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LDL cholesterol not the primary culprit in ASCVD?
Two new studies suggest that LDL cholesterol (LDL-C) may be not the main driver of atherosclerotic cardiovascular disease (ASCVD).
The findings instead implicate remnant cholesterol (remnant-C) and very-low-density lipoprotein (VLDL) cholesterol in the development of cardiovascular disease (CVD) and MI.
The PREDIMED study, conducted in Spain, examined the association of triglycerides and remnant-C with major cardiovascular events (MACE) in older individuals with high CVD risk. It found that levels of triglycerides and remnant-C were associated with MACE independently of other risk factors, but there was no similar association with LDL-C.
“These findings lead [clinicians] to consider in the clinical management of dyslipidemias a greater control of the lipid profiles as a whole, including remnant-cholesterol and/or triglycerides,” Montserrat Fitó Colomer, MD, PhD, of the Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute, Barcelona, said in an interview.
In a separate analysis, the Copenhagen General Population Study, which focused on 25,000 individuals who were not taking lipid-lowering therapy, looked at the role of VLDL cholesterol and triglycerides in driving MI risk from apolipoprotein B (apoB)–containing lipoproteins.
“Elevated VLDL cholesterol explained a larger fraction of risk than did elevated LDL cholesterol, or elevated VLDL triglycerides,” Børge G. Nordestgaard, MD, DMSc, professor, University of Copenhagen, said in an interview.
Both studies were published online Nov. 30 in the Journal of the American College of Cardiology.
But in an editorial accompanying both reports, John Burnett, MD, PhD, from the University of Western Australia, Perth, and colleagues cautioned that it would be “premature to discard LDL-C based on PREDIMED.”
The findings are “insufficient to offset the mountain of literally hundreds of studies that uphold the value of LDL-C in prediction and intervention of ASCVD,” Dr. Burnett and coauthors wrote.
Similarly, the editorialists cautioned that, although the findings from the study by Dr. Nordestgaard and colleagues indicate that VLDL cholesterol is the “new kid in town for prediction, LDL cholesterol retains predictive power.” Clinical cardiologists should not “shelve LDL cholesterol and embrace VLDL and remnant cholesterol as the new oracles of ASCVD risk.”
In a comment, Dr. Burnett said, “The take-home message for clinicians in both papers is that LDL-C is the main lipid measurement to guide clinical decisions; however, residual risk of atherosclerotic cardiovascular disease remains, even after LCL-C is treated.
“Assessment of residual ASCVD risk with nontraditional lipid biomarkers, including VLDL cholesterol and remnant cholesterol, as well as lipoprotein (a) and apoB, may improve prognostication and help guide preventive treatments,” he added.
“Affordable and inexpensive”
In their report, the PREDIMED study authors explained that atherogenic dyslipidemia is characterized by “an excess of serum triglycerides” contained in VLDL cholesterol, intermediate-density lipoproteins, and their remnants, all of which are called “triglyceride-rich lipoproteins (TRLs).”
TRLs and remnant-C “have the capacity to cross the arterial wall,” and may therefore play a causal role in atherosclerosis development, they wrote.
The main PREDIMED trial compared a low-fat diet with the Mediterranean diet for the primary prevention of CVD in high-risk participants. Those enrolled in the trial “had a high prevalence of diabetes, obesity, and metabolic syndrome, conditions that are associated with insulin resistance, hypertriglyceridemia, and atherogenic dyslipidemia,” the authors wrote. “Thus, this cohort of subjects at high cardiovascular risk was well suited to investigate the association of triglycerides and TRLs with cardiovascular outcomes.”
The researchers investigated the role of triglycerides and remnant-C in incident CVD among these high-risk individuals, particularly those with chronic cardiometabolic disorders (prediabetes, type 2 diabetes, and poorly controlled diabetes), overweight and obesity, metabolic syndrome, and renal failure.
Their 6,901 participants (42.6% male, mean age 67 years, mean BMI 30.0 kg/m2) had a diagnosis of type 2 diabetes or at least three CVD risk factors including current smoking, hypertension, elevated LDL-C levels, low HDL cholesterol levels, elevated body mass index, or family history of premature coronary heart disease.
The primary study endpoint was a composite of adverse cardiovascular events (MACE): MI, stroke, or cardiovascular death. Participants were followed for a mean of 4.8 years, during which there was a total of 263 MACE events.
Multivariable-adjusted analyses showed that levels of triglycerides and remnant-C were both associated with MACE independent of other risk factors (hazard ratio, 1.04; 95% confidence interval, 1.02-1.06; and HR, 1.21; 95% CI, 1.10-1.33 per 10 mg/dl, respectively, both P < .001). Non–HDL cholesterol was also associated with MACE (HR, 1.05; 95% CI, 1.01-1.10 per 10 mg/dl, P = .026).
In particular, elevated remnant-C (≥30 mg/dL), compared with lower concentrations, flagged subjects at a higher risk of MACE, even if their LDL-C levels were at target (defined as ≤ 100 mg/dL).
Levels of LDL-C and HDL cholesterol were not associated with MACE.
“The indirect calculation of remnant-C is an affordable and inexpensive method, which could provide valuable data for clinical management,” Dr. Fitó Colomer said.
“The results of this study suggest that, in individuals at high cardiovascular risk with well-controlled LDL-C, triglycerides and mainly remnant-C should be considered as a treatment target,” she proposed.
New oracles?
Evidence has pointed to triglyceride-rich remnants or VLDL cholesterol as contributing to atherosclerotic CVD, together with LDL-C, but it is “unclear which fraction of risk is explained by, respectively, cholesterol and triglycerides in VLDL,” write the authors of the Copenhagen population study.
Dr. Nordestgaard said their study was motivated by an awareness that “in clinical practice, the focus for lipid-related risk is almost solely on reduction of LDL-C for prevention of ASCVD,” so the current focus needs to be reevaluated because patients with low LDL-C but elevated VLDL cholesterol and plasma triglycerides “may not be offered adequate preventive lipid-lowering therapy in order to prevent future MI and ASCVD.”
His group therefore tested the hypothesis that VLDL cholesterol and triglycerides may each explain part of the MI risk from apoB-containing lipoproteins.
They used measurements of plasma apoB and cholesterol and triglyceride content of VLDL cholesterol, intermediate-density-lipoprotein cholesterol, and LDL-C in the study participants (N = 25,480, median age 61 years, 53% female), who were required to be free of MI and not receiving lipid-lowering therapy at baseline.
During a median 11-year follow-up period, 1,816 participants experienced an MI. They tended to be older, compared with those who did not experience an MI, and also more likely to be male, to smoke, and to have higher systolic blood pressure.
Each 39-mg/dL increase in lipid level was found to be associated with higher MI risk.
The researchers looked at MI-associated risk of specific subfractions of apoB-containing lipoproteins. “VLDL cholesterol explained half of the MI risk from elevated apoB-containing lipoproteins, and [intermediate-density-lipoprotein] and LDL-C together accounted for only 29% of the risk,” Dr. Nordestgaard said.
“If LDL cholesterol is adequately reduced, clinicians need to evaluate possible elevated triglyceride-rich lipoproteins, either as elevated plasma triglycerides, remnant cholesterol, or elevated VLDL cholesterol; and, if elevated, consideration should also be given to reduction of triglyceride-rich lipoproteins,” he advised.
The Copenhagen General Population study was funded by the Danish Heart Foundation and the Novo Nordisk Foundation. Dr. Nordestgaard disclosed consulting for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin, Novartis, Novo Nordisk, and Silence Therapeutrics. PREDIMED was supported by grants from the Instituto de Salud Carlos III- FEDER, Fundació La Marató de TV3, and Agència de Gestió d’Ajuts Universitaris i de Recerca. Dr. Fitó Colomer disclosed no relevant financial relationships. Dr. Burnett disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Two new studies suggest that LDL cholesterol (LDL-C) may be not the main driver of atherosclerotic cardiovascular disease (ASCVD).
The findings instead implicate remnant cholesterol (remnant-C) and very-low-density lipoprotein (VLDL) cholesterol in the development of cardiovascular disease (CVD) and MI.
The PREDIMED study, conducted in Spain, examined the association of triglycerides and remnant-C with major cardiovascular events (MACE) in older individuals with high CVD risk. It found that levels of triglycerides and remnant-C were associated with MACE independently of other risk factors, but there was no similar association with LDL-C.
“These findings lead [clinicians] to consider in the clinical management of dyslipidemias a greater control of the lipid profiles as a whole, including remnant-cholesterol and/or triglycerides,” Montserrat Fitó Colomer, MD, PhD, of the Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute, Barcelona, said in an interview.
In a separate analysis, the Copenhagen General Population Study, which focused on 25,000 individuals who were not taking lipid-lowering therapy, looked at the role of VLDL cholesterol and triglycerides in driving MI risk from apolipoprotein B (apoB)–containing lipoproteins.
“Elevated VLDL cholesterol explained a larger fraction of risk than did elevated LDL cholesterol, or elevated VLDL triglycerides,” Børge G. Nordestgaard, MD, DMSc, professor, University of Copenhagen, said in an interview.
Both studies were published online Nov. 30 in the Journal of the American College of Cardiology.
But in an editorial accompanying both reports, John Burnett, MD, PhD, from the University of Western Australia, Perth, and colleagues cautioned that it would be “premature to discard LDL-C based on PREDIMED.”
The findings are “insufficient to offset the mountain of literally hundreds of studies that uphold the value of LDL-C in prediction and intervention of ASCVD,” Dr. Burnett and coauthors wrote.
Similarly, the editorialists cautioned that, although the findings from the study by Dr. Nordestgaard and colleagues indicate that VLDL cholesterol is the “new kid in town for prediction, LDL cholesterol retains predictive power.” Clinical cardiologists should not “shelve LDL cholesterol and embrace VLDL and remnant cholesterol as the new oracles of ASCVD risk.”
In a comment, Dr. Burnett said, “The take-home message for clinicians in both papers is that LDL-C is the main lipid measurement to guide clinical decisions; however, residual risk of atherosclerotic cardiovascular disease remains, even after LCL-C is treated.
“Assessment of residual ASCVD risk with nontraditional lipid biomarkers, including VLDL cholesterol and remnant cholesterol, as well as lipoprotein (a) and apoB, may improve prognostication and help guide preventive treatments,” he added.
“Affordable and inexpensive”
In their report, the PREDIMED study authors explained that atherogenic dyslipidemia is characterized by “an excess of serum triglycerides” contained in VLDL cholesterol, intermediate-density lipoproteins, and their remnants, all of which are called “triglyceride-rich lipoproteins (TRLs).”
TRLs and remnant-C “have the capacity to cross the arterial wall,” and may therefore play a causal role in atherosclerosis development, they wrote.
The main PREDIMED trial compared a low-fat diet with the Mediterranean diet for the primary prevention of CVD in high-risk participants. Those enrolled in the trial “had a high prevalence of diabetes, obesity, and metabolic syndrome, conditions that are associated with insulin resistance, hypertriglyceridemia, and atherogenic dyslipidemia,” the authors wrote. “Thus, this cohort of subjects at high cardiovascular risk was well suited to investigate the association of triglycerides and TRLs with cardiovascular outcomes.”
The researchers investigated the role of triglycerides and remnant-C in incident CVD among these high-risk individuals, particularly those with chronic cardiometabolic disorders (prediabetes, type 2 diabetes, and poorly controlled diabetes), overweight and obesity, metabolic syndrome, and renal failure.
Their 6,901 participants (42.6% male, mean age 67 years, mean BMI 30.0 kg/m2) had a diagnosis of type 2 diabetes or at least three CVD risk factors including current smoking, hypertension, elevated LDL-C levels, low HDL cholesterol levels, elevated body mass index, or family history of premature coronary heart disease.
The primary study endpoint was a composite of adverse cardiovascular events (MACE): MI, stroke, or cardiovascular death. Participants were followed for a mean of 4.8 years, during which there was a total of 263 MACE events.
Multivariable-adjusted analyses showed that levels of triglycerides and remnant-C were both associated with MACE independent of other risk factors (hazard ratio, 1.04; 95% confidence interval, 1.02-1.06; and HR, 1.21; 95% CI, 1.10-1.33 per 10 mg/dl, respectively, both P < .001). Non–HDL cholesterol was also associated with MACE (HR, 1.05; 95% CI, 1.01-1.10 per 10 mg/dl, P = .026).
In particular, elevated remnant-C (≥30 mg/dL), compared with lower concentrations, flagged subjects at a higher risk of MACE, even if their LDL-C levels were at target (defined as ≤ 100 mg/dL).
Levels of LDL-C and HDL cholesterol were not associated with MACE.
“The indirect calculation of remnant-C is an affordable and inexpensive method, which could provide valuable data for clinical management,” Dr. Fitó Colomer said.
“The results of this study suggest that, in individuals at high cardiovascular risk with well-controlled LDL-C, triglycerides and mainly remnant-C should be considered as a treatment target,” she proposed.
New oracles?
Evidence has pointed to triglyceride-rich remnants or VLDL cholesterol as contributing to atherosclerotic CVD, together with LDL-C, but it is “unclear which fraction of risk is explained by, respectively, cholesterol and triglycerides in VLDL,” write the authors of the Copenhagen population study.
Dr. Nordestgaard said their study was motivated by an awareness that “in clinical practice, the focus for lipid-related risk is almost solely on reduction of LDL-C for prevention of ASCVD,” so the current focus needs to be reevaluated because patients with low LDL-C but elevated VLDL cholesterol and plasma triglycerides “may not be offered adequate preventive lipid-lowering therapy in order to prevent future MI and ASCVD.”
His group therefore tested the hypothesis that VLDL cholesterol and triglycerides may each explain part of the MI risk from apoB-containing lipoproteins.
They used measurements of plasma apoB and cholesterol and triglyceride content of VLDL cholesterol, intermediate-density-lipoprotein cholesterol, and LDL-C in the study participants (N = 25,480, median age 61 years, 53% female), who were required to be free of MI and not receiving lipid-lowering therapy at baseline.
During a median 11-year follow-up period, 1,816 participants experienced an MI. They tended to be older, compared with those who did not experience an MI, and also more likely to be male, to smoke, and to have higher systolic blood pressure.
Each 39-mg/dL increase in lipid level was found to be associated with higher MI risk.
The researchers looked at MI-associated risk of specific subfractions of apoB-containing lipoproteins. “VLDL cholesterol explained half of the MI risk from elevated apoB-containing lipoproteins, and [intermediate-density-lipoprotein] and LDL-C together accounted for only 29% of the risk,” Dr. Nordestgaard said.
“If LDL cholesterol is adequately reduced, clinicians need to evaluate possible elevated triglyceride-rich lipoproteins, either as elevated plasma triglycerides, remnant cholesterol, or elevated VLDL cholesterol; and, if elevated, consideration should also be given to reduction of triglyceride-rich lipoproteins,” he advised.
The Copenhagen General Population study was funded by the Danish Heart Foundation and the Novo Nordisk Foundation. Dr. Nordestgaard disclosed consulting for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin, Novartis, Novo Nordisk, and Silence Therapeutrics. PREDIMED was supported by grants from the Instituto de Salud Carlos III- FEDER, Fundació La Marató de TV3, and Agència de Gestió d’Ajuts Universitaris i de Recerca. Dr. Fitó Colomer disclosed no relevant financial relationships. Dr. Burnett disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Two new studies suggest that LDL cholesterol (LDL-C) may be not the main driver of atherosclerotic cardiovascular disease (ASCVD).
The findings instead implicate remnant cholesterol (remnant-C) and very-low-density lipoprotein (VLDL) cholesterol in the development of cardiovascular disease (CVD) and MI.
The PREDIMED study, conducted in Spain, examined the association of triglycerides and remnant-C with major cardiovascular events (MACE) in older individuals with high CVD risk. It found that levels of triglycerides and remnant-C were associated with MACE independently of other risk factors, but there was no similar association with LDL-C.
“These findings lead [clinicians] to consider in the clinical management of dyslipidemias a greater control of the lipid profiles as a whole, including remnant-cholesterol and/or triglycerides,” Montserrat Fitó Colomer, MD, PhD, of the Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute, Barcelona, said in an interview.
In a separate analysis, the Copenhagen General Population Study, which focused on 25,000 individuals who were not taking lipid-lowering therapy, looked at the role of VLDL cholesterol and triglycerides in driving MI risk from apolipoprotein B (apoB)–containing lipoproteins.
“Elevated VLDL cholesterol explained a larger fraction of risk than did elevated LDL cholesterol, or elevated VLDL triglycerides,” Børge G. Nordestgaard, MD, DMSc, professor, University of Copenhagen, said in an interview.
Both studies were published online Nov. 30 in the Journal of the American College of Cardiology.
But in an editorial accompanying both reports, John Burnett, MD, PhD, from the University of Western Australia, Perth, and colleagues cautioned that it would be “premature to discard LDL-C based on PREDIMED.”
The findings are “insufficient to offset the mountain of literally hundreds of studies that uphold the value of LDL-C in prediction and intervention of ASCVD,” Dr. Burnett and coauthors wrote.
Similarly, the editorialists cautioned that, although the findings from the study by Dr. Nordestgaard and colleagues indicate that VLDL cholesterol is the “new kid in town for prediction, LDL cholesterol retains predictive power.” Clinical cardiologists should not “shelve LDL cholesterol and embrace VLDL and remnant cholesterol as the new oracles of ASCVD risk.”
In a comment, Dr. Burnett said, “The take-home message for clinicians in both papers is that LDL-C is the main lipid measurement to guide clinical decisions; however, residual risk of atherosclerotic cardiovascular disease remains, even after LCL-C is treated.
“Assessment of residual ASCVD risk with nontraditional lipid biomarkers, including VLDL cholesterol and remnant cholesterol, as well as lipoprotein (a) and apoB, may improve prognostication and help guide preventive treatments,” he added.
“Affordable and inexpensive”
In their report, the PREDIMED study authors explained that atherogenic dyslipidemia is characterized by “an excess of serum triglycerides” contained in VLDL cholesterol, intermediate-density lipoproteins, and their remnants, all of which are called “triglyceride-rich lipoproteins (TRLs).”
TRLs and remnant-C “have the capacity to cross the arterial wall,” and may therefore play a causal role in atherosclerosis development, they wrote.
The main PREDIMED trial compared a low-fat diet with the Mediterranean diet for the primary prevention of CVD in high-risk participants. Those enrolled in the trial “had a high prevalence of diabetes, obesity, and metabolic syndrome, conditions that are associated with insulin resistance, hypertriglyceridemia, and atherogenic dyslipidemia,” the authors wrote. “Thus, this cohort of subjects at high cardiovascular risk was well suited to investigate the association of triglycerides and TRLs with cardiovascular outcomes.”
The researchers investigated the role of triglycerides and remnant-C in incident CVD among these high-risk individuals, particularly those with chronic cardiometabolic disorders (prediabetes, type 2 diabetes, and poorly controlled diabetes), overweight and obesity, metabolic syndrome, and renal failure.
Their 6,901 participants (42.6% male, mean age 67 years, mean BMI 30.0 kg/m2) had a diagnosis of type 2 diabetes or at least three CVD risk factors including current smoking, hypertension, elevated LDL-C levels, low HDL cholesterol levels, elevated body mass index, or family history of premature coronary heart disease.
The primary study endpoint was a composite of adverse cardiovascular events (MACE): MI, stroke, or cardiovascular death. Participants were followed for a mean of 4.8 years, during which there was a total of 263 MACE events.
Multivariable-adjusted analyses showed that levels of triglycerides and remnant-C were both associated with MACE independent of other risk factors (hazard ratio, 1.04; 95% confidence interval, 1.02-1.06; and HR, 1.21; 95% CI, 1.10-1.33 per 10 mg/dl, respectively, both P < .001). Non–HDL cholesterol was also associated with MACE (HR, 1.05; 95% CI, 1.01-1.10 per 10 mg/dl, P = .026).
In particular, elevated remnant-C (≥30 mg/dL), compared with lower concentrations, flagged subjects at a higher risk of MACE, even if their LDL-C levels were at target (defined as ≤ 100 mg/dL).
Levels of LDL-C and HDL cholesterol were not associated with MACE.
“The indirect calculation of remnant-C is an affordable and inexpensive method, which could provide valuable data for clinical management,” Dr. Fitó Colomer said.
“The results of this study suggest that, in individuals at high cardiovascular risk with well-controlled LDL-C, triglycerides and mainly remnant-C should be considered as a treatment target,” she proposed.
New oracles?
Evidence has pointed to triglyceride-rich remnants or VLDL cholesterol as contributing to atherosclerotic CVD, together with LDL-C, but it is “unclear which fraction of risk is explained by, respectively, cholesterol and triglycerides in VLDL,” write the authors of the Copenhagen population study.
Dr. Nordestgaard said their study was motivated by an awareness that “in clinical practice, the focus for lipid-related risk is almost solely on reduction of LDL-C for prevention of ASCVD,” so the current focus needs to be reevaluated because patients with low LDL-C but elevated VLDL cholesterol and plasma triglycerides “may not be offered adequate preventive lipid-lowering therapy in order to prevent future MI and ASCVD.”
His group therefore tested the hypothesis that VLDL cholesterol and triglycerides may each explain part of the MI risk from apoB-containing lipoproteins.
They used measurements of plasma apoB and cholesterol and triglyceride content of VLDL cholesterol, intermediate-density-lipoprotein cholesterol, and LDL-C in the study participants (N = 25,480, median age 61 years, 53% female), who were required to be free of MI and not receiving lipid-lowering therapy at baseline.
During a median 11-year follow-up period, 1,816 participants experienced an MI. They tended to be older, compared with those who did not experience an MI, and also more likely to be male, to smoke, and to have higher systolic blood pressure.
Each 39-mg/dL increase in lipid level was found to be associated with higher MI risk.
The researchers looked at MI-associated risk of specific subfractions of apoB-containing lipoproteins. “VLDL cholesterol explained half of the MI risk from elevated apoB-containing lipoproteins, and [intermediate-density-lipoprotein] and LDL-C together accounted for only 29% of the risk,” Dr. Nordestgaard said.
“If LDL cholesterol is adequately reduced, clinicians need to evaluate possible elevated triglyceride-rich lipoproteins, either as elevated plasma triglycerides, remnant cholesterol, or elevated VLDL cholesterol; and, if elevated, consideration should also be given to reduction of triglyceride-rich lipoproteins,” he advised.
The Copenhagen General Population study was funded by the Danish Heart Foundation and the Novo Nordisk Foundation. Dr. Nordestgaard disclosed consulting for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin, Novartis, Novo Nordisk, and Silence Therapeutrics. PREDIMED was supported by grants from the Instituto de Salud Carlos III- FEDER, Fundació La Marató de TV3, and Agència de Gestió d’Ajuts Universitaris i de Recerca. Dr. Fitó Colomer disclosed no relevant financial relationships. Dr. Burnett disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Peripheral neuropathy tied to mortality in adults without diabetes
researchers reported in Annals of Internal Medicine.
The findings do not necessarily mean that doctors should implement broader screening for peripheral neuropathy at this time, however, the investigators said.
“Doctors don’t typically screen for peripheral neuropathy in persons without diabetes,” senior author Elizabeth Selvin, PhD, MPH, professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, Baltimore, said in an interview.
“Our study shows that peripheral neuropathy – as assessed by decreased sensation in the feet – is common, even in people without diabetes,” Dr. Selvin explained. “It is not yet clear whether we should be screening people without diabetes since we don’t have clear treatments, but our study does suggest that this condition is an underrecognized condition that is associated with poor outcomes.”
Patients with diabetes typically undergo annual foot examinations that include screening for peripheral neuropathy, but that’s not the case for most adults in the absence of diabetes.
“I don’t know if we can make the jump that we should be screening people without diabetes,” said first author Caitlin W. Hicks, MD, assistant professor of surgery, division of vascular surgery and endovascular therapy, Johns Hopkins University, Baltimore. “Right now, we do not exactly know what it means in the people without diabetes, and we definitely do not know how to treat it. So, screening for it will tell us that this person has this and is at higher risk of mortality than someone who doesn’t, but we do not know what to do with that information yet.”
Nevertheless, the study raises the question of whether physicians should pay more attention to peripheral neuropathy in people without diabetes, said Dr. Hicks, director of research at the university’s diabetic foot and wound service.
Heightened risk
To examine associations between peripheral neuropathy and all-cause and cardiovascular mortality in U.S. adults, Dr. Hicks and colleagues analyzed data from 7,116 adults aged 40 years or older who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004.
The study included participants who underwent monofilament testing for peripheral neuropathy. During testing, technicians used a standard 5.07 Semmes-Weinstein nylon monofilament to apply slight pressure to the bottom of each foot at three sites. If participants could not correctly identify where pressure was applied, the test was repeated. After participants gave two incorrect or undeterminable responses for a site, the site was defined as insensate. The researchers defined peripheral neuropathy as at least one insensate site on either foot.
The researchers determined deaths and causes of death using death certificate records from the National Death Index through 2015.
In all, 13.5% of the participants had peripheral neuropathy, including 27% of adults with diabetes and 11.6% of adults without diabetes. Those with peripheral neuropathy were older, were more likely to be male, and had lower levels of education, compared with participants without peripheral neuropathy. They also had higher body mass index, were more often former or current smokers, and had a higher prevalence of hypertension, hypercholesterolemia, and cardiovascular disease.
During a median follow-up of 13 years, 2,128 participants died, including 488 who died of cardiovascular causes.
The incidence rate of all-cause mortality per 1,000 person-years was 57.6 in adults with diabetes and peripheral neuropathy, 34.3 in adults with peripheral neuropathy but no diabetes, 27.1 in adults with diabetes but no peripheral neuropathy, and 13.0 in adults without diabetes or peripheral neuropathy.
Among participants with diabetes, the leading cause of death was cardiovascular disease (31% of deaths), whereas among participants without diabetes, the leading cause of death was malignant neoplasms (27% of deaths).
After adjustment for age, sex, race, or ethnicity, and risk factors such as cardiovascular disease, peripheral neuropathy was significantly associated with all-cause mortality (hazard ratio [HR], 1.49) and cardiovascular mortality (HR, 1.66) in participants with diabetes. In participants without diabetes, peripheral neuropathy was significantly associated with all-cause mortality (HR, 1.31), but its association with cardiovascular mortality was not statistically significant.
The association between peripheral neuropathy and all-cause mortality persisted in a sensitivity analysis that focused on adults with normoglycemia.
Related conditions
The study confirms findings from prior studies that examined the prevalence of loss of peripheral sensation in populations of older adults with and without diabetes, said Elsa S. Strotmeyer, PhD, MPH, associate professor of epidemiology at the University of Pittsburgh. “The clinical significance of the loss of peripheral sensation in older adults without diabetes is not fully appreciated,” she said.
A limitation of the study is that peripheral neuropathy was not a clinical diagnosis. “Monofilament testing at the foot is a quick clinical screen for decreased lower-extremity sensation that likely is a result of sensory peripheral nerve decline,” Dr. Strotmeyer said.
Another limitation is that death certificates are less accurate than medical records for determining cause of death.
“Past studies have indicated that peripheral nerve decline is related to common conditions in aging such as the metabolic syndrome and cardiovascular disease, cancer treatment, and physical function loss,” Dr. Strotmeyer said. “Therefore it is not surprising that is related to mortality as these conditions in aging are associated with increased mortality. Loss of peripheral sensation at the foot may also be related to fall injuries, and mortality from fall injuries has increased dramatically in older adults over the past several decades.”
Prior research has suggested that monofilament testing may play a role in screening for fall risk in older adults without diabetes, Dr. Strotmeyer added.
“For older adults both with and without diabetes, past studies have recommended monofilament testing be incorporated in geriatric screening for fall risk. Therefore, this article expands implications of clinical importance to understanding the pathology and consequences of loss of sensation at the foot in older patients,” she said.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute. Dr. Hicks, Dr. Selvin, and a coauthor, Kunihiro Matsushita, MD, PhD, disclosed NIH grants. In addition, Dr. Selvin disclosed personal fees from Novo Nordisk and grants from the Foundation for the National Institutes of Health outside the submitted work, and Dr. Matsushita disclosed grants and personal fees from Fukuda Denshi outside the submitted work. Dr. Strotmeyer receives funding from the National Institute on Aging and the National Institute of Arthritis and Musculoskeletal and Skin Diseases and is chair of the health sciences section of the Gerontological Society of America.
A version of this article originally appeared on Medscape.com.
researchers reported in Annals of Internal Medicine.
The findings do not necessarily mean that doctors should implement broader screening for peripheral neuropathy at this time, however, the investigators said.
“Doctors don’t typically screen for peripheral neuropathy in persons without diabetes,” senior author Elizabeth Selvin, PhD, MPH, professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, Baltimore, said in an interview.
“Our study shows that peripheral neuropathy – as assessed by decreased sensation in the feet – is common, even in people without diabetes,” Dr. Selvin explained. “It is not yet clear whether we should be screening people without diabetes since we don’t have clear treatments, but our study does suggest that this condition is an underrecognized condition that is associated with poor outcomes.”
Patients with diabetes typically undergo annual foot examinations that include screening for peripheral neuropathy, but that’s not the case for most adults in the absence of diabetes.
“I don’t know if we can make the jump that we should be screening people without diabetes,” said first author Caitlin W. Hicks, MD, assistant professor of surgery, division of vascular surgery and endovascular therapy, Johns Hopkins University, Baltimore. “Right now, we do not exactly know what it means in the people without diabetes, and we definitely do not know how to treat it. So, screening for it will tell us that this person has this and is at higher risk of mortality than someone who doesn’t, but we do not know what to do with that information yet.”
Nevertheless, the study raises the question of whether physicians should pay more attention to peripheral neuropathy in people without diabetes, said Dr. Hicks, director of research at the university’s diabetic foot and wound service.
Heightened risk
To examine associations between peripheral neuropathy and all-cause and cardiovascular mortality in U.S. adults, Dr. Hicks and colleagues analyzed data from 7,116 adults aged 40 years or older who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004.
The study included participants who underwent monofilament testing for peripheral neuropathy. During testing, technicians used a standard 5.07 Semmes-Weinstein nylon monofilament to apply slight pressure to the bottom of each foot at three sites. If participants could not correctly identify where pressure was applied, the test was repeated. After participants gave two incorrect or undeterminable responses for a site, the site was defined as insensate. The researchers defined peripheral neuropathy as at least one insensate site on either foot.
The researchers determined deaths and causes of death using death certificate records from the National Death Index through 2015.
In all, 13.5% of the participants had peripheral neuropathy, including 27% of adults with diabetes and 11.6% of adults without diabetes. Those with peripheral neuropathy were older, were more likely to be male, and had lower levels of education, compared with participants without peripheral neuropathy. They also had higher body mass index, were more often former or current smokers, and had a higher prevalence of hypertension, hypercholesterolemia, and cardiovascular disease.
During a median follow-up of 13 years, 2,128 participants died, including 488 who died of cardiovascular causes.
The incidence rate of all-cause mortality per 1,000 person-years was 57.6 in adults with diabetes and peripheral neuropathy, 34.3 in adults with peripheral neuropathy but no diabetes, 27.1 in adults with diabetes but no peripheral neuropathy, and 13.0 in adults without diabetes or peripheral neuropathy.
Among participants with diabetes, the leading cause of death was cardiovascular disease (31% of deaths), whereas among participants without diabetes, the leading cause of death was malignant neoplasms (27% of deaths).
After adjustment for age, sex, race, or ethnicity, and risk factors such as cardiovascular disease, peripheral neuropathy was significantly associated with all-cause mortality (hazard ratio [HR], 1.49) and cardiovascular mortality (HR, 1.66) in participants with diabetes. In participants without diabetes, peripheral neuropathy was significantly associated with all-cause mortality (HR, 1.31), but its association with cardiovascular mortality was not statistically significant.
The association between peripheral neuropathy and all-cause mortality persisted in a sensitivity analysis that focused on adults with normoglycemia.
Related conditions
The study confirms findings from prior studies that examined the prevalence of loss of peripheral sensation in populations of older adults with and without diabetes, said Elsa S. Strotmeyer, PhD, MPH, associate professor of epidemiology at the University of Pittsburgh. “The clinical significance of the loss of peripheral sensation in older adults without diabetes is not fully appreciated,” she said.
A limitation of the study is that peripheral neuropathy was not a clinical diagnosis. “Monofilament testing at the foot is a quick clinical screen for decreased lower-extremity sensation that likely is a result of sensory peripheral nerve decline,” Dr. Strotmeyer said.
Another limitation is that death certificates are less accurate than medical records for determining cause of death.
“Past studies have indicated that peripheral nerve decline is related to common conditions in aging such as the metabolic syndrome and cardiovascular disease, cancer treatment, and physical function loss,” Dr. Strotmeyer said. “Therefore it is not surprising that is related to mortality as these conditions in aging are associated with increased mortality. Loss of peripheral sensation at the foot may also be related to fall injuries, and mortality from fall injuries has increased dramatically in older adults over the past several decades.”
Prior research has suggested that monofilament testing may play a role in screening for fall risk in older adults without diabetes, Dr. Strotmeyer added.
“For older adults both with and without diabetes, past studies have recommended monofilament testing be incorporated in geriatric screening for fall risk. Therefore, this article expands implications of clinical importance to understanding the pathology and consequences of loss of sensation at the foot in older patients,” she said.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute. Dr. Hicks, Dr. Selvin, and a coauthor, Kunihiro Matsushita, MD, PhD, disclosed NIH grants. In addition, Dr. Selvin disclosed personal fees from Novo Nordisk and grants from the Foundation for the National Institutes of Health outside the submitted work, and Dr. Matsushita disclosed grants and personal fees from Fukuda Denshi outside the submitted work. Dr. Strotmeyer receives funding from the National Institute on Aging and the National Institute of Arthritis and Musculoskeletal and Skin Diseases and is chair of the health sciences section of the Gerontological Society of America.
A version of this article originally appeared on Medscape.com.
researchers reported in Annals of Internal Medicine.
The findings do not necessarily mean that doctors should implement broader screening for peripheral neuropathy at this time, however, the investigators said.
“Doctors don’t typically screen for peripheral neuropathy in persons without diabetes,” senior author Elizabeth Selvin, PhD, MPH, professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, Baltimore, said in an interview.
“Our study shows that peripheral neuropathy – as assessed by decreased sensation in the feet – is common, even in people without diabetes,” Dr. Selvin explained. “It is not yet clear whether we should be screening people without diabetes since we don’t have clear treatments, but our study does suggest that this condition is an underrecognized condition that is associated with poor outcomes.”
Patients with diabetes typically undergo annual foot examinations that include screening for peripheral neuropathy, but that’s not the case for most adults in the absence of diabetes.
“I don’t know if we can make the jump that we should be screening people without diabetes,” said first author Caitlin W. Hicks, MD, assistant professor of surgery, division of vascular surgery and endovascular therapy, Johns Hopkins University, Baltimore. “Right now, we do not exactly know what it means in the people without diabetes, and we definitely do not know how to treat it. So, screening for it will tell us that this person has this and is at higher risk of mortality than someone who doesn’t, but we do not know what to do with that information yet.”
Nevertheless, the study raises the question of whether physicians should pay more attention to peripheral neuropathy in people without diabetes, said Dr. Hicks, director of research at the university’s diabetic foot and wound service.
Heightened risk
To examine associations between peripheral neuropathy and all-cause and cardiovascular mortality in U.S. adults, Dr. Hicks and colleagues analyzed data from 7,116 adults aged 40 years or older who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004.
The study included participants who underwent monofilament testing for peripheral neuropathy. During testing, technicians used a standard 5.07 Semmes-Weinstein nylon monofilament to apply slight pressure to the bottom of each foot at three sites. If participants could not correctly identify where pressure was applied, the test was repeated. After participants gave two incorrect or undeterminable responses for a site, the site was defined as insensate. The researchers defined peripheral neuropathy as at least one insensate site on either foot.
The researchers determined deaths and causes of death using death certificate records from the National Death Index through 2015.
In all, 13.5% of the participants had peripheral neuropathy, including 27% of adults with diabetes and 11.6% of adults without diabetes. Those with peripheral neuropathy were older, were more likely to be male, and had lower levels of education, compared with participants without peripheral neuropathy. They also had higher body mass index, were more often former or current smokers, and had a higher prevalence of hypertension, hypercholesterolemia, and cardiovascular disease.
During a median follow-up of 13 years, 2,128 participants died, including 488 who died of cardiovascular causes.
The incidence rate of all-cause mortality per 1,000 person-years was 57.6 in adults with diabetes and peripheral neuropathy, 34.3 in adults with peripheral neuropathy but no diabetes, 27.1 in adults with diabetes but no peripheral neuropathy, and 13.0 in adults without diabetes or peripheral neuropathy.
Among participants with diabetes, the leading cause of death was cardiovascular disease (31% of deaths), whereas among participants without diabetes, the leading cause of death was malignant neoplasms (27% of deaths).
After adjustment for age, sex, race, or ethnicity, and risk factors such as cardiovascular disease, peripheral neuropathy was significantly associated with all-cause mortality (hazard ratio [HR], 1.49) and cardiovascular mortality (HR, 1.66) in participants with diabetes. In participants without diabetes, peripheral neuropathy was significantly associated with all-cause mortality (HR, 1.31), but its association with cardiovascular mortality was not statistically significant.
The association between peripheral neuropathy and all-cause mortality persisted in a sensitivity analysis that focused on adults with normoglycemia.
Related conditions
The study confirms findings from prior studies that examined the prevalence of loss of peripheral sensation in populations of older adults with and without diabetes, said Elsa S. Strotmeyer, PhD, MPH, associate professor of epidemiology at the University of Pittsburgh. “The clinical significance of the loss of peripheral sensation in older adults without diabetes is not fully appreciated,” she said.
A limitation of the study is that peripheral neuropathy was not a clinical diagnosis. “Monofilament testing at the foot is a quick clinical screen for decreased lower-extremity sensation that likely is a result of sensory peripheral nerve decline,” Dr. Strotmeyer said.
Another limitation is that death certificates are less accurate than medical records for determining cause of death.
“Past studies have indicated that peripheral nerve decline is related to common conditions in aging such as the metabolic syndrome and cardiovascular disease, cancer treatment, and physical function loss,” Dr. Strotmeyer said. “Therefore it is not surprising that is related to mortality as these conditions in aging are associated with increased mortality. Loss of peripheral sensation at the foot may also be related to fall injuries, and mortality from fall injuries has increased dramatically in older adults over the past several decades.”
Prior research has suggested that monofilament testing may play a role in screening for fall risk in older adults without diabetes, Dr. Strotmeyer added.
“For older adults both with and without diabetes, past studies have recommended monofilament testing be incorporated in geriatric screening for fall risk. Therefore, this article expands implications of clinical importance to understanding the pathology and consequences of loss of sensation at the foot in older patients,” she said.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute. Dr. Hicks, Dr. Selvin, and a coauthor, Kunihiro Matsushita, MD, PhD, disclosed NIH grants. In addition, Dr. Selvin disclosed personal fees from Novo Nordisk and grants from the Foundation for the National Institutes of Health outside the submitted work, and Dr. Matsushita disclosed grants and personal fees from Fukuda Denshi outside the submitted work. Dr. Strotmeyer receives funding from the National Institute on Aging and the National Institute of Arthritis and Musculoskeletal and Skin Diseases and is chair of the health sciences section of the Gerontological Society of America.
A version of this article originally appeared on Medscape.com.
Calcium burden drives CV risk whether coronary disease is obstructive or not
Coronary artery calcium (CAC) score as a measure of plaque burden more reliably predicts future cardiovascular (CV) risk in patients with suspected coronary disease (CAD) than whether or not the disease is obstructive, a large retrospective study suggests.
Indeed, CV risk went up in tandem with growing plaque burden regardless of whether there was obstructive disease in any coronary artery, defined as a 50% or greater stenosis by computed tomographic angiography (CTA).
The findings argue for plaque burden as measured by CAC score, rather than percent-stenosis severity, for guiding further treatment decisions in such patients, researchers say.
The research was based on more than 20,000 symptomatic patients referred to diagnostic CTA in the Western Denmark Heart Registry who were then followed for about 4 years for major CV events, including death, myocardial infarction, or stroke.
“What we show is that CAC is important for prognosis, and that patients with no stenosis have similar high risk as patients with stenosis when CAC burden is similar,” Martin Bødtker Mortensen, MD, PhD, Aarhus (Denmark) University Hospital, said in an interview.
The guidelines “distinguish between primary and secondary prevention patients” based on the presence or absence of obstructive CAD, he said, but “our results challenge this long-held approach. We show that patients with nonobstructive CAD carry similar risk as patients with obstructive CAD.”
In practice, risk tends to be greater in patients with obstructive compared with nonobstructive CAD. But the reason “is simply that they normally have higher atherosclerosis burden,” Dr. Mortensen said. “When you stratify based on atherosclerosis burden, then patients with obstructive and nonobstructive CAD have similar risk.”
The analysis was published online Dec. 7 in the Journal of the American College of Cardiology with Mortensen as lead author.
Until recently, it had long been believed that CV-event risk was driven by ischemia – but “ischemia is just a surrogate for the extent of atherosclerotic disease,” Armin Arbab Zadeh, MD, PhD, MPH, who is not connected with the current study, said in an interview.
The finding that CV risk climbs with growing coronary plaque burden “essentially confirms” other recent studies, but with “added value in showing how well the calcium scores, compared to obstructive disease, track with risk. So it’s definitely a nice extension of the evidence,” said Dr. Zadeh, director of cardiac CT at Johns Hopkins University, Baltimore.
“This study clearly shows that there is no ischemia ‘threshold,’ that the risk starts from mild and goes up with the burden of atherosclerotic disease. We were essentially taught wrong for decades.”
Dr. Mortensen said that the new results “are in line with previous studies showing that atherosclerosis burden is very important for risk.” They also help explain why revascularization of patients with stable angina failed to cut the risk of MI or death in trials like COURAGE, FAME-2, and ISCHEMIA. It’s because “stenosis per se explains little of the risk compared to atherosclerosis burden.”
In the current analysis, for example, about 65% of events were in patients who did not show obstructive CAD at CTA. Its 23,759 patients with symptoms suggestive of CAD were referred for CTA from 2008 through 2017; 5,043 (21.2%) were found to have obstructive disease and 18,716 (78.8%) either had no CAD or nonobstructive disease.
About 4.4% of patients experienced a first major CV event over a median follow-up of 4.3 years. Only events occurring later than 90 days after CTA were counted in an effort to exclude any directly related to revascularization, Dr. Mortensen noted.
The risk of events went up proportionally with both CAC score and the number of coronaries with obstructive disease.
The number of major CV events per 1,000 person-years was 6.2 for patients with a CAC score of 0, of whom 87% had no CAD by CTA, 7% had nonobstructive CAD, and 6% had obstructive CAD.
The corresponding rate was 17.5 among patients with a CAC score >100-399 for a hazard ratio (HR) of 1.7 (95% confidence interval [CI] 1.4-2.1) vs. a CAC score of 0.
And it was 42.3 per 1,000 patient-years among patients with CAC score >1000, HR 3.4 (95% CI, 2.5-4.6) vs. a CAC score of 0. Among those with the highest-tier CAC score, none were without CAD by CTA, 17% had nonobstructive disease, and 83% had obstructive CAD.
The major CV event rate rose similarly by number of coronaries with obstructive disease. It was 6.1 per 1,000 person-years in patients with no CAD. But it was 12.3 in those with nonobstructive disease, HR 1.3 (95% CI 1.1-1.6), up to 34.7 in those with triple-vessel obstructive disease, HR 2.9 (95% CI 2.2-3.9), vs. no CAD.
However, in an analysis with stratification by CAC score tier (0, 1-99, 100-399, 400-1,000, and >1,000), obstructive CAD was not associated with increased major CV-event risk in any stratum. The findings were similar in each subgroup with 1-vessel, 2-vessel, or 3-vessel CAD when stratified by CAC score.
Nor did major CV event risk track with obstructive CAD in analyses by age or after excluding all patients who underwent coronary revascularization within 90 days of CTA, the group reported.
“I believe these results support the use of CTA as a first-line test in patients with symptoms suggestive of CAD, as it provides valuable information for both diagnosis and prognosis in symptomatic patients,” Dr. Mortensen said. Those found to have a higher burden of atherosclerosis, he added, should receive aggressive preventive therapy regardless of whether or not they have obstructive disease.
The evidence from this study and others “supports a CTA-based approach” in such patients, Dr. Zadeh said. “And I would go further to say that a stress test is really inadequate,” in that it “detects the disease at such a late stage, you’re missing the opportunity to identify these patients who have atherosclerotic disease while you can do something about it.”
Its continued use as a first-line test, Dr. Zadeh said, “is essentially, in my mind, dismissing the evidence.”
An accompanying editorial Todd C. Villines, MD, and Patricia Rodriguez Lozano, MD, of the University of Virginia, Charlottesville agreed that “it is time that the traditional definitions of primary and secondary prevention evolve to incorporate CAC and CTA measures of patient risk based on coronary artery plaque burden.”
But they pointed out some limitations of the current study.
“The authors compared CAC with ≥50% stenosis, not CAC to comprehensive, contemporary coronary CTA,” and so “did not assess numerous other well-validated measures of coronary plaque burden that are routinely obtained from coronary CTA that typically improve the prognostic accuracy of coronary CTA beyond stenosis alone.” Also not performed was “plaque quantification on coronary CTA, an emerging field of study.”
The editorialists noted that noncontrast CT as used in the study for CAC scoring “is generally not recommended as a standalone test in symptomatic patients. Most studies have shown that coronary CTA, a test that accurately detects stenosis and identifies all types of coronary atherosclerosis (calcified and noncalcified), has significantly higher diagnostic and prognostic accuracy than CAC when performed in symptomatic patients without known coronary artery disease.”
Dr. Mortensen has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Dr. Villines and Dr. Rodriguez Lozano have disclosed no relevant financial relationships. Dr. Zadeh disclosed receiving grant support from Canon Medical Systems.
A version of this article originally appeared on Medscape.com.
Coronary artery calcium (CAC) score as a measure of plaque burden more reliably predicts future cardiovascular (CV) risk in patients with suspected coronary disease (CAD) than whether or not the disease is obstructive, a large retrospective study suggests.
Indeed, CV risk went up in tandem with growing plaque burden regardless of whether there was obstructive disease in any coronary artery, defined as a 50% or greater stenosis by computed tomographic angiography (CTA).
The findings argue for plaque burden as measured by CAC score, rather than percent-stenosis severity, for guiding further treatment decisions in such patients, researchers say.
The research was based on more than 20,000 symptomatic patients referred to diagnostic CTA in the Western Denmark Heart Registry who were then followed for about 4 years for major CV events, including death, myocardial infarction, or stroke.
“What we show is that CAC is important for prognosis, and that patients with no stenosis have similar high risk as patients with stenosis when CAC burden is similar,” Martin Bødtker Mortensen, MD, PhD, Aarhus (Denmark) University Hospital, said in an interview.
The guidelines “distinguish between primary and secondary prevention patients” based on the presence or absence of obstructive CAD, he said, but “our results challenge this long-held approach. We show that patients with nonobstructive CAD carry similar risk as patients with obstructive CAD.”
In practice, risk tends to be greater in patients with obstructive compared with nonobstructive CAD. But the reason “is simply that they normally have higher atherosclerosis burden,” Dr. Mortensen said. “When you stratify based on atherosclerosis burden, then patients with obstructive and nonobstructive CAD have similar risk.”
The analysis was published online Dec. 7 in the Journal of the American College of Cardiology with Mortensen as lead author.
Until recently, it had long been believed that CV-event risk was driven by ischemia – but “ischemia is just a surrogate for the extent of atherosclerotic disease,” Armin Arbab Zadeh, MD, PhD, MPH, who is not connected with the current study, said in an interview.
The finding that CV risk climbs with growing coronary plaque burden “essentially confirms” other recent studies, but with “added value in showing how well the calcium scores, compared to obstructive disease, track with risk. So it’s definitely a nice extension of the evidence,” said Dr. Zadeh, director of cardiac CT at Johns Hopkins University, Baltimore.
“This study clearly shows that there is no ischemia ‘threshold,’ that the risk starts from mild and goes up with the burden of atherosclerotic disease. We were essentially taught wrong for decades.”
Dr. Mortensen said that the new results “are in line with previous studies showing that atherosclerosis burden is very important for risk.” They also help explain why revascularization of patients with stable angina failed to cut the risk of MI or death in trials like COURAGE, FAME-2, and ISCHEMIA. It’s because “stenosis per se explains little of the risk compared to atherosclerosis burden.”
In the current analysis, for example, about 65% of events were in patients who did not show obstructive CAD at CTA. Its 23,759 patients with symptoms suggestive of CAD were referred for CTA from 2008 through 2017; 5,043 (21.2%) were found to have obstructive disease and 18,716 (78.8%) either had no CAD or nonobstructive disease.
About 4.4% of patients experienced a first major CV event over a median follow-up of 4.3 years. Only events occurring later than 90 days after CTA were counted in an effort to exclude any directly related to revascularization, Dr. Mortensen noted.
The risk of events went up proportionally with both CAC score and the number of coronaries with obstructive disease.
The number of major CV events per 1,000 person-years was 6.2 for patients with a CAC score of 0, of whom 87% had no CAD by CTA, 7% had nonobstructive CAD, and 6% had obstructive CAD.
The corresponding rate was 17.5 among patients with a CAC score >100-399 for a hazard ratio (HR) of 1.7 (95% confidence interval [CI] 1.4-2.1) vs. a CAC score of 0.
And it was 42.3 per 1,000 patient-years among patients with CAC score >1000, HR 3.4 (95% CI, 2.5-4.6) vs. a CAC score of 0. Among those with the highest-tier CAC score, none were without CAD by CTA, 17% had nonobstructive disease, and 83% had obstructive CAD.
The major CV event rate rose similarly by number of coronaries with obstructive disease. It was 6.1 per 1,000 person-years in patients with no CAD. But it was 12.3 in those with nonobstructive disease, HR 1.3 (95% CI 1.1-1.6), up to 34.7 in those with triple-vessel obstructive disease, HR 2.9 (95% CI 2.2-3.9), vs. no CAD.
However, in an analysis with stratification by CAC score tier (0, 1-99, 100-399, 400-1,000, and >1,000), obstructive CAD was not associated with increased major CV-event risk in any stratum. The findings were similar in each subgroup with 1-vessel, 2-vessel, or 3-vessel CAD when stratified by CAC score.
Nor did major CV event risk track with obstructive CAD in analyses by age or after excluding all patients who underwent coronary revascularization within 90 days of CTA, the group reported.
“I believe these results support the use of CTA as a first-line test in patients with symptoms suggestive of CAD, as it provides valuable information for both diagnosis and prognosis in symptomatic patients,” Dr. Mortensen said. Those found to have a higher burden of atherosclerosis, he added, should receive aggressive preventive therapy regardless of whether or not they have obstructive disease.
The evidence from this study and others “supports a CTA-based approach” in such patients, Dr. Zadeh said. “And I would go further to say that a stress test is really inadequate,” in that it “detects the disease at such a late stage, you’re missing the opportunity to identify these patients who have atherosclerotic disease while you can do something about it.”
Its continued use as a first-line test, Dr. Zadeh said, “is essentially, in my mind, dismissing the evidence.”
An accompanying editorial Todd C. Villines, MD, and Patricia Rodriguez Lozano, MD, of the University of Virginia, Charlottesville agreed that “it is time that the traditional definitions of primary and secondary prevention evolve to incorporate CAC and CTA measures of patient risk based on coronary artery plaque burden.”
But they pointed out some limitations of the current study.
“The authors compared CAC with ≥50% stenosis, not CAC to comprehensive, contemporary coronary CTA,” and so “did not assess numerous other well-validated measures of coronary plaque burden that are routinely obtained from coronary CTA that typically improve the prognostic accuracy of coronary CTA beyond stenosis alone.” Also not performed was “plaque quantification on coronary CTA, an emerging field of study.”
The editorialists noted that noncontrast CT as used in the study for CAC scoring “is generally not recommended as a standalone test in symptomatic patients. Most studies have shown that coronary CTA, a test that accurately detects stenosis and identifies all types of coronary atherosclerosis (calcified and noncalcified), has significantly higher diagnostic and prognostic accuracy than CAC when performed in symptomatic patients without known coronary artery disease.”
Dr. Mortensen has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Dr. Villines and Dr. Rodriguez Lozano have disclosed no relevant financial relationships. Dr. Zadeh disclosed receiving grant support from Canon Medical Systems.
A version of this article originally appeared on Medscape.com.
Coronary artery calcium (CAC) score as a measure of plaque burden more reliably predicts future cardiovascular (CV) risk in patients with suspected coronary disease (CAD) than whether or not the disease is obstructive, a large retrospective study suggests.
Indeed, CV risk went up in tandem with growing plaque burden regardless of whether there was obstructive disease in any coronary artery, defined as a 50% or greater stenosis by computed tomographic angiography (CTA).
The findings argue for plaque burden as measured by CAC score, rather than percent-stenosis severity, for guiding further treatment decisions in such patients, researchers say.
The research was based on more than 20,000 symptomatic patients referred to diagnostic CTA in the Western Denmark Heart Registry who were then followed for about 4 years for major CV events, including death, myocardial infarction, or stroke.
“What we show is that CAC is important for prognosis, and that patients with no stenosis have similar high risk as patients with stenosis when CAC burden is similar,” Martin Bødtker Mortensen, MD, PhD, Aarhus (Denmark) University Hospital, said in an interview.
The guidelines “distinguish between primary and secondary prevention patients” based on the presence or absence of obstructive CAD, he said, but “our results challenge this long-held approach. We show that patients with nonobstructive CAD carry similar risk as patients with obstructive CAD.”
In practice, risk tends to be greater in patients with obstructive compared with nonobstructive CAD. But the reason “is simply that they normally have higher atherosclerosis burden,” Dr. Mortensen said. “When you stratify based on atherosclerosis burden, then patients with obstructive and nonobstructive CAD have similar risk.”
The analysis was published online Dec. 7 in the Journal of the American College of Cardiology with Mortensen as lead author.
Until recently, it had long been believed that CV-event risk was driven by ischemia – but “ischemia is just a surrogate for the extent of atherosclerotic disease,” Armin Arbab Zadeh, MD, PhD, MPH, who is not connected with the current study, said in an interview.
The finding that CV risk climbs with growing coronary plaque burden “essentially confirms” other recent studies, but with “added value in showing how well the calcium scores, compared to obstructive disease, track with risk. So it’s definitely a nice extension of the evidence,” said Dr. Zadeh, director of cardiac CT at Johns Hopkins University, Baltimore.
“This study clearly shows that there is no ischemia ‘threshold,’ that the risk starts from mild and goes up with the burden of atherosclerotic disease. We were essentially taught wrong for decades.”
Dr. Mortensen said that the new results “are in line with previous studies showing that atherosclerosis burden is very important for risk.” They also help explain why revascularization of patients with stable angina failed to cut the risk of MI or death in trials like COURAGE, FAME-2, and ISCHEMIA. It’s because “stenosis per se explains little of the risk compared to atherosclerosis burden.”
In the current analysis, for example, about 65% of events were in patients who did not show obstructive CAD at CTA. Its 23,759 patients with symptoms suggestive of CAD were referred for CTA from 2008 through 2017; 5,043 (21.2%) were found to have obstructive disease and 18,716 (78.8%) either had no CAD or nonobstructive disease.
About 4.4% of patients experienced a first major CV event over a median follow-up of 4.3 years. Only events occurring later than 90 days after CTA were counted in an effort to exclude any directly related to revascularization, Dr. Mortensen noted.
The risk of events went up proportionally with both CAC score and the number of coronaries with obstructive disease.
The number of major CV events per 1,000 person-years was 6.2 for patients with a CAC score of 0, of whom 87% had no CAD by CTA, 7% had nonobstructive CAD, and 6% had obstructive CAD.
The corresponding rate was 17.5 among patients with a CAC score >100-399 for a hazard ratio (HR) of 1.7 (95% confidence interval [CI] 1.4-2.1) vs. a CAC score of 0.
And it was 42.3 per 1,000 patient-years among patients with CAC score >1000, HR 3.4 (95% CI, 2.5-4.6) vs. a CAC score of 0. Among those with the highest-tier CAC score, none were without CAD by CTA, 17% had nonobstructive disease, and 83% had obstructive CAD.
The major CV event rate rose similarly by number of coronaries with obstructive disease. It was 6.1 per 1,000 person-years in patients with no CAD. But it was 12.3 in those with nonobstructive disease, HR 1.3 (95% CI 1.1-1.6), up to 34.7 in those with triple-vessel obstructive disease, HR 2.9 (95% CI 2.2-3.9), vs. no CAD.
However, in an analysis with stratification by CAC score tier (0, 1-99, 100-399, 400-1,000, and >1,000), obstructive CAD was not associated with increased major CV-event risk in any stratum. The findings were similar in each subgroup with 1-vessel, 2-vessel, or 3-vessel CAD when stratified by CAC score.
Nor did major CV event risk track with obstructive CAD in analyses by age or after excluding all patients who underwent coronary revascularization within 90 days of CTA, the group reported.
“I believe these results support the use of CTA as a first-line test in patients with symptoms suggestive of CAD, as it provides valuable information for both diagnosis and prognosis in symptomatic patients,” Dr. Mortensen said. Those found to have a higher burden of atherosclerosis, he added, should receive aggressive preventive therapy regardless of whether or not they have obstructive disease.
The evidence from this study and others “supports a CTA-based approach” in such patients, Dr. Zadeh said. “And I would go further to say that a stress test is really inadequate,” in that it “detects the disease at such a late stage, you’re missing the opportunity to identify these patients who have atherosclerotic disease while you can do something about it.”
Its continued use as a first-line test, Dr. Zadeh said, “is essentially, in my mind, dismissing the evidence.”
An accompanying editorial Todd C. Villines, MD, and Patricia Rodriguez Lozano, MD, of the University of Virginia, Charlottesville agreed that “it is time that the traditional definitions of primary and secondary prevention evolve to incorporate CAC and CTA measures of patient risk based on coronary artery plaque burden.”
But they pointed out some limitations of the current study.
“The authors compared CAC with ≥50% stenosis, not CAC to comprehensive, contemporary coronary CTA,” and so “did not assess numerous other well-validated measures of coronary plaque burden that are routinely obtained from coronary CTA that typically improve the prognostic accuracy of coronary CTA beyond stenosis alone.” Also not performed was “plaque quantification on coronary CTA, an emerging field of study.”
The editorialists noted that noncontrast CT as used in the study for CAC scoring “is generally not recommended as a standalone test in symptomatic patients. Most studies have shown that coronary CTA, a test that accurately detects stenosis and identifies all types of coronary atherosclerosis (calcified and noncalcified), has significantly higher diagnostic and prognostic accuracy than CAC when performed in symptomatic patients without known coronary artery disease.”
Dr. Mortensen has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Dr. Villines and Dr. Rodriguez Lozano have disclosed no relevant financial relationships. Dr. Zadeh disclosed receiving grant support from Canon Medical Systems.
A version of this article originally appeared on Medscape.com.
COVID-19 fuels surge in overdose-related cardiac arrests
There has been a sharp increase in overdose-related cardiac arrests in the United States during the COVID-19 pandemic, a new analysis shows.
Overall rates in 2020 were elevated above the baseline from 2018 and 2019 by about 50%, the data show.
and efforts to combat the COVID-19 pandemic have not been effective at reducing overdoses,” Joseph Friedman, MPH, MD/PhD student, medical scientist training program, University of California, Los Angeles, said in an interview.
“We need to invest heavily in substance use treatment, harm reduction, and the structural drivers of overdose as core elements of the COVID-19 response,” said Mr. Friedman, who coauthored the study with UCLA colleague David Schriger, MD, MPH, and Leo Beletsky, JD, MPH, Northeastern University, Boston.
The study was published as a research letter Dec. 3 in JAMA Psychiatry.
Social isolation a key driver
Emergency medical services (EMS) data are available in near real time, providing a novel source of up-to-date information to monitor epidemiological shifts during the COVID-19 pandemic.
For the study, the researchers leveraged data from the National EMS Information System, a large registry of more than 10,000 EMS agencies in 47 states that represent over 80% of all EMS calls nationally in 2020. They used the data to track shifts in overdose-related cardiac arrests observed by EMS.
They found clear evidence of a large-scale uptick in overdose-related deaths during the COVID-19 pandemic.
The overall rate of overdose-related cardiac arrests in 2020 was about 50% higher than trends observed during 2018 and 2019, including a maximum peak of 123% above baseline reached in early May.
All overdose-related incidents (fatal and nonfatal) were elevated in 2020, by about 17% above baseline. However, there were larger increases in fatal overdose-related incidents, compared to all incidents, which may suggest a rising case fatality rate, the authors noted.
The observed trends line up in time with reductions in mobility (a metric of social interaction), as measured using cell phone data, they wrote.
“Many of the trends predicted by experts at the beginning of the pandemic could cause these shifts. Increases in social isolation likely play an important role, as people using [drugs] alone are less likely to receive help when they need it. Also shifts in the drug supply, and reduced access to healthcare and treatment,” said Mr. Friedman.
“We need to undertake short- and long-term strategies to combat the rising tide of overdose mortality in the United States,” he added.
In the short term, Mr. Friedman suggested reducing financial and logistical barriers for accessing a safe opioid supply. Such measures include allowing pharmacies to dispense methadone, allowing all physicians to prescribe buprenorphine without a special waiver, and releasing emergency funds to make these medications universally affordable.
“In the longer term, we should acknowledge that overdose is a symptom of structural problems in the U.S. We need to invest in making employment, housing, education, and health care accessible to all to address the upstream drivers of overdose,” he added.
The study had no commercial funding. The authors disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
There has been a sharp increase in overdose-related cardiac arrests in the United States during the COVID-19 pandemic, a new analysis shows.
Overall rates in 2020 were elevated above the baseline from 2018 and 2019 by about 50%, the data show.
and efforts to combat the COVID-19 pandemic have not been effective at reducing overdoses,” Joseph Friedman, MPH, MD/PhD student, medical scientist training program, University of California, Los Angeles, said in an interview.
“We need to invest heavily in substance use treatment, harm reduction, and the structural drivers of overdose as core elements of the COVID-19 response,” said Mr. Friedman, who coauthored the study with UCLA colleague David Schriger, MD, MPH, and Leo Beletsky, JD, MPH, Northeastern University, Boston.
The study was published as a research letter Dec. 3 in JAMA Psychiatry.
Social isolation a key driver
Emergency medical services (EMS) data are available in near real time, providing a novel source of up-to-date information to monitor epidemiological shifts during the COVID-19 pandemic.
For the study, the researchers leveraged data from the National EMS Information System, a large registry of more than 10,000 EMS agencies in 47 states that represent over 80% of all EMS calls nationally in 2020. They used the data to track shifts in overdose-related cardiac arrests observed by EMS.
They found clear evidence of a large-scale uptick in overdose-related deaths during the COVID-19 pandemic.
The overall rate of overdose-related cardiac arrests in 2020 was about 50% higher than trends observed during 2018 and 2019, including a maximum peak of 123% above baseline reached in early May.
All overdose-related incidents (fatal and nonfatal) were elevated in 2020, by about 17% above baseline. However, there were larger increases in fatal overdose-related incidents, compared to all incidents, which may suggest a rising case fatality rate, the authors noted.
The observed trends line up in time with reductions in mobility (a metric of social interaction), as measured using cell phone data, they wrote.
“Many of the trends predicted by experts at the beginning of the pandemic could cause these shifts. Increases in social isolation likely play an important role, as people using [drugs] alone are less likely to receive help when they need it. Also shifts in the drug supply, and reduced access to healthcare and treatment,” said Mr. Friedman.
“We need to undertake short- and long-term strategies to combat the rising tide of overdose mortality in the United States,” he added.
In the short term, Mr. Friedman suggested reducing financial and logistical barriers for accessing a safe opioid supply. Such measures include allowing pharmacies to dispense methadone, allowing all physicians to prescribe buprenorphine without a special waiver, and releasing emergency funds to make these medications universally affordable.
“In the longer term, we should acknowledge that overdose is a symptom of structural problems in the U.S. We need to invest in making employment, housing, education, and health care accessible to all to address the upstream drivers of overdose,” he added.
The study had no commercial funding. The authors disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
There has been a sharp increase in overdose-related cardiac arrests in the United States during the COVID-19 pandemic, a new analysis shows.
Overall rates in 2020 were elevated above the baseline from 2018 and 2019 by about 50%, the data show.
and efforts to combat the COVID-19 pandemic have not been effective at reducing overdoses,” Joseph Friedman, MPH, MD/PhD student, medical scientist training program, University of California, Los Angeles, said in an interview.
“We need to invest heavily in substance use treatment, harm reduction, and the structural drivers of overdose as core elements of the COVID-19 response,” said Mr. Friedman, who coauthored the study with UCLA colleague David Schriger, MD, MPH, and Leo Beletsky, JD, MPH, Northeastern University, Boston.
The study was published as a research letter Dec. 3 in JAMA Psychiatry.
Social isolation a key driver
Emergency medical services (EMS) data are available in near real time, providing a novel source of up-to-date information to monitor epidemiological shifts during the COVID-19 pandemic.
For the study, the researchers leveraged data from the National EMS Information System, a large registry of more than 10,000 EMS agencies in 47 states that represent over 80% of all EMS calls nationally in 2020. They used the data to track shifts in overdose-related cardiac arrests observed by EMS.
They found clear evidence of a large-scale uptick in overdose-related deaths during the COVID-19 pandemic.
The overall rate of overdose-related cardiac arrests in 2020 was about 50% higher than trends observed during 2018 and 2019, including a maximum peak of 123% above baseline reached in early May.
All overdose-related incidents (fatal and nonfatal) were elevated in 2020, by about 17% above baseline. However, there were larger increases in fatal overdose-related incidents, compared to all incidents, which may suggest a rising case fatality rate, the authors noted.
The observed trends line up in time with reductions in mobility (a metric of social interaction), as measured using cell phone data, they wrote.
“Many of the trends predicted by experts at the beginning of the pandemic could cause these shifts. Increases in social isolation likely play an important role, as people using [drugs] alone are less likely to receive help when they need it. Also shifts in the drug supply, and reduced access to healthcare and treatment,” said Mr. Friedman.
“We need to undertake short- and long-term strategies to combat the rising tide of overdose mortality in the United States,” he added.
In the short term, Mr. Friedman suggested reducing financial and logistical barriers for accessing a safe opioid supply. Such measures include allowing pharmacies to dispense methadone, allowing all physicians to prescribe buprenorphine without a special waiver, and releasing emergency funds to make these medications universally affordable.
“In the longer term, we should acknowledge that overdose is a symptom of structural problems in the U.S. We need to invest in making employment, housing, education, and health care accessible to all to address the upstream drivers of overdose,” he added.
The study had no commercial funding. The authors disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
New AHA scientific statement on menopause and CVD risk
Changes in hormones, body composition, lipids, and vascular health during the menopause transition can increase a woman’s chance of developing cardiovascular disease (CVD) after menopause, the American Heart Association said in a scientific statement.
“This statement aims to raise awareness of both healthcare providers and women about the menopause transition as a time of increasing heart disease risk,” Samar R. El Khoudary, PhD, MPH, who chaired the writing group, said in an interview.
“As such, it emphasizes the importance of monitoring women’s health during midlife and targeting this stage as a critical window for applying early intervention strategies that aim to maintain a healthy heart and reduce the risk of heart disease,” said Dr. El Khoudary, of the University of Pittsburgh.
The statement was published online Nov. 30 in Circulation.
Evolution in knowledge
During the past 20 years, knowledge of how menopause might contribute to CVD has evolved “dramatically,” Dr. El Khoudary noted. The accumulated data consistently point to the menopause transition as a time of change in heart health.
“Importantly,” she said, the latest AHA guidelines for CVD prevention in women, published in 2011, do not include data now available on the menopause transition as a time of increased CVD risk.
“As such, there is a compelling need to discuss the implications of the accumulating body of literature on this topic,” said Dr. El Khoudary.
The statement provides a contemporary synthesis of the existing data on menopause and how it relates to CVD, the leading cause of death of U.S. women.
Earlier age at natural menopause has generally been found to be a marker of greater CVD risk. Iatrogenically induced menopause (bilateral oophorectomy) during the premenopausal period is also associated with higher CVD risk, the data suggest.
Vasomotor symptoms are associated with worse levels of CVD risk factors and measures of subclinical atherosclerosis. Sleep disturbance has also been linked to greater risk for subclinical CVD and worse CV health indexes in women during midlife.
Increases in central/visceral fat and decreases in lean muscle mass are more pronounced during the menopause transition. This increased central adiposity is associated with increased risk for mortality, even among those with normal body mass index, the writing group found.
Increases in lipid levels (LDL cholesterol and apolipoprotein B), metabolic syndrome risk, and vascular remodeling at midlife are driven by the menopause transition more than aging, whereas increases in blood pressure, insulin level, and glucose level are likely more influenced by chronological aging, they reported.
Lifestyle interventions
The writing group noted that, because of the increase in overall life expectancy in the United States, a significant proportion of women will spend up to 40% of their lives after menopause.
Yet data suggest that only 7.2% of women transitioning to menopause are meeting physical activity guidelines and that fewer than 20% of those women are consistently maintaining a healthy diet.
Limited data from randomized, controlled trials suggest that a multidimensional lifestyle intervention during the menopause transition can prevent weight gain and reduce blood pressure and levels of triglycerides, blood glucose, and insulin and reduce the incidence of subclinical carotid atherosclerosis, they pointed out.
“Novel data” indicate a reversal in the associations of HDL cholesterol with CVD risk over the menopause transition, suggesting that higher HDL cholesterol levels may not consistently reflect good cardiovascular health in middle-aged women, the group noted.
There are also data suggesting that starting menopause hormone therapy when younger than 60 years or within 10 years of menopause is associated with reduced CVD risk.
The group said further research is needed into the cardiometabolic effects of menopause hormone therapy, including effects associated with form, route, and duration of administration, in women traversing menopause.
They also noted that data for the primary and secondary prevention of atherosclerotic CVD and improved survival with lipid-lowering interventions “remain elusive” for women and that further study is needed to develop evidence-based recommendations tailored specifically to women.
The research had no commercial funding. Dr. El Khoudary has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Changes in hormones, body composition, lipids, and vascular health during the menopause transition can increase a woman’s chance of developing cardiovascular disease (CVD) after menopause, the American Heart Association said in a scientific statement.
“This statement aims to raise awareness of both healthcare providers and women about the menopause transition as a time of increasing heart disease risk,” Samar R. El Khoudary, PhD, MPH, who chaired the writing group, said in an interview.
“As such, it emphasizes the importance of monitoring women’s health during midlife and targeting this stage as a critical window for applying early intervention strategies that aim to maintain a healthy heart and reduce the risk of heart disease,” said Dr. El Khoudary, of the University of Pittsburgh.
The statement was published online Nov. 30 in Circulation.
Evolution in knowledge
During the past 20 years, knowledge of how menopause might contribute to CVD has evolved “dramatically,” Dr. El Khoudary noted. The accumulated data consistently point to the menopause transition as a time of change in heart health.
“Importantly,” she said, the latest AHA guidelines for CVD prevention in women, published in 2011, do not include data now available on the menopause transition as a time of increased CVD risk.
“As such, there is a compelling need to discuss the implications of the accumulating body of literature on this topic,” said Dr. El Khoudary.
The statement provides a contemporary synthesis of the existing data on menopause and how it relates to CVD, the leading cause of death of U.S. women.
Earlier age at natural menopause has generally been found to be a marker of greater CVD risk. Iatrogenically induced menopause (bilateral oophorectomy) during the premenopausal period is also associated with higher CVD risk, the data suggest.
Vasomotor symptoms are associated with worse levels of CVD risk factors and measures of subclinical atherosclerosis. Sleep disturbance has also been linked to greater risk for subclinical CVD and worse CV health indexes in women during midlife.
Increases in central/visceral fat and decreases in lean muscle mass are more pronounced during the menopause transition. This increased central adiposity is associated with increased risk for mortality, even among those with normal body mass index, the writing group found.
Increases in lipid levels (LDL cholesterol and apolipoprotein B), metabolic syndrome risk, and vascular remodeling at midlife are driven by the menopause transition more than aging, whereas increases in blood pressure, insulin level, and glucose level are likely more influenced by chronological aging, they reported.
Lifestyle interventions
The writing group noted that, because of the increase in overall life expectancy in the United States, a significant proportion of women will spend up to 40% of their lives after menopause.
Yet data suggest that only 7.2% of women transitioning to menopause are meeting physical activity guidelines and that fewer than 20% of those women are consistently maintaining a healthy diet.
Limited data from randomized, controlled trials suggest that a multidimensional lifestyle intervention during the menopause transition can prevent weight gain and reduce blood pressure and levels of triglycerides, blood glucose, and insulin and reduce the incidence of subclinical carotid atherosclerosis, they pointed out.
“Novel data” indicate a reversal in the associations of HDL cholesterol with CVD risk over the menopause transition, suggesting that higher HDL cholesterol levels may not consistently reflect good cardiovascular health in middle-aged women, the group noted.
There are also data suggesting that starting menopause hormone therapy when younger than 60 years or within 10 years of menopause is associated with reduced CVD risk.
The group said further research is needed into the cardiometabolic effects of menopause hormone therapy, including effects associated with form, route, and duration of administration, in women traversing menopause.
They also noted that data for the primary and secondary prevention of atherosclerotic CVD and improved survival with lipid-lowering interventions “remain elusive” for women and that further study is needed to develop evidence-based recommendations tailored specifically to women.
The research had no commercial funding. Dr. El Khoudary has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Changes in hormones, body composition, lipids, and vascular health during the menopause transition can increase a woman’s chance of developing cardiovascular disease (CVD) after menopause, the American Heart Association said in a scientific statement.
“This statement aims to raise awareness of both healthcare providers and women about the menopause transition as a time of increasing heart disease risk,” Samar R. El Khoudary, PhD, MPH, who chaired the writing group, said in an interview.
“As such, it emphasizes the importance of monitoring women’s health during midlife and targeting this stage as a critical window for applying early intervention strategies that aim to maintain a healthy heart and reduce the risk of heart disease,” said Dr. El Khoudary, of the University of Pittsburgh.
The statement was published online Nov. 30 in Circulation.
Evolution in knowledge
During the past 20 years, knowledge of how menopause might contribute to CVD has evolved “dramatically,” Dr. El Khoudary noted. The accumulated data consistently point to the menopause transition as a time of change in heart health.
“Importantly,” she said, the latest AHA guidelines for CVD prevention in women, published in 2011, do not include data now available on the menopause transition as a time of increased CVD risk.
“As such, there is a compelling need to discuss the implications of the accumulating body of literature on this topic,” said Dr. El Khoudary.
The statement provides a contemporary synthesis of the existing data on menopause and how it relates to CVD, the leading cause of death of U.S. women.
Earlier age at natural menopause has generally been found to be a marker of greater CVD risk. Iatrogenically induced menopause (bilateral oophorectomy) during the premenopausal period is also associated with higher CVD risk, the data suggest.
Vasomotor symptoms are associated with worse levels of CVD risk factors and measures of subclinical atherosclerosis. Sleep disturbance has also been linked to greater risk for subclinical CVD and worse CV health indexes in women during midlife.
Increases in central/visceral fat and decreases in lean muscle mass are more pronounced during the menopause transition. This increased central adiposity is associated with increased risk for mortality, even among those with normal body mass index, the writing group found.
Increases in lipid levels (LDL cholesterol and apolipoprotein B), metabolic syndrome risk, and vascular remodeling at midlife are driven by the menopause transition more than aging, whereas increases in blood pressure, insulin level, and glucose level are likely more influenced by chronological aging, they reported.
Lifestyle interventions
The writing group noted that, because of the increase in overall life expectancy in the United States, a significant proportion of women will spend up to 40% of their lives after menopause.
Yet data suggest that only 7.2% of women transitioning to menopause are meeting physical activity guidelines and that fewer than 20% of those women are consistently maintaining a healthy diet.
Limited data from randomized, controlled trials suggest that a multidimensional lifestyle intervention during the menopause transition can prevent weight gain and reduce blood pressure and levels of triglycerides, blood glucose, and insulin and reduce the incidence of subclinical carotid atherosclerosis, they pointed out.
“Novel data” indicate a reversal in the associations of HDL cholesterol with CVD risk over the menopause transition, suggesting that higher HDL cholesterol levels may not consistently reflect good cardiovascular health in middle-aged women, the group noted.
There are also data suggesting that starting menopause hormone therapy when younger than 60 years or within 10 years of menopause is associated with reduced CVD risk.
The group said further research is needed into the cardiometabolic effects of menopause hormone therapy, including effects associated with form, route, and duration of administration, in women traversing menopause.
They also noted that data for the primary and secondary prevention of atherosclerotic CVD and improved survival with lipid-lowering interventions “remain elusive” for women and that further study is needed to develop evidence-based recommendations tailored specifically to women.
The research had no commercial funding. Dr. El Khoudary has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Potential new option: 1-month DAPT post DES, then aspirin alone
One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.
This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.
“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”
The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
Patients with stable angina fared best
The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.
Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.
Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
Trial’s shortcomings temper reaction
“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.
That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.
Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.
“Let’s provide these patients with some options,” the cardiologist urged.
He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.
“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.
Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”
“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.
“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”
Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.
One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.
This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.
“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”
The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
Patients with stable angina fared best
The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.
Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.
Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
Trial’s shortcomings temper reaction
“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.
That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.
Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.
“Let’s provide these patients with some options,” the cardiologist urged.
He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.
“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.
Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”
“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.
“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”
Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.
One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.
This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.
“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”
The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
Patients with stable angina fared best
The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.
Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.
Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
Trial’s shortcomings temper reaction
“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.
That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.
Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.
“Let’s provide these patients with some options,” the cardiologist urged.
He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.
“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.
Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”
“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.
“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”
Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.
FROM AHA 2020
Stenotic lesion outcomes better if fractional flow reserve guides PCI
Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.
For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.
“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”
The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.
“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.
In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.
The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.
Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.
In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.
In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.
It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.
“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.
Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.
“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.
“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.
Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.
For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.
“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”
The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.
“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.
In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.
The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.
Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.
In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.
In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.
It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.
“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.
Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.
“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.
“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.
Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.
For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.
“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”
The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.
“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.
In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.
The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.
Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.
In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.
In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.
It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.
“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.
Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.
“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.
“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.
FROM AHA 2020
SAMSON pins most muscle pain experienced with statins on the nocebo effect
A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.
The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).
“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.
Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.
“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.
Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.
For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.
“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”
Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.
In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.
All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.
So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”
Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”
The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.
Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.
Eleven patients were unable to complete all 12 1-month segments of the trial.
The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.
A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.
In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”
The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”
SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.
A version of this article originally appeared on Medscape.com.
A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.
The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).
“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.
Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.
“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.
Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.
For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.
“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”
Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.
In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.
All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.
So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”
Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”
The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.
Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.
Eleven patients were unable to complete all 12 1-month segments of the trial.
The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.
A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.
In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”
The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”
SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.
A version of this article originally appeared on Medscape.com.
A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.
The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).
“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.
Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.
“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.
Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.
For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.
“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”
Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.
In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.
All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.
So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”
Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”
The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.
Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.
Eleven patients were unable to complete all 12 1-month segments of the trial.
The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.
A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.
In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”
The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”
SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.
A version of this article originally appeared on Medscape.com.
STRENGTH trial questions CV benefit of high-dose omega-3s
Questions about the cardiovascular benefit of omega-3 fatty acids and the high-dose eicosapentaenoic acid (EPA) product, icosapent ethyl (Vascepa, Amarin), have resurfaced with the presentation and publication of the STRENGTH trial using a combined high-dose omega-3 fatty acid product.
The STRENGTH trial showed no benefit on cardiovascular event rates of a high-dose combination of EPA and docosahexaenoic acid (DHA) in a new branded product (Epanova, AstraZeneca).
It was announced in January that the trial was being stopped because of a low likelihood of showing any benefit.
Full results were presented Nov. 15 at the virtual American Heart Association scientific sessions and simultaneously published online in JAMA.
These results showed similar cardiovascular event rates with the high-dose EPA/DHA product and placebo, with a hazard ratio for the primary endpoint of 0.99. In addition to no benefit, more adverse effects occurred in the active treatment arm, with a higher rate of gastrointestinal adverse events and atrial fibrillation.
“We found no benefit of a high-dose combination of EPA and DHA. Despite a 270% to 300% increase in EPA, the hazard curves for the active and placebo groups were superimposable,” STRENGTH investigator A. Michael Lincoff, MD, of the Cleveland Clinic, said at the AHA meeting.
The big question is how the negative results of the STRENGTH trial can be reconciled with the very positive results of the REDUCE-IT trial, which showed an impressive 25% relative risk reduction in major adverse cardiovascular events with the high-dose purified EPA product, icosapent ethyl.
Dr. Lincoff proposed several possible explanations for the different results between these two trials, although he cautioned that all explanations were speculative.
The one explanation that Dr. Lincoff highlighted in particular was the different placebos used in the two trials. REDUCE-IT used a placebo of mineral oil, which Dr. Lincoff noted increases LDL, apolipoprotein B, and high-sensitivity C-reactive protein, whereas the corn oil placebo used in STRENGTH “is truly neutral on a broad range lipid and cardiovascular biomarkers,” he said.
“It must therefore be considered that at least part of the benefit in REDUCE-IT is due to an increase in adverse cardiovascular event rate in the control arm, and our results from STRENGTH cast uncertainly on the net benefit or harm of any omega-3 fatty acid preparation,” Dr. Lincoff said.
Asked whether he used omega-3 fatty acids in his practice, Dr. Lincoff replied, “Aside from patients with triglycerides greater than 500 – for which there is other evidence of benefit – I do not routinely prescribe omega-3 fatty acids. For the reasons discussed, I think there are questions about whether the risks and benefits have a favorable ratio.”
Asked at an AHA press conference what advice he would give to other physicians on the use of Vascepa, Dr. Lincoff said, “On the one hand, we could take the REDUCE-IT study results at face value, but there are potential concerns on the construct of that trial and whether the effects were exaggerated. That having been said, the [Food and Drug Administration] has approved that initial indication, so this is not a straightforward issue of whether or not that trial result is valid.
“What I would like to see is a trial in future with a clearly neutral comparator. It’s hard to recommend taking your patients off Vascepa now, but I have a high threshold at this point to start patients on it because of these concerns,” he added.
A “manufactured controversy”
The lead investigator of the REDUCE-IT trial, Deepak L. Bhatt, MD, professor of medicine, Harvard Medical School, Boston, described Dr. Lincoff’s comments as “absurd.”
In an interview, he said the Japanese JELIS trial, while having some limitations, also showed a benefit of icosapent ethyl, which “in the context of this manufactured controversy about the mineral oil placebo in REDUCE-IT, completely rebuts concerns about the placebo in REDUCE-IT being toxic.”
Dr. Bhatt also suggested that DHA may counter some of the benefits of EPA. “It appears that the STRENGTH trial leadership is trying to stir up controversy, rather than just reporting objectively that they have a negative trial,” he added.
Dr. Lincoff outlined other possible explanations for the difference between the two trials.
He noted that icosapent ethyl increased levels of EPA by 45% in REDUCE-IT more than did the combined product used in STRENGTH. “But this moderate difference seems insufficient to account for the markedly different results of the two trials,” Dr. Lincoff added, “and both trials showed a 19% reduction in triglycerides, suggesting they have similar biochemical effects.”
There is also the possibility of an adverse effect of DHA, he noted, “but this has never been seen in previous studies.”
Another explanation could be differences in trial populations, with REDUCE-IT including more patients with established cardiovascular disease. “But the results were no different in this group compared to the patients without established cardiovascular disease, so this explanation is unlikely,” Dr. Lincoff suggested.
STRENGTH trial
The STRENGTH trial included 13,078 statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of HDL cholesterol from 22 countries.
They were randomly assigned to a 4 g per day of carboxylic acid formulation of EPA and DHA or to corn oil as an inert comparator.
The trial was halted when 1,384 patients had experienced a primary endpoint event (of a planned 1,600 events), based on an interim analysis that indicated a low probability of clinical benefit of the active treatment.
At this point, the primary efficacy endpoint – a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization – occurred in 12.0% of patients treated with the omega-3 product vs. 12.2% of those who received corn oil (hazard ratio [HR], 0.99; P = .84).
A greater rate of gastrointestinal adverse events was observed in the omega-3 group (24.7%) than in corn oil–treated patients (14.7%). An increased rate of new-onset atrial fibrillation was also observed in the omega-3 group (2.2% vs 1.3%; HR, 1.69).
Uncertainty prevails
The moderator of an AHA press conference at which the STRENGTH trial was discussed, Amit Khera, MD, professor of medicine and director of preventive cardiology at UT Southwestern Medical Center, Dallas, said in an interview that questions about how Vascepa brought about the benefits shown in REDUCE-IT have been ongoing since that trial was published.
“I think for now, we have to accept the REDUCE-IT results as a positive finding. However, the STRENGTH trial did amplify these questions a bit since there was no signal at all for benefit, and this heightens the call for additional trials of high-dose EPA formulations, including icosapent ethyl, versus corn oil or another neutral comparator,” he said.
Discussant of the STRENGTH trial at the AHA late-breaker session, Alberico Catapano, MD, PhD, University of Milan, noted that DHA may have less biological activity than EPA.
“We don’t know for certain, but there are studies suggesting that EPA may have more effect on stabilizing plaque membranes,” Dr. Catapano said. “Certainly, the dose of EPA was different in the two studies, and in my view this could be part of the explanation. But we are still in place where we need more evidence.”
In an editorial accompanying the JAMA publication of STRENGTH, Garima Sharma, MD, Seth S. Martin, MD, and Roger S. Blumenthal, MD, Johns Hopkins University, Baltimore, said the trial’s findings “may invigorate further investigation regarding IPE [icosapent ethyl], generate additional constructive debate around the optimal placebo control, and should prompt reconsideration of over-the-counter mixed omega-3 fatty acid products for ASCVD [atherosclerotic cardiovascular disease] prevention.
“This latter point is especially important given the lack of evidence for benefit, and the potential for harm due to increased AF [atrial fibrillation],” they noted.
“The reasons the findings from the REDUCE-IT trial were positive and the STRENGTH trial were not, and that EPA levels correlated with outcomes in REDUCE-IT but did not in STRENGTH, remain uncertain,” they concluded. “The importance of the specific omega-3 formulation in achieving ASCVD risk reduction and the degree to which the placebo (i.e., mineral oil vs corn oil) may have affected outcomes remain unresolved.”
The STRENGTH trial was sponsored by AstraZeneca. Dr. Lincoff reported receiving grants from AstraZeneca during the conduct of the study. Dr. Catapano has received honoraria, lecture fees, or research grants from Sigma-Tau, Manarini, Kowa Pharmaceuticals, Recordati, Eli Lilly, AstraZeneca, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, Amgen, Genzyme, Bayer, Sanofi, Regeneron Daiichi Sankyo, and Amarin. Dr. Martin reports receiving consulting fees from AstraZeneca, Amgen, Esperion, and REGENXBIO, and has a patent pending for a system of LDL-C estimation filed by Johns Hopkins University. Dr. Bhatt reports serving as principal investigator for REDUCE-IT and that Brigham and Women’s Hospital has received research funding from Amarin.
A version of this article originally appeared on Medscape.com.
Questions about the cardiovascular benefit of omega-3 fatty acids and the high-dose eicosapentaenoic acid (EPA) product, icosapent ethyl (Vascepa, Amarin), have resurfaced with the presentation and publication of the STRENGTH trial using a combined high-dose omega-3 fatty acid product.
The STRENGTH trial showed no benefit on cardiovascular event rates of a high-dose combination of EPA and docosahexaenoic acid (DHA) in a new branded product (Epanova, AstraZeneca).
It was announced in January that the trial was being stopped because of a low likelihood of showing any benefit.
Full results were presented Nov. 15 at the virtual American Heart Association scientific sessions and simultaneously published online in JAMA.
These results showed similar cardiovascular event rates with the high-dose EPA/DHA product and placebo, with a hazard ratio for the primary endpoint of 0.99. In addition to no benefit, more adverse effects occurred in the active treatment arm, with a higher rate of gastrointestinal adverse events and atrial fibrillation.
“We found no benefit of a high-dose combination of EPA and DHA. Despite a 270% to 300% increase in EPA, the hazard curves for the active and placebo groups were superimposable,” STRENGTH investigator A. Michael Lincoff, MD, of the Cleveland Clinic, said at the AHA meeting.
The big question is how the negative results of the STRENGTH trial can be reconciled with the very positive results of the REDUCE-IT trial, which showed an impressive 25% relative risk reduction in major adverse cardiovascular events with the high-dose purified EPA product, icosapent ethyl.
Dr. Lincoff proposed several possible explanations for the different results between these two trials, although he cautioned that all explanations were speculative.
The one explanation that Dr. Lincoff highlighted in particular was the different placebos used in the two trials. REDUCE-IT used a placebo of mineral oil, which Dr. Lincoff noted increases LDL, apolipoprotein B, and high-sensitivity C-reactive protein, whereas the corn oil placebo used in STRENGTH “is truly neutral on a broad range lipid and cardiovascular biomarkers,” he said.
“It must therefore be considered that at least part of the benefit in REDUCE-IT is due to an increase in adverse cardiovascular event rate in the control arm, and our results from STRENGTH cast uncertainly on the net benefit or harm of any omega-3 fatty acid preparation,” Dr. Lincoff said.
Asked whether he used omega-3 fatty acids in his practice, Dr. Lincoff replied, “Aside from patients with triglycerides greater than 500 – for which there is other evidence of benefit – I do not routinely prescribe omega-3 fatty acids. For the reasons discussed, I think there are questions about whether the risks and benefits have a favorable ratio.”
Asked at an AHA press conference what advice he would give to other physicians on the use of Vascepa, Dr. Lincoff said, “On the one hand, we could take the REDUCE-IT study results at face value, but there are potential concerns on the construct of that trial and whether the effects were exaggerated. That having been said, the [Food and Drug Administration] has approved that initial indication, so this is not a straightforward issue of whether or not that trial result is valid.
“What I would like to see is a trial in future with a clearly neutral comparator. It’s hard to recommend taking your patients off Vascepa now, but I have a high threshold at this point to start patients on it because of these concerns,” he added.
A “manufactured controversy”
The lead investigator of the REDUCE-IT trial, Deepak L. Bhatt, MD, professor of medicine, Harvard Medical School, Boston, described Dr. Lincoff’s comments as “absurd.”
In an interview, he said the Japanese JELIS trial, while having some limitations, also showed a benefit of icosapent ethyl, which “in the context of this manufactured controversy about the mineral oil placebo in REDUCE-IT, completely rebuts concerns about the placebo in REDUCE-IT being toxic.”
Dr. Bhatt also suggested that DHA may counter some of the benefits of EPA. “It appears that the STRENGTH trial leadership is trying to stir up controversy, rather than just reporting objectively that they have a negative trial,” he added.
Dr. Lincoff outlined other possible explanations for the difference between the two trials.
He noted that icosapent ethyl increased levels of EPA by 45% in REDUCE-IT more than did the combined product used in STRENGTH. “But this moderate difference seems insufficient to account for the markedly different results of the two trials,” Dr. Lincoff added, “and both trials showed a 19% reduction in triglycerides, suggesting they have similar biochemical effects.”
There is also the possibility of an adverse effect of DHA, he noted, “but this has never been seen in previous studies.”
Another explanation could be differences in trial populations, with REDUCE-IT including more patients with established cardiovascular disease. “But the results were no different in this group compared to the patients without established cardiovascular disease, so this explanation is unlikely,” Dr. Lincoff suggested.
STRENGTH trial
The STRENGTH trial included 13,078 statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of HDL cholesterol from 22 countries.
They were randomly assigned to a 4 g per day of carboxylic acid formulation of EPA and DHA or to corn oil as an inert comparator.
The trial was halted when 1,384 patients had experienced a primary endpoint event (of a planned 1,600 events), based on an interim analysis that indicated a low probability of clinical benefit of the active treatment.
At this point, the primary efficacy endpoint – a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization – occurred in 12.0% of patients treated with the omega-3 product vs. 12.2% of those who received corn oil (hazard ratio [HR], 0.99; P = .84).
A greater rate of gastrointestinal adverse events was observed in the omega-3 group (24.7%) than in corn oil–treated patients (14.7%). An increased rate of new-onset atrial fibrillation was also observed in the omega-3 group (2.2% vs 1.3%; HR, 1.69).
Uncertainty prevails
The moderator of an AHA press conference at which the STRENGTH trial was discussed, Amit Khera, MD, professor of medicine and director of preventive cardiology at UT Southwestern Medical Center, Dallas, said in an interview that questions about how Vascepa brought about the benefits shown in REDUCE-IT have been ongoing since that trial was published.
“I think for now, we have to accept the REDUCE-IT results as a positive finding. However, the STRENGTH trial did amplify these questions a bit since there was no signal at all for benefit, and this heightens the call for additional trials of high-dose EPA formulations, including icosapent ethyl, versus corn oil or another neutral comparator,” he said.
Discussant of the STRENGTH trial at the AHA late-breaker session, Alberico Catapano, MD, PhD, University of Milan, noted that DHA may have less biological activity than EPA.
“We don’t know for certain, but there are studies suggesting that EPA may have more effect on stabilizing plaque membranes,” Dr. Catapano said. “Certainly, the dose of EPA was different in the two studies, and in my view this could be part of the explanation. But we are still in place where we need more evidence.”
In an editorial accompanying the JAMA publication of STRENGTH, Garima Sharma, MD, Seth S. Martin, MD, and Roger S. Blumenthal, MD, Johns Hopkins University, Baltimore, said the trial’s findings “may invigorate further investigation regarding IPE [icosapent ethyl], generate additional constructive debate around the optimal placebo control, and should prompt reconsideration of over-the-counter mixed omega-3 fatty acid products for ASCVD [atherosclerotic cardiovascular disease] prevention.
“This latter point is especially important given the lack of evidence for benefit, and the potential for harm due to increased AF [atrial fibrillation],” they noted.
“The reasons the findings from the REDUCE-IT trial were positive and the STRENGTH trial were not, and that EPA levels correlated with outcomes in REDUCE-IT but did not in STRENGTH, remain uncertain,” they concluded. “The importance of the specific omega-3 formulation in achieving ASCVD risk reduction and the degree to which the placebo (i.e., mineral oil vs corn oil) may have affected outcomes remain unresolved.”
The STRENGTH trial was sponsored by AstraZeneca. Dr. Lincoff reported receiving grants from AstraZeneca during the conduct of the study. Dr. Catapano has received honoraria, lecture fees, or research grants from Sigma-Tau, Manarini, Kowa Pharmaceuticals, Recordati, Eli Lilly, AstraZeneca, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, Amgen, Genzyme, Bayer, Sanofi, Regeneron Daiichi Sankyo, and Amarin. Dr. Martin reports receiving consulting fees from AstraZeneca, Amgen, Esperion, and REGENXBIO, and has a patent pending for a system of LDL-C estimation filed by Johns Hopkins University. Dr. Bhatt reports serving as principal investigator for REDUCE-IT and that Brigham and Women’s Hospital has received research funding from Amarin.
A version of this article originally appeared on Medscape.com.
Questions about the cardiovascular benefit of omega-3 fatty acids and the high-dose eicosapentaenoic acid (EPA) product, icosapent ethyl (Vascepa, Amarin), have resurfaced with the presentation and publication of the STRENGTH trial using a combined high-dose omega-3 fatty acid product.
The STRENGTH trial showed no benefit on cardiovascular event rates of a high-dose combination of EPA and docosahexaenoic acid (DHA) in a new branded product (Epanova, AstraZeneca).
It was announced in January that the trial was being stopped because of a low likelihood of showing any benefit.
Full results were presented Nov. 15 at the virtual American Heart Association scientific sessions and simultaneously published online in JAMA.
These results showed similar cardiovascular event rates with the high-dose EPA/DHA product and placebo, with a hazard ratio for the primary endpoint of 0.99. In addition to no benefit, more adverse effects occurred in the active treatment arm, with a higher rate of gastrointestinal adverse events and atrial fibrillation.
“We found no benefit of a high-dose combination of EPA and DHA. Despite a 270% to 300% increase in EPA, the hazard curves for the active and placebo groups were superimposable,” STRENGTH investigator A. Michael Lincoff, MD, of the Cleveland Clinic, said at the AHA meeting.
The big question is how the negative results of the STRENGTH trial can be reconciled with the very positive results of the REDUCE-IT trial, which showed an impressive 25% relative risk reduction in major adverse cardiovascular events with the high-dose purified EPA product, icosapent ethyl.
Dr. Lincoff proposed several possible explanations for the different results between these two trials, although he cautioned that all explanations were speculative.
The one explanation that Dr. Lincoff highlighted in particular was the different placebos used in the two trials. REDUCE-IT used a placebo of mineral oil, which Dr. Lincoff noted increases LDL, apolipoprotein B, and high-sensitivity C-reactive protein, whereas the corn oil placebo used in STRENGTH “is truly neutral on a broad range lipid and cardiovascular biomarkers,” he said.
“It must therefore be considered that at least part of the benefit in REDUCE-IT is due to an increase in adverse cardiovascular event rate in the control arm, and our results from STRENGTH cast uncertainly on the net benefit or harm of any omega-3 fatty acid preparation,” Dr. Lincoff said.
Asked whether he used omega-3 fatty acids in his practice, Dr. Lincoff replied, “Aside from patients with triglycerides greater than 500 – for which there is other evidence of benefit – I do not routinely prescribe omega-3 fatty acids. For the reasons discussed, I think there are questions about whether the risks and benefits have a favorable ratio.”
Asked at an AHA press conference what advice he would give to other physicians on the use of Vascepa, Dr. Lincoff said, “On the one hand, we could take the REDUCE-IT study results at face value, but there are potential concerns on the construct of that trial and whether the effects were exaggerated. That having been said, the [Food and Drug Administration] has approved that initial indication, so this is not a straightforward issue of whether or not that trial result is valid.
“What I would like to see is a trial in future with a clearly neutral comparator. It’s hard to recommend taking your patients off Vascepa now, but I have a high threshold at this point to start patients on it because of these concerns,” he added.
A “manufactured controversy”
The lead investigator of the REDUCE-IT trial, Deepak L. Bhatt, MD, professor of medicine, Harvard Medical School, Boston, described Dr. Lincoff’s comments as “absurd.”
In an interview, he said the Japanese JELIS trial, while having some limitations, also showed a benefit of icosapent ethyl, which “in the context of this manufactured controversy about the mineral oil placebo in REDUCE-IT, completely rebuts concerns about the placebo in REDUCE-IT being toxic.”
Dr. Bhatt also suggested that DHA may counter some of the benefits of EPA. “It appears that the STRENGTH trial leadership is trying to stir up controversy, rather than just reporting objectively that they have a negative trial,” he added.
Dr. Lincoff outlined other possible explanations for the difference between the two trials.
He noted that icosapent ethyl increased levels of EPA by 45% in REDUCE-IT more than did the combined product used in STRENGTH. “But this moderate difference seems insufficient to account for the markedly different results of the two trials,” Dr. Lincoff added, “and both trials showed a 19% reduction in triglycerides, suggesting they have similar biochemical effects.”
There is also the possibility of an adverse effect of DHA, he noted, “but this has never been seen in previous studies.”
Another explanation could be differences in trial populations, with REDUCE-IT including more patients with established cardiovascular disease. “But the results were no different in this group compared to the patients without established cardiovascular disease, so this explanation is unlikely,” Dr. Lincoff suggested.
STRENGTH trial
The STRENGTH trial included 13,078 statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of HDL cholesterol from 22 countries.
They were randomly assigned to a 4 g per day of carboxylic acid formulation of EPA and DHA or to corn oil as an inert comparator.
The trial was halted when 1,384 patients had experienced a primary endpoint event (of a planned 1,600 events), based on an interim analysis that indicated a low probability of clinical benefit of the active treatment.
At this point, the primary efficacy endpoint – a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization – occurred in 12.0% of patients treated with the omega-3 product vs. 12.2% of those who received corn oil (hazard ratio [HR], 0.99; P = .84).
A greater rate of gastrointestinal adverse events was observed in the omega-3 group (24.7%) than in corn oil–treated patients (14.7%). An increased rate of new-onset atrial fibrillation was also observed in the omega-3 group (2.2% vs 1.3%; HR, 1.69).
Uncertainty prevails
The moderator of an AHA press conference at which the STRENGTH trial was discussed, Amit Khera, MD, professor of medicine and director of preventive cardiology at UT Southwestern Medical Center, Dallas, said in an interview that questions about how Vascepa brought about the benefits shown in REDUCE-IT have been ongoing since that trial was published.
“I think for now, we have to accept the REDUCE-IT results as a positive finding. However, the STRENGTH trial did amplify these questions a bit since there was no signal at all for benefit, and this heightens the call for additional trials of high-dose EPA formulations, including icosapent ethyl, versus corn oil or another neutral comparator,” he said.
Discussant of the STRENGTH trial at the AHA late-breaker session, Alberico Catapano, MD, PhD, University of Milan, noted that DHA may have less biological activity than EPA.
“We don’t know for certain, but there are studies suggesting that EPA may have more effect on stabilizing plaque membranes,” Dr. Catapano said. “Certainly, the dose of EPA was different in the two studies, and in my view this could be part of the explanation. But we are still in place where we need more evidence.”
In an editorial accompanying the JAMA publication of STRENGTH, Garima Sharma, MD, Seth S. Martin, MD, and Roger S. Blumenthal, MD, Johns Hopkins University, Baltimore, said the trial’s findings “may invigorate further investigation regarding IPE [icosapent ethyl], generate additional constructive debate around the optimal placebo control, and should prompt reconsideration of over-the-counter mixed omega-3 fatty acid products for ASCVD [atherosclerotic cardiovascular disease] prevention.
“This latter point is especially important given the lack of evidence for benefit, and the potential for harm due to increased AF [atrial fibrillation],” they noted.
“The reasons the findings from the REDUCE-IT trial were positive and the STRENGTH trial were not, and that EPA levels correlated with outcomes in REDUCE-IT but did not in STRENGTH, remain uncertain,” they concluded. “The importance of the specific omega-3 formulation in achieving ASCVD risk reduction and the degree to which the placebo (i.e., mineral oil vs corn oil) may have affected outcomes remain unresolved.”
The STRENGTH trial was sponsored by AstraZeneca. Dr. Lincoff reported receiving grants from AstraZeneca during the conduct of the study. Dr. Catapano has received honoraria, lecture fees, or research grants from Sigma-Tau, Manarini, Kowa Pharmaceuticals, Recordati, Eli Lilly, AstraZeneca, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, Amgen, Genzyme, Bayer, Sanofi, Regeneron Daiichi Sankyo, and Amarin. Dr. Martin reports receiving consulting fees from AstraZeneca, Amgen, Esperion, and REGENXBIO, and has a patent pending for a system of LDL-C estimation filed by Johns Hopkins University. Dr. Bhatt reports serving as principal investigator for REDUCE-IT and that Brigham and Women’s Hospital has received research funding from Amarin.
A version of this article originally appeared on Medscape.com.
Chronic inflammatory diseases vary widely in CHD risk
Not all chronic systemic inflammatory diseases are equal enhancers of atherosclerotic cardiovascular disease risk, according to a large case-control study.
Current AHA/American College of Cardiology guidelines cite three chronic inflammatory diseases as atherosclerotic cardiovascular disease risk enhancers: rheumatoid arthritis, psoriasis, and HIV infection. But this study of those three diseases, along with three others marked by elevated high sensitivity C-reactive protein (systemic sclerosis, inflammatory bowel disease, and systemic lupus erythematosus [SLE]), showed that chronic inflammatory diseases are not monolithic in terms of their associated risk of incident coronary heart disease (CHD).
Indeed, two of the six inflammatory diseases – psoriasis and inflammatory bowel disease – turned out to be not at all associated with increased cardiovascular risk in the 37,117-patient study. The highest-risk disease was SLE, not specifically mentioned in the guidelines, Arjun Sinha, MD, a cardiology fellow at Northwestern University, Chicago, noted in his presentation at the virtual American Heart Association scientific sessions.
The study included 18,129 patients with one of the six chronic inflammatory diseases and 18,988 matched controls, none with CHD at baseline. All regularly received outpatient care at Northwestern during 2000-2019. There were 1,011 incident CHD events during a median of 3.5 years of follow-up.
In a Cox proportional hazards analysis adjusted for demographics, insurance status, hypertension, diabetes, current smoking, total cholesterol, and estimated glomerular filtration rate, here’s how the chronic inflammatory diseases stacked up in terms of incident CHD and MI risks:
- SLE: hazard ratio for CHD, 2.85; for MI, 4.76.
- Systemic sclerosis: HR for CHD, 2.14; for MI, 3.19.
- HIV: HR for CHD, 1.38; for MI, 1.69.
- Rheumatoid arthritis: HR for CHD, 1.22; for MI, 1.45.
- Psoriasis: no significant increase.
- Inflammatory bowel disease: no significant increase.
In an exploratory analysis, Dr. Sinha and coinvestigators evaluated the risk of incident CHD stratified by disease severity. For lack of standardized disease severity scales, the investigators relied upon tertiles of CD4 T cell count in the HIV group and CRP in the others. The HR for new-onset CHD in the more than 5,000 patients with psoriasis didn’t vary by CRP tertile. However, there was a nonsignificant trend for greater disease severity, as reflected by CRP tertile, to be associated with increased incident CHD risk in the HIV and inflammatory bowel disease groups.
In contrast, patients with rheumatoid arthritis or systemic sclerosis who were in the top CRP tertile had a significantly greater risk of developing CHD than that of controls, with HRs of 2.11 in the rheumatoid arthritis group and 4.59 with systemic sclerosis, although patients in the other two tertiles weren’t at significantly increased risk. But all three tertiles of CRP in patients with SLE were associated with significantly increased CHD risk: 3.17-fold in the lowest tertile of lupus severity, 5.38-fold in the middle tertile, and 4.04-fold in the top tertile for inflammation.
These findings could be used in clinical practice to fine-tune atherosclerotic cardiovascular disease risk assessment based upon chronic inflammatory disease type and severity. That’s information which in turn can help guide the timing and intensity of preventive therapy for patients with each disease type.
But studying the association between chronic systemic inflammatory diseases and CHD risk can be useful in additional ways, according to Dr. Sinha. These inflammatory diseases can serve as models of atherosclerosis that shed light on the non–lipid-related mechanisms involved in cardiovascular disease.
“The gradient in risk may be hypothesis-generating with respect to which specific inflammatory pathways may contribute to CHD,” he explained.
Each of these six chronic inflammatory diseases is characterized by a different form of major immune dysfunction, Dr. Sinha continued. A case in point is SLE, the inflammatory disease associated with the highest risk of CHD and MI. Lupus is characterized by a form of neutrophil dysfunction marked by increased formation and reduced degradation of neutrophil extracellular traps, or NETs, as well as by an increase in autoreactive B cells and dysfunctional CD4+ T helper cells. The increase in NETs of of particular interest because NETs have also been shown to contribute to the development of atherosclerosis, endothelial dysfunction, plaque erosion, and thrombosis.
In another exploratory analysis, Dr. Sinha and coworkers found that SLE patients with a neutrophil count above the median level were twice as likely to develop CHD than were those with a neutrophil count below the median.
A better understanding of the upstream pathways linking NET formation in SLE and atherosclerosis could lead to development of new or repurposed medications that target immune dysfunction in order to curb atherosclerosis, said Dr. Sinha, whose study won the AHA’s Samuel A. Levine Early Career Clinical Investigator Award.
He reported having no financial conflicts regarding his study.
Not all chronic systemic inflammatory diseases are equal enhancers of atherosclerotic cardiovascular disease risk, according to a large case-control study.
Current AHA/American College of Cardiology guidelines cite three chronic inflammatory diseases as atherosclerotic cardiovascular disease risk enhancers: rheumatoid arthritis, psoriasis, and HIV infection. But this study of those three diseases, along with three others marked by elevated high sensitivity C-reactive protein (systemic sclerosis, inflammatory bowel disease, and systemic lupus erythematosus [SLE]), showed that chronic inflammatory diseases are not monolithic in terms of their associated risk of incident coronary heart disease (CHD).
Indeed, two of the six inflammatory diseases – psoriasis and inflammatory bowel disease – turned out to be not at all associated with increased cardiovascular risk in the 37,117-patient study. The highest-risk disease was SLE, not specifically mentioned in the guidelines, Arjun Sinha, MD, a cardiology fellow at Northwestern University, Chicago, noted in his presentation at the virtual American Heart Association scientific sessions.
The study included 18,129 patients with one of the six chronic inflammatory diseases and 18,988 matched controls, none with CHD at baseline. All regularly received outpatient care at Northwestern during 2000-2019. There were 1,011 incident CHD events during a median of 3.5 years of follow-up.
In a Cox proportional hazards analysis adjusted for demographics, insurance status, hypertension, diabetes, current smoking, total cholesterol, and estimated glomerular filtration rate, here’s how the chronic inflammatory diseases stacked up in terms of incident CHD and MI risks:
- SLE: hazard ratio for CHD, 2.85; for MI, 4.76.
- Systemic sclerosis: HR for CHD, 2.14; for MI, 3.19.
- HIV: HR for CHD, 1.38; for MI, 1.69.
- Rheumatoid arthritis: HR for CHD, 1.22; for MI, 1.45.
- Psoriasis: no significant increase.
- Inflammatory bowel disease: no significant increase.
In an exploratory analysis, Dr. Sinha and coinvestigators evaluated the risk of incident CHD stratified by disease severity. For lack of standardized disease severity scales, the investigators relied upon tertiles of CD4 T cell count in the HIV group and CRP in the others. The HR for new-onset CHD in the more than 5,000 patients with psoriasis didn’t vary by CRP tertile. However, there was a nonsignificant trend for greater disease severity, as reflected by CRP tertile, to be associated with increased incident CHD risk in the HIV and inflammatory bowel disease groups.
In contrast, patients with rheumatoid arthritis or systemic sclerosis who were in the top CRP tertile had a significantly greater risk of developing CHD than that of controls, with HRs of 2.11 in the rheumatoid arthritis group and 4.59 with systemic sclerosis, although patients in the other two tertiles weren’t at significantly increased risk. But all three tertiles of CRP in patients with SLE were associated with significantly increased CHD risk: 3.17-fold in the lowest tertile of lupus severity, 5.38-fold in the middle tertile, and 4.04-fold in the top tertile for inflammation.
These findings could be used in clinical practice to fine-tune atherosclerotic cardiovascular disease risk assessment based upon chronic inflammatory disease type and severity. That’s information which in turn can help guide the timing and intensity of preventive therapy for patients with each disease type.
But studying the association between chronic systemic inflammatory diseases and CHD risk can be useful in additional ways, according to Dr. Sinha. These inflammatory diseases can serve as models of atherosclerosis that shed light on the non–lipid-related mechanisms involved in cardiovascular disease.
“The gradient in risk may be hypothesis-generating with respect to which specific inflammatory pathways may contribute to CHD,” he explained.
Each of these six chronic inflammatory diseases is characterized by a different form of major immune dysfunction, Dr. Sinha continued. A case in point is SLE, the inflammatory disease associated with the highest risk of CHD and MI. Lupus is characterized by a form of neutrophil dysfunction marked by increased formation and reduced degradation of neutrophil extracellular traps, or NETs, as well as by an increase in autoreactive B cells and dysfunctional CD4+ T helper cells. The increase in NETs of of particular interest because NETs have also been shown to contribute to the development of atherosclerosis, endothelial dysfunction, plaque erosion, and thrombosis.
In another exploratory analysis, Dr. Sinha and coworkers found that SLE patients with a neutrophil count above the median level were twice as likely to develop CHD than were those with a neutrophil count below the median.
A better understanding of the upstream pathways linking NET formation in SLE and atherosclerosis could lead to development of new or repurposed medications that target immune dysfunction in order to curb atherosclerosis, said Dr. Sinha, whose study won the AHA’s Samuel A. Levine Early Career Clinical Investigator Award.
He reported having no financial conflicts regarding his study.
Not all chronic systemic inflammatory diseases are equal enhancers of atherosclerotic cardiovascular disease risk, according to a large case-control study.
Current AHA/American College of Cardiology guidelines cite three chronic inflammatory diseases as atherosclerotic cardiovascular disease risk enhancers: rheumatoid arthritis, psoriasis, and HIV infection. But this study of those three diseases, along with three others marked by elevated high sensitivity C-reactive protein (systemic sclerosis, inflammatory bowel disease, and systemic lupus erythematosus [SLE]), showed that chronic inflammatory diseases are not monolithic in terms of their associated risk of incident coronary heart disease (CHD).
Indeed, two of the six inflammatory diseases – psoriasis and inflammatory bowel disease – turned out to be not at all associated with increased cardiovascular risk in the 37,117-patient study. The highest-risk disease was SLE, not specifically mentioned in the guidelines, Arjun Sinha, MD, a cardiology fellow at Northwestern University, Chicago, noted in his presentation at the virtual American Heart Association scientific sessions.
The study included 18,129 patients with one of the six chronic inflammatory diseases and 18,988 matched controls, none with CHD at baseline. All regularly received outpatient care at Northwestern during 2000-2019. There were 1,011 incident CHD events during a median of 3.5 years of follow-up.
In a Cox proportional hazards analysis adjusted for demographics, insurance status, hypertension, diabetes, current smoking, total cholesterol, and estimated glomerular filtration rate, here’s how the chronic inflammatory diseases stacked up in terms of incident CHD and MI risks:
- SLE: hazard ratio for CHD, 2.85; for MI, 4.76.
- Systemic sclerosis: HR for CHD, 2.14; for MI, 3.19.
- HIV: HR for CHD, 1.38; for MI, 1.69.
- Rheumatoid arthritis: HR for CHD, 1.22; for MI, 1.45.
- Psoriasis: no significant increase.
- Inflammatory bowel disease: no significant increase.
In an exploratory analysis, Dr. Sinha and coinvestigators evaluated the risk of incident CHD stratified by disease severity. For lack of standardized disease severity scales, the investigators relied upon tertiles of CD4 T cell count in the HIV group and CRP in the others. The HR for new-onset CHD in the more than 5,000 patients with psoriasis didn’t vary by CRP tertile. However, there was a nonsignificant trend for greater disease severity, as reflected by CRP tertile, to be associated with increased incident CHD risk in the HIV and inflammatory bowel disease groups.
In contrast, patients with rheumatoid arthritis or systemic sclerosis who were in the top CRP tertile had a significantly greater risk of developing CHD than that of controls, with HRs of 2.11 in the rheumatoid arthritis group and 4.59 with systemic sclerosis, although patients in the other two tertiles weren’t at significantly increased risk. But all three tertiles of CRP in patients with SLE were associated with significantly increased CHD risk: 3.17-fold in the lowest tertile of lupus severity, 5.38-fold in the middle tertile, and 4.04-fold in the top tertile for inflammation.
These findings could be used in clinical practice to fine-tune atherosclerotic cardiovascular disease risk assessment based upon chronic inflammatory disease type and severity. That’s information which in turn can help guide the timing and intensity of preventive therapy for patients with each disease type.
But studying the association between chronic systemic inflammatory diseases and CHD risk can be useful in additional ways, according to Dr. Sinha. These inflammatory diseases can serve as models of atherosclerosis that shed light on the non–lipid-related mechanisms involved in cardiovascular disease.
“The gradient in risk may be hypothesis-generating with respect to which specific inflammatory pathways may contribute to CHD,” he explained.
Each of these six chronic inflammatory diseases is characterized by a different form of major immune dysfunction, Dr. Sinha continued. A case in point is SLE, the inflammatory disease associated with the highest risk of CHD and MI. Lupus is characterized by a form of neutrophil dysfunction marked by increased formation and reduced degradation of neutrophil extracellular traps, or NETs, as well as by an increase in autoreactive B cells and dysfunctional CD4+ T helper cells. The increase in NETs of of particular interest because NETs have also been shown to contribute to the development of atherosclerosis, endothelial dysfunction, plaque erosion, and thrombosis.
In another exploratory analysis, Dr. Sinha and coworkers found that SLE patients with a neutrophil count above the median level were twice as likely to develop CHD than were those with a neutrophil count below the median.
A better understanding of the upstream pathways linking NET formation in SLE and atherosclerosis could lead to development of new or repurposed medications that target immune dysfunction in order to curb atherosclerosis, said Dr. Sinha, whose study won the AHA’s Samuel A. Levine Early Career Clinical Investigator Award.
He reported having no financial conflicts regarding his study.
FROM AHA 2020