal medical therapy versus those on optimal medical therapy alone in the primary combined outcome of cardiovascular death, MI, heart failure, cardiac arrest, or hospitalization for unstable angina.

Of note, 35% of participants in the ISCHEMIA trial had moderate or severe silent ischemia. Like those who had angina, they achieved no additional benefit from a strategy of routine revascularization in terms of the primary outcome. ISCHEMIA participants with angina did show significant and durable improvements in quality of life and angina control with routine revascularization; however, those with silent ischemia showed little or no such improvement with an invasive strategy.

That being said, Dr. O’Gara added that he supports the ISCHEMIA investigators’ efforts to obtain funding from the National Institutes of Health for another 5 years or so of follow-up in order to determine whether revascularization actually does lead to improvement in the hard outcomes.

“Remember, in the STICH trial it took 10 years to show superiority of CABG [coronary artery bypass surgery] versus medical therapy to treat ischemic cardiomyopathy [N Engl J Med 2016; 374:1511-20]. My own view is that it’s too premature to throw the baby out with the bathwater. I think shared decision making is still very important, and I think, for many of our patients, relief of angina and improved quality of life are legitimate reasons in a low-risk situation with a good interventionalist to proceed,” he said.

Dr. O’Gara traced the history of medical thinking about silent ischemia. The notion that silent ischemia carried a clinical significance comparable with ischemia with angina gained wide credence more than 30 years ago, when investigators from the National Institutes of Health–sponsored Coronary Artery Surgery Study registry reported: “Patients with either silent or symptomatic ischemia during exercise testing have a similar risk of developing an acute myocardial infarction or sudden death – except in the three-vessel CAD subgroup, where the risk is greater in silent ischemia” (Am J Cardiol. 1988 Dec 1;62[17]:1155-8).

“This was a very important observation and led to many, many recommendations about screening and making sure that you took the expression of ST-segment depression on exercise treadmill testing pretty seriously, even if your patient did not have angina,” Dr. O’Gara recalled.

The prevailing wisdom that silent ischemia was detrimental took a hit in the Detection of Ischemia in Asymptomatic Diabetics (DIAC) trial. DIAC was conducted at a time when it had become clear that type 2 diabetes was a condition associated with increased cardiovascular risk, and that various methods of imaging were more accurate than treadmill exercise testing for the detection of underlying CAD. But when 1,123 DIAC participants with type 2 diabetes were randomized to screening with adenosine-stress radionuclide myocardial perfusion imaging or not and prospectively followed for roughly 5 years, it turned out there was no between-group difference in cardiac death or MI (JAMA. 2009 Apr 15;301[15]:1547-55).

“This pretty much put the lid on going out of one’s way to do routine screening of this nature in persons with diabetes who were considered to be at higher than average risk for the development of coronary disease,” the cardiologist commented.

Another fissure in the idea that silent ischemia was worth searching for and treating came from CLARIFY, an observational international registry of more than 20,000 individuals with stable CAD, roughly 12% of whom had silent ischemia, a figure in line with the prevalence reported in other studies. The 2-year rate of cardiovascular death or MI in the group with silent ischemia didn’t differ from the rate in patients with neither angina nor provocable ischemia. In contrast, rates of cardiovascular death or MI were significantly higher in the groups with angina but no ischemia or angina with ischemia (JAMA Intern Med. 2014 Oct;174[10]:1651-9).

“There’s something about the expression of angina that’s a very key clinical marker,” Dr. O’Gara observed.

He noted that just a few months before the ISCHEMIA trial results were released, a report from the far-smaller, randomized second Medicine, Angioplasty, or Surgery Study “threw cold water” on the notion that stress-induced ischemia in patients with multivessel CAD is a bad thing. Over 10 years of follow-up, the risk of major adverse cardiovascular events or deterioration in left ventricular function was identical in patients with or without baseline ischemia on stress testing performed after percutaneous coronary intervention, CABG surgery, or initiation of medical therapy (JAMA Intern Med. 2019 Jul 22. doi: 10.1001/jamainternmed.2019.2227).
 

What the guidelines say

The 6-year-old U.S. guidelines on the diagnosis and management of patients with stable ischemic heart disease are clearly out of date on the topic of silent ischemia (Circulation. 2014 Nov 4;130[19]:1749-67). The recommendations are based on expert opinion formed prior to the massive amount of new evidence that has since become available. For example, the current guidelines state as a class IIa, level of evidence C recommendation that exercise or pharmacologic stress can be useful for follow-up assessment at 2-year or greater intervals in patients with stable ischemic heart disease with prior evidence of silent ischemia.

“This is a very weak recommendation. The class of recommendation says it would be reasonable, but in the absence of an evidence base and in light of newer information, I’m not sure that it approaches even a class IIa level of recommendation,” according to Dr. O’Gara.

The 2019 European Society of Cardiology guidelines on chronic coronary syndromes are similarly weak on silent ischemia. The European guidelines state that patients with diabetes or chronic kidney disease may have a higher burden of silent ischemia, might be at higher risk for atherosclerotic cardiovascular disease events, and that periodic ECGs and functional testing every 3-5 years might be considered.

“Obviously there’s a lot of leeway there in how you wish to interpret that,” Dr. O’Gara said. “And this did not rise to the level where they’d put it in the table of recommendations, but it’s simply included as part of the explanatory text.”
 

What’s coming next in stable ischemic heart disease

“Nowadays all the rage has to do with coronary microvascular dysfunction,” according to Dr. O’Gara. “I think all of the research interest currently is focused on the coronary microcirculation as perhaps the next frontier in our understanding of why it is that ischemia can occur in the absence of epicardial coronary disease.”

He highly recommended a review article entitled: “Reappraisal of Ischemic Heart Disease,” in which an international trio of prominent cardiologists asserted that coronary microvascular dysfunction not only plays a pivotal pathogenic role in angina pectoris, but also in a phenomenon known as microvascular angina – that is, angina in the absence of obstructive CAD. Microvascular angina may explain the roughly one-third of patients who experience acute coronary syndrome without epicardial coronary artery stenosis or thrombosis. The authors delved into the structural and functional mechanisms underlying coronary microvascular dysfunction, while noting that effective treatment of this common phenomenon remains a major unmet need (Circulation. 2018 Oct 2;138[14]:1463-80).

Dr. O’Gara reported receiving funding from the National Heart, Lung, and Blood Institute; from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial; from Edwards Lifesciences for the ongoing EARLY TAVR trial; and from Medtrace Pharma, a Danish company developing an innovative form of PET diagnostic imaging.

bjancin@mdedge.com