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DOACs offered after heart valve surgery despite absence of data
Direct oral anticoagulants (DOACs) are used in about 1% of patients undergoing surgical mechanical aortic and mitral valve replacement, but in up to 6% of surgical bioprosthetic valve replacements, according to registry data presented at CRT 2021.
In an analysis of the Society of Thoracic Surgery (STS) registry during 2014-2017, DOAC use increased steadily among those undergoing surgical bioprosthetic valve replacement, reaching a number that is potentially clinically significant, according to Ankur Kalra, MD, an interventional cardiologist at Akron General Hospital who has an academic appointment at the Cleveland Clinic.
There was no increase in the use of DOACs observed among patients undergoing mechanical valve replacement, “but even if the number is 1%, they should probably not be used at all until we accrue more data,” Dr. Kalra said.
DOACs discouraged in patients with mechanical or bioprosthetic valves
In Food and Drug Administration labeling, DOACs are contraindicated or not recommended. This can be traced to the randomized RE-ALIGN trial, which was stopped prematurely due to evidence of harm from a DOAC, according to Dr. Kalra.
In RE-ALIGN, which enrolled patients undergoing mechanical aortic or mitral valve replacement, dabigatran was associated not only with more bleeding events than warfarin, but also more thromboembolic events.
There are no randomized data comparing the factor Xa inhibitors rivaroxaban or apixaban to warfarin in heart valve surgery, but Dr. Kalra noted cautionary language is found in the labeling of both, “perhaps due to the RE-ALIGN data.”
Registry shows trends in prescribing
In the STS registry data, 193 (1.1%) of the 18,142 patients undergoing mechanical aortic valve surgery, 139 (1.0%) of the 13,942 patients undergoing mechanical mitral valve surgery, 5,625 (4.7%) of the 116,203 patients undergoing aortic bioprosthetic aortic valve surgery, and 2,180 (5.9%) of the 39,243 patients undergoing bioprosthetic mitral valve surgery were on a DOAC at discharge.
Among those receiving a mechanical value and placed on a DOAC, about two-thirds were on a factor Xa inhibitor rather than dabigatran. For those receiving a bioprosthetic value, the proportion was greater than 80%. Dr. Kalra speculated that the RE-ALIGN trial might be the reason factor Xa inhibitors were favored.
In both types of valves, whether mechanical or bioprosthetic, more comorbidities predicted a greater likelihood of receiving a DOAC rather than warfarin. For those receiving mechanical values, the comorbidities with a significant association with greater DOAC use included hypertension (P = .003), dyslipidemia (P = .02), arrhythmia (P < .001), and peripheral arterial disease (P < 0.001).
The same factors were significant for predicting increased likelihood of a DOAC following bioprosthetic valve replacement, but there were additional factors, including atrial fibrillation independent of other types of arrhythmias (P < .001), a factor not significant for mechanical valves, as well as diabetes (P < .001), cerebrovascular disease (P < .001), dialysis (P < .001), and endocarditis (P < .001).
“This is probably intuitive, but patients who were on a factor Xa inhibitor before their valve replacement were also more likely to be discharged on a factor Xa inhibitor,” Dr. Kalra said at the virtual meeting, sponsored by MedStar Heart & Vascular Institute.
The year-to-year increase in DOAC use among those undergoing bioprosthetic valve replacement over the study period, which was a significant trend, was not observed among those undergoing mechanical valve replacement. Rather, the 1% proportion remained stable over the study period.
“We wanted to look at outcomes, but we found that the STS database, which only includes data out to 30 days, is not structured for this type of analysis,” Dr. Kalra said. He was also concerned about the limitations of a comparison in which 1% of the sample was being compared to 99%.
Expert: One percent is ‘very small number’
David J. Cohen, MD, commented on the 1% figure, which was so low that a moderator questioned whether it could be due mostly to coding errors.
“This is a very, very small number so at some level it is reassuring that it is so low in the mechanical valves,” Dr. Cohen said. However, he was more circumspect about the larger number in bioprosthetic valves.
“I have always thought it was a bit strange there was a warning against using them in bioprosthetic valves, especially in the aortic position,” he said.
“The trials that established the benefits of DOACs were all in nonvalvular atrial fibrillation, but this did not mean non–aortic stenosis; it meant non–mitral valvular. There have been articles written about how that has been misinterpreted,” said Dr. Cohen, director of clinical and outcomes research at the Cardiovascular Research Foundation and director of academic affairs at St. Francis Hospital, Roslyn, N.Y.
For his part, Dr. Kalra reported that he does not consider DOACs in patients who have undergone a surgical mechanical valve replacement. For bioprosthetic valves, he “prefers” warfarin over DOACs.
Overall, the evidence from the registry led Dr. Kalra to suggest that physicians should continue to “exercise caution” in using DOACs instead of warfarin after any surgical valve replacement “until randomized clinical trials provide sufficient evidence” to make a judgment about relative efficacy and safety.
Results of the study were published online as a research letter in Jama Network Open after Dr. Kalra’s presentation. Dr. Kalra and Dr. Cohen report no potential conflicts of interest.
Direct oral anticoagulants (DOACs) are used in about 1% of patients undergoing surgical mechanical aortic and mitral valve replacement, but in up to 6% of surgical bioprosthetic valve replacements, according to registry data presented at CRT 2021.
In an analysis of the Society of Thoracic Surgery (STS) registry during 2014-2017, DOAC use increased steadily among those undergoing surgical bioprosthetic valve replacement, reaching a number that is potentially clinically significant, according to Ankur Kalra, MD, an interventional cardiologist at Akron General Hospital who has an academic appointment at the Cleveland Clinic.
There was no increase in the use of DOACs observed among patients undergoing mechanical valve replacement, “but even if the number is 1%, they should probably not be used at all until we accrue more data,” Dr. Kalra said.
DOACs discouraged in patients with mechanical or bioprosthetic valves
In Food and Drug Administration labeling, DOACs are contraindicated or not recommended. This can be traced to the randomized RE-ALIGN trial, which was stopped prematurely due to evidence of harm from a DOAC, according to Dr. Kalra.
In RE-ALIGN, which enrolled patients undergoing mechanical aortic or mitral valve replacement, dabigatran was associated not only with more bleeding events than warfarin, but also more thromboembolic events.
There are no randomized data comparing the factor Xa inhibitors rivaroxaban or apixaban to warfarin in heart valve surgery, but Dr. Kalra noted cautionary language is found in the labeling of both, “perhaps due to the RE-ALIGN data.”
Registry shows trends in prescribing
In the STS registry data, 193 (1.1%) of the 18,142 patients undergoing mechanical aortic valve surgery, 139 (1.0%) of the 13,942 patients undergoing mechanical mitral valve surgery, 5,625 (4.7%) of the 116,203 patients undergoing aortic bioprosthetic aortic valve surgery, and 2,180 (5.9%) of the 39,243 patients undergoing bioprosthetic mitral valve surgery were on a DOAC at discharge.
Among those receiving a mechanical value and placed on a DOAC, about two-thirds were on a factor Xa inhibitor rather than dabigatran. For those receiving a bioprosthetic value, the proportion was greater than 80%. Dr. Kalra speculated that the RE-ALIGN trial might be the reason factor Xa inhibitors were favored.
In both types of valves, whether mechanical or bioprosthetic, more comorbidities predicted a greater likelihood of receiving a DOAC rather than warfarin. For those receiving mechanical values, the comorbidities with a significant association with greater DOAC use included hypertension (P = .003), dyslipidemia (P = .02), arrhythmia (P < .001), and peripheral arterial disease (P < 0.001).
The same factors were significant for predicting increased likelihood of a DOAC following bioprosthetic valve replacement, but there were additional factors, including atrial fibrillation independent of other types of arrhythmias (P < .001), a factor not significant for mechanical valves, as well as diabetes (P < .001), cerebrovascular disease (P < .001), dialysis (P < .001), and endocarditis (P < .001).
“This is probably intuitive, but patients who were on a factor Xa inhibitor before their valve replacement were also more likely to be discharged on a factor Xa inhibitor,” Dr. Kalra said at the virtual meeting, sponsored by MedStar Heart & Vascular Institute.
The year-to-year increase in DOAC use among those undergoing bioprosthetic valve replacement over the study period, which was a significant trend, was not observed among those undergoing mechanical valve replacement. Rather, the 1% proportion remained stable over the study period.
“We wanted to look at outcomes, but we found that the STS database, which only includes data out to 30 days, is not structured for this type of analysis,” Dr. Kalra said. He was also concerned about the limitations of a comparison in which 1% of the sample was being compared to 99%.
Expert: One percent is ‘very small number’
David J. Cohen, MD, commented on the 1% figure, which was so low that a moderator questioned whether it could be due mostly to coding errors.
“This is a very, very small number so at some level it is reassuring that it is so low in the mechanical valves,” Dr. Cohen said. However, he was more circumspect about the larger number in bioprosthetic valves.
“I have always thought it was a bit strange there was a warning against using them in bioprosthetic valves, especially in the aortic position,” he said.
“The trials that established the benefits of DOACs were all in nonvalvular atrial fibrillation, but this did not mean non–aortic stenosis; it meant non–mitral valvular. There have been articles written about how that has been misinterpreted,” said Dr. Cohen, director of clinical and outcomes research at the Cardiovascular Research Foundation and director of academic affairs at St. Francis Hospital, Roslyn, N.Y.
For his part, Dr. Kalra reported that he does not consider DOACs in patients who have undergone a surgical mechanical valve replacement. For bioprosthetic valves, he “prefers” warfarin over DOACs.
Overall, the evidence from the registry led Dr. Kalra to suggest that physicians should continue to “exercise caution” in using DOACs instead of warfarin after any surgical valve replacement “until randomized clinical trials provide sufficient evidence” to make a judgment about relative efficacy and safety.
Results of the study were published online as a research letter in Jama Network Open after Dr. Kalra’s presentation. Dr. Kalra and Dr. Cohen report no potential conflicts of interest.
Direct oral anticoagulants (DOACs) are used in about 1% of patients undergoing surgical mechanical aortic and mitral valve replacement, but in up to 6% of surgical bioprosthetic valve replacements, according to registry data presented at CRT 2021.
In an analysis of the Society of Thoracic Surgery (STS) registry during 2014-2017, DOAC use increased steadily among those undergoing surgical bioprosthetic valve replacement, reaching a number that is potentially clinically significant, according to Ankur Kalra, MD, an interventional cardiologist at Akron General Hospital who has an academic appointment at the Cleveland Clinic.
There was no increase in the use of DOACs observed among patients undergoing mechanical valve replacement, “but even if the number is 1%, they should probably not be used at all until we accrue more data,” Dr. Kalra said.
DOACs discouraged in patients with mechanical or bioprosthetic valves
In Food and Drug Administration labeling, DOACs are contraindicated or not recommended. This can be traced to the randomized RE-ALIGN trial, which was stopped prematurely due to evidence of harm from a DOAC, according to Dr. Kalra.
In RE-ALIGN, which enrolled patients undergoing mechanical aortic or mitral valve replacement, dabigatran was associated not only with more bleeding events than warfarin, but also more thromboembolic events.
There are no randomized data comparing the factor Xa inhibitors rivaroxaban or apixaban to warfarin in heart valve surgery, but Dr. Kalra noted cautionary language is found in the labeling of both, “perhaps due to the RE-ALIGN data.”
Registry shows trends in prescribing
In the STS registry data, 193 (1.1%) of the 18,142 patients undergoing mechanical aortic valve surgery, 139 (1.0%) of the 13,942 patients undergoing mechanical mitral valve surgery, 5,625 (4.7%) of the 116,203 patients undergoing aortic bioprosthetic aortic valve surgery, and 2,180 (5.9%) of the 39,243 patients undergoing bioprosthetic mitral valve surgery were on a DOAC at discharge.
Among those receiving a mechanical value and placed on a DOAC, about two-thirds were on a factor Xa inhibitor rather than dabigatran. For those receiving a bioprosthetic value, the proportion was greater than 80%. Dr. Kalra speculated that the RE-ALIGN trial might be the reason factor Xa inhibitors were favored.
In both types of valves, whether mechanical or bioprosthetic, more comorbidities predicted a greater likelihood of receiving a DOAC rather than warfarin. For those receiving mechanical values, the comorbidities with a significant association with greater DOAC use included hypertension (P = .003), dyslipidemia (P = .02), arrhythmia (P < .001), and peripheral arterial disease (P < 0.001).
The same factors were significant for predicting increased likelihood of a DOAC following bioprosthetic valve replacement, but there were additional factors, including atrial fibrillation independent of other types of arrhythmias (P < .001), a factor not significant for mechanical valves, as well as diabetes (P < .001), cerebrovascular disease (P < .001), dialysis (P < .001), and endocarditis (P < .001).
“This is probably intuitive, but patients who were on a factor Xa inhibitor before their valve replacement were also more likely to be discharged on a factor Xa inhibitor,” Dr. Kalra said at the virtual meeting, sponsored by MedStar Heart & Vascular Institute.
The year-to-year increase in DOAC use among those undergoing bioprosthetic valve replacement over the study period, which was a significant trend, was not observed among those undergoing mechanical valve replacement. Rather, the 1% proportion remained stable over the study period.
“We wanted to look at outcomes, but we found that the STS database, which only includes data out to 30 days, is not structured for this type of analysis,” Dr. Kalra said. He was also concerned about the limitations of a comparison in which 1% of the sample was being compared to 99%.
Expert: One percent is ‘very small number’
David J. Cohen, MD, commented on the 1% figure, which was so low that a moderator questioned whether it could be due mostly to coding errors.
“This is a very, very small number so at some level it is reassuring that it is so low in the mechanical valves,” Dr. Cohen said. However, he was more circumspect about the larger number in bioprosthetic valves.
“I have always thought it was a bit strange there was a warning against using them in bioprosthetic valves, especially in the aortic position,” he said.
“The trials that established the benefits of DOACs were all in nonvalvular atrial fibrillation, but this did not mean non–aortic stenosis; it meant non–mitral valvular. There have been articles written about how that has been misinterpreted,” said Dr. Cohen, director of clinical and outcomes research at the Cardiovascular Research Foundation and director of academic affairs at St. Francis Hospital, Roslyn, N.Y.
For his part, Dr. Kalra reported that he does not consider DOACs in patients who have undergone a surgical mechanical valve replacement. For bioprosthetic valves, he “prefers” warfarin over DOACs.
Overall, the evidence from the registry led Dr. Kalra to suggest that physicians should continue to “exercise caution” in using DOACs instead of warfarin after any surgical valve replacement “until randomized clinical trials provide sufficient evidence” to make a judgment about relative efficacy and safety.
Results of the study were published online as a research letter in Jama Network Open after Dr. Kalra’s presentation. Dr. Kalra and Dr. Cohen report no potential conflicts of interest.
FROM CRT 2021
Heart health in pregnancy tied to CV risk in adolescent offspring
Children born to mothers in poor cardiovascular health during pregnancy had an almost eight times higher risk for landing in the poorest cardiovascular health category in early adolescence than children born to mothers who had ideal cardiovascular health during pregnancy.
In an observational cohort study that involved 2,302 mother-child dyads, 6.0% of mothers and 2.6% of children were considered to be in the poorest category of cardiovascular health on the basis of specific risk factors.
The children of mothers with any “intermediate” cardiovascular health metrics in pregnancy – for example, being overweight but not obese – were at just more than two times higher risk for poor cardiovascular health in early adolescence.
Although acknowledging the limitations of observational data, Amanda M. Perak, MD, Northwestern University, Chicago, suggested that focusing on whether or not the relationships seen in this study are causal might be throwing the baby out with the bathwater.
“I would suggest that it may not actually matter whether there is causality or correlation here, because if you can identify newborns at birth who have an eight times higher risk for poor cardiovascular health in childhood based on mom’s health during pregnancy, that’s valuable information either way,” said Dr. Perak.
“Even if you don’t know why their risk is elevated, you might be able to target those children for more intensive preventative efforts throughout childhood to help them hold on to their cardiovascular health for longer.”
That said, she thinks it’s possible that the intrauterine environment might actually directly affect offspring health, either through epigenetics modifications to cardiometabolic regulatory genes or possibly through actual organ development. Her group is collecting epigenetic data to study this further.
“We also need to do a study to see if intervening during pregnancy with mothers leads to better cardiovascular health in offspring, and that’s a question we can answer with a clinical trial,” said Dr. Perak.
This study was published on Feb. 16, 2021, in JAMA.
Equal footing
“We’ve always talked about cardiovascular health as if everyone is born with ideal cardiovascular health and loses it from there, and I think what this article points out is that not everybody starts on equal footing,” said Stephen R. Daniels, MD, PhD, University of Colorado at Denver, Aurora, who wrote an editorial accompanying the study.
“We need to start upstream, working with mothers before and during pregnancy, but it’s also important to understand, from a pediatric standpoint, that with some of these kids the horse is kind of already out of the barn very early.”
Dr. Daniels is pediatrician in chief and chair of pediatrics at Children’s Hospital Colorado in Aurora.
This study is the first to examine the relevance of maternal gestational cardiovascular health to offspring cardiovascular health and an important first step toward developing new approaches to address the concept of primordial prevention, he said.
“If primary prevention is identifying risk factors and treating them, I think of primordial prevention as preventing the development of those risk factors in the first place,” said Dr. Daniels.
Future trials, he added, should focus on the various mechanistic pathways – biological effects, shared genetics, and lifestyle being the options – to better understand opportunities for intervention.
Mother-child pairs
Dr. Perak and colleagues used data from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study and the HAPO Follow-up Study.
Participants were 2,302 mother-child pairs from nine field centers in Barbados, Canada, China, Thailand, United Kingdom, and the United States, and represented a racially and ethnically diverse cohort.
The mean ages were 29.6 years for pregnant mothers and 11.3 years for children. The pregnancies occurred between 2000 and 2006, and the children were examined from 2013 to 2016, when the children were aged 10-14 years.
Using the American Heart Association’s definition of cardiovascular health, the scientists categorized pregnancy health for mothers based on their measures of body mass index, blood pressure, total cholesterol, glucose level, and smoking status at 28 weeks’ gestation. These five metrics of gestational cardiovascular health have been significantly associated with adverse pregnancy outcomes.
They categorized cardiovascular health for offspring at age 10-14 years based on four of these five metrics: body mass index, blood pressure, cholesterol, and glucose.
Only 32.8% of mothers and 42.2% of children had ideal cardiovascular health.
In analyses adjusted for pregnancy and birth outcomes, the associations seen between poor gestational maternal health and offspring cardiovascular health persisted but were attenuated.
Dr. Perak reported receiving grants from the Woman’s Board of Northwestern Memorial Hospital; the Dixon Family; the American Heart Association; and the National Heart, Lung, and Blood Institute. Dr. Daniels reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
Children born to mothers in poor cardiovascular health during pregnancy had an almost eight times higher risk for landing in the poorest cardiovascular health category in early adolescence than children born to mothers who had ideal cardiovascular health during pregnancy.
In an observational cohort study that involved 2,302 mother-child dyads, 6.0% of mothers and 2.6% of children were considered to be in the poorest category of cardiovascular health on the basis of specific risk factors.
The children of mothers with any “intermediate” cardiovascular health metrics in pregnancy – for example, being overweight but not obese – were at just more than two times higher risk for poor cardiovascular health in early adolescence.
Although acknowledging the limitations of observational data, Amanda M. Perak, MD, Northwestern University, Chicago, suggested that focusing on whether or not the relationships seen in this study are causal might be throwing the baby out with the bathwater.
“I would suggest that it may not actually matter whether there is causality or correlation here, because if you can identify newborns at birth who have an eight times higher risk for poor cardiovascular health in childhood based on mom’s health during pregnancy, that’s valuable information either way,” said Dr. Perak.
“Even if you don’t know why their risk is elevated, you might be able to target those children for more intensive preventative efforts throughout childhood to help them hold on to their cardiovascular health for longer.”
That said, she thinks it’s possible that the intrauterine environment might actually directly affect offspring health, either through epigenetics modifications to cardiometabolic regulatory genes or possibly through actual organ development. Her group is collecting epigenetic data to study this further.
“We also need to do a study to see if intervening during pregnancy with mothers leads to better cardiovascular health in offspring, and that’s a question we can answer with a clinical trial,” said Dr. Perak.
This study was published on Feb. 16, 2021, in JAMA.
Equal footing
“We’ve always talked about cardiovascular health as if everyone is born with ideal cardiovascular health and loses it from there, and I think what this article points out is that not everybody starts on equal footing,” said Stephen R. Daniels, MD, PhD, University of Colorado at Denver, Aurora, who wrote an editorial accompanying the study.
“We need to start upstream, working with mothers before and during pregnancy, but it’s also important to understand, from a pediatric standpoint, that with some of these kids the horse is kind of already out of the barn very early.”
Dr. Daniels is pediatrician in chief and chair of pediatrics at Children’s Hospital Colorado in Aurora.
This study is the first to examine the relevance of maternal gestational cardiovascular health to offspring cardiovascular health and an important first step toward developing new approaches to address the concept of primordial prevention, he said.
“If primary prevention is identifying risk factors and treating them, I think of primordial prevention as preventing the development of those risk factors in the first place,” said Dr. Daniels.
Future trials, he added, should focus on the various mechanistic pathways – biological effects, shared genetics, and lifestyle being the options – to better understand opportunities for intervention.
Mother-child pairs
Dr. Perak and colleagues used data from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study and the HAPO Follow-up Study.
Participants were 2,302 mother-child pairs from nine field centers in Barbados, Canada, China, Thailand, United Kingdom, and the United States, and represented a racially and ethnically diverse cohort.
The mean ages were 29.6 years for pregnant mothers and 11.3 years for children. The pregnancies occurred between 2000 and 2006, and the children were examined from 2013 to 2016, when the children were aged 10-14 years.
Using the American Heart Association’s definition of cardiovascular health, the scientists categorized pregnancy health for mothers based on their measures of body mass index, blood pressure, total cholesterol, glucose level, and smoking status at 28 weeks’ gestation. These five metrics of gestational cardiovascular health have been significantly associated with adverse pregnancy outcomes.
They categorized cardiovascular health for offspring at age 10-14 years based on four of these five metrics: body mass index, blood pressure, cholesterol, and glucose.
Only 32.8% of mothers and 42.2% of children had ideal cardiovascular health.
In analyses adjusted for pregnancy and birth outcomes, the associations seen between poor gestational maternal health and offspring cardiovascular health persisted but were attenuated.
Dr. Perak reported receiving grants from the Woman’s Board of Northwestern Memorial Hospital; the Dixon Family; the American Heart Association; and the National Heart, Lung, and Blood Institute. Dr. Daniels reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
Children born to mothers in poor cardiovascular health during pregnancy had an almost eight times higher risk for landing in the poorest cardiovascular health category in early adolescence than children born to mothers who had ideal cardiovascular health during pregnancy.
In an observational cohort study that involved 2,302 mother-child dyads, 6.0% of mothers and 2.6% of children were considered to be in the poorest category of cardiovascular health on the basis of specific risk factors.
The children of mothers with any “intermediate” cardiovascular health metrics in pregnancy – for example, being overweight but not obese – were at just more than two times higher risk for poor cardiovascular health in early adolescence.
Although acknowledging the limitations of observational data, Amanda M. Perak, MD, Northwestern University, Chicago, suggested that focusing on whether or not the relationships seen in this study are causal might be throwing the baby out with the bathwater.
“I would suggest that it may not actually matter whether there is causality or correlation here, because if you can identify newborns at birth who have an eight times higher risk for poor cardiovascular health in childhood based on mom’s health during pregnancy, that’s valuable information either way,” said Dr. Perak.
“Even if you don’t know why their risk is elevated, you might be able to target those children for more intensive preventative efforts throughout childhood to help them hold on to their cardiovascular health for longer.”
That said, she thinks it’s possible that the intrauterine environment might actually directly affect offspring health, either through epigenetics modifications to cardiometabolic regulatory genes or possibly through actual organ development. Her group is collecting epigenetic data to study this further.
“We also need to do a study to see if intervening during pregnancy with mothers leads to better cardiovascular health in offspring, and that’s a question we can answer with a clinical trial,” said Dr. Perak.
This study was published on Feb. 16, 2021, in JAMA.
Equal footing
“We’ve always talked about cardiovascular health as if everyone is born with ideal cardiovascular health and loses it from there, and I think what this article points out is that not everybody starts on equal footing,” said Stephen R. Daniels, MD, PhD, University of Colorado at Denver, Aurora, who wrote an editorial accompanying the study.
“We need to start upstream, working with mothers before and during pregnancy, but it’s also important to understand, from a pediatric standpoint, that with some of these kids the horse is kind of already out of the barn very early.”
Dr. Daniels is pediatrician in chief and chair of pediatrics at Children’s Hospital Colorado in Aurora.
This study is the first to examine the relevance of maternal gestational cardiovascular health to offspring cardiovascular health and an important first step toward developing new approaches to address the concept of primordial prevention, he said.
“If primary prevention is identifying risk factors and treating them, I think of primordial prevention as preventing the development of those risk factors in the first place,” said Dr. Daniels.
Future trials, he added, should focus on the various mechanistic pathways – biological effects, shared genetics, and lifestyle being the options – to better understand opportunities for intervention.
Mother-child pairs
Dr. Perak and colleagues used data from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study and the HAPO Follow-up Study.
Participants were 2,302 mother-child pairs from nine field centers in Barbados, Canada, China, Thailand, United Kingdom, and the United States, and represented a racially and ethnically diverse cohort.
The mean ages were 29.6 years for pregnant mothers and 11.3 years for children. The pregnancies occurred between 2000 and 2006, and the children were examined from 2013 to 2016, when the children were aged 10-14 years.
Using the American Heart Association’s definition of cardiovascular health, the scientists categorized pregnancy health for mothers based on their measures of body mass index, blood pressure, total cholesterol, glucose level, and smoking status at 28 weeks’ gestation. These five metrics of gestational cardiovascular health have been significantly associated with adverse pregnancy outcomes.
They categorized cardiovascular health for offspring at age 10-14 years based on four of these five metrics: body mass index, blood pressure, cholesterol, and glucose.
Only 32.8% of mothers and 42.2% of children had ideal cardiovascular health.
In analyses adjusted for pregnancy and birth outcomes, the associations seen between poor gestational maternal health and offspring cardiovascular health persisted but were attenuated.
Dr. Perak reported receiving grants from the Woman’s Board of Northwestern Memorial Hospital; the Dixon Family; the American Heart Association; and the National Heart, Lung, and Blood Institute. Dr. Daniels reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
No vascular benefit of testosterone over exercise in aging men
Exercise training – but not testosterone therapy – improved vascular health in aging men with widening midsections and low to normal testosterone, new research suggests.
“Previous studies have suggested that men with higher levels of testosterone, who were more physically active, might have better health outcomes,” Bu Beng Yeap, MBBS, PhD, University of Western Australia, Perth, said in an interview. “We formulated the hypothesis that the combination of testosterone treatment and exercise training would improve the health of arteries more than either alone.”
To test this hypothesis, the investigators randomly assigned 80 men, aged 50-70 years, to 12 weeks of 5% testosterone cream 2 mL applied daily or placebo plus a supervised exercise program that included machine-based resistance and aerobic (cycling) exercises two to three times a week or no additional exercise.
The men (mean age, 59 years) had low-normal testosterone (6-14 nmol/L), a waist circumference of at least 95 cm (37.4 inches), and no known cardiovascular disease (CVD), type 1 diabetes, or other clinically significant illnesses. Current smokers and men on testosterone or medications that would alter testosterone levels were also excluded.
High-resolution ultrasound of the brachial artery was used to assess flow-mediated dilation (FMD) and sublingual glyceryl trinitrate (GTN) responses. FMD has been shown to be predictive of CVD risk, with a 1% increase in FMD associated with a 9%-13% decrease in future CVD events.
Based on participants’ daily dairies, testosterone adherence was 97.6%. Exercise adherence was 96.5% for twice-weekly attendance and 80.0% for thrice-weekly attendance, with no between-group differences.
As reported Feb. 22, 2021, in Hypertension, testosterone levels increased, on average, 3.0 nmol/L in both testosterone groups by week 12 (P = .003). In all, 62% of these men had levels of the hormone exceeding 14 nmol/L, compared with 29% of those receiving placebo.
Testosterone levels improved with exercise training plus placebo by 0.9 nmol/L, but fell with no exercise and placebo by 0.9 nmol/L.
In terms of vascular function, exercise training increased FMD when expressed as both the delta change (mm; P = .004) and relative rise from baseline diameter (%; P = .033).
There was no effect of exercise on GTN%, which is generally in line with exercise literature indicating that shear-mediated adaptations in response to episodic exercise occur largely in endothelial cells, the authors noted.
Testosterone did not affect any measures of FMD nor was there an effect on GTN response, despite previous evidence that lower testosterone doses might enhance smooth muscle function.
“Our main finding was that testosterone – at this dose over this duration of treatment – did not have a beneficial effect on artery health, nor did it enhance the effect of exercise,” said Dr. Yeap, who is also president of the Endocrine Society of Australia. “For middle-aged and older men wanting to improve the health of their arteries, exercise is better than testosterone!”
Shalender Bhasin, MBBS, director of research programs in men’s health, aging, and metabolism at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston, said the study is interesting from a mechanistic perspective and adds to the overall body of evidence on how testosterone affects performance, but was narrowly focused.
“They looked at very specific markers and what they’re showing is that this is not the mechanism by which testosterone improves performance,” he said. “That may be so, but it doesn’t negate the finding that testosterone improves endurance and has other vascular effects: it increases capillarity, increases blood flow to the tissues, and improves myocardial function.”
Although well done, the study doesn’t get at the larger question of whether testosterone increases cardiovascular risk, observed Dr. Bhasin. “None of the randomized studies have been large enough or long enough to determine the effect on cardiovascular events rates. There’s a lot of argument on both sides but we need some data to address that.”
The 6,000-patient TRAVERSE trial is specifically looking at long-term major cardiovascular events with topical testosterone, compared with placebo, in hypogonadal men aged 45-80 years age who have evidence of or are at increased risk for CVD. The study, which is set to be completed in April 2022, should also provide information on fracture risk in these men, said Dr. Bhasin, one of the trial’s principal investigators and lead author of the Endocrine Society’s 2018 clinical practice guideline on testosterone therapy for hypogonadism in men.
William Evans, MD, adjunct professor of human nutrition, University of California, Berkley, said in an interview that the positive effects of testosterone occur at much lower doses in men and women who are hypogonadal but, in this particular population, exercise is the key and the major recommendation.
“Testosterone has been overprescribed and overadvertised for essentially a lifetime of sedentary living, and it’s advertised as a way to get all that back without having to work for it,” he said. “Exercise has a profound and positive effect on control of blood pressure, function, and strength, and testosterone may only affect in people who are sick, people who have really low levels.”
The study was funded by the Heart Foundation of Australia. Lawley Pharmaceuticals provided the study medication and placebo. Dr. Yeap has received speaker honoraria and conference support from Bayer, Eli Lilly, and Besins Healthcare; research support from Bayer, Lily, and Lawley; and served as an adviser for Lily, Besins Healthcare, Ferring, and Lawley. Dr. Shalender reports consultation or advisement for GTx, Pfizer, and TAP; grant or other research support from Solvay and GlaxoSmithKline; and honoraria from Solvay and Auxilium. Dr. Evans reported having no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Exercise training – but not testosterone therapy – improved vascular health in aging men with widening midsections and low to normal testosterone, new research suggests.
“Previous studies have suggested that men with higher levels of testosterone, who were more physically active, might have better health outcomes,” Bu Beng Yeap, MBBS, PhD, University of Western Australia, Perth, said in an interview. “We formulated the hypothesis that the combination of testosterone treatment and exercise training would improve the health of arteries more than either alone.”
To test this hypothesis, the investigators randomly assigned 80 men, aged 50-70 years, to 12 weeks of 5% testosterone cream 2 mL applied daily or placebo plus a supervised exercise program that included machine-based resistance and aerobic (cycling) exercises two to three times a week or no additional exercise.
The men (mean age, 59 years) had low-normal testosterone (6-14 nmol/L), a waist circumference of at least 95 cm (37.4 inches), and no known cardiovascular disease (CVD), type 1 diabetes, or other clinically significant illnesses. Current smokers and men on testosterone or medications that would alter testosterone levels were also excluded.
High-resolution ultrasound of the brachial artery was used to assess flow-mediated dilation (FMD) and sublingual glyceryl trinitrate (GTN) responses. FMD has been shown to be predictive of CVD risk, with a 1% increase in FMD associated with a 9%-13% decrease in future CVD events.
Based on participants’ daily dairies, testosterone adherence was 97.6%. Exercise adherence was 96.5% for twice-weekly attendance and 80.0% for thrice-weekly attendance, with no between-group differences.
As reported Feb. 22, 2021, in Hypertension, testosterone levels increased, on average, 3.0 nmol/L in both testosterone groups by week 12 (P = .003). In all, 62% of these men had levels of the hormone exceeding 14 nmol/L, compared with 29% of those receiving placebo.
Testosterone levels improved with exercise training plus placebo by 0.9 nmol/L, but fell with no exercise and placebo by 0.9 nmol/L.
In terms of vascular function, exercise training increased FMD when expressed as both the delta change (mm; P = .004) and relative rise from baseline diameter (%; P = .033).
There was no effect of exercise on GTN%, which is generally in line with exercise literature indicating that shear-mediated adaptations in response to episodic exercise occur largely in endothelial cells, the authors noted.
Testosterone did not affect any measures of FMD nor was there an effect on GTN response, despite previous evidence that lower testosterone doses might enhance smooth muscle function.
“Our main finding was that testosterone – at this dose over this duration of treatment – did not have a beneficial effect on artery health, nor did it enhance the effect of exercise,” said Dr. Yeap, who is also president of the Endocrine Society of Australia. “For middle-aged and older men wanting to improve the health of their arteries, exercise is better than testosterone!”
Shalender Bhasin, MBBS, director of research programs in men’s health, aging, and metabolism at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston, said the study is interesting from a mechanistic perspective and adds to the overall body of evidence on how testosterone affects performance, but was narrowly focused.
“They looked at very specific markers and what they’re showing is that this is not the mechanism by which testosterone improves performance,” he said. “That may be so, but it doesn’t negate the finding that testosterone improves endurance and has other vascular effects: it increases capillarity, increases blood flow to the tissues, and improves myocardial function.”
Although well done, the study doesn’t get at the larger question of whether testosterone increases cardiovascular risk, observed Dr. Bhasin. “None of the randomized studies have been large enough or long enough to determine the effect on cardiovascular events rates. There’s a lot of argument on both sides but we need some data to address that.”
The 6,000-patient TRAVERSE trial is specifically looking at long-term major cardiovascular events with topical testosterone, compared with placebo, in hypogonadal men aged 45-80 years age who have evidence of or are at increased risk for CVD. The study, which is set to be completed in April 2022, should also provide information on fracture risk in these men, said Dr. Bhasin, one of the trial’s principal investigators and lead author of the Endocrine Society’s 2018 clinical practice guideline on testosterone therapy for hypogonadism in men.
William Evans, MD, adjunct professor of human nutrition, University of California, Berkley, said in an interview that the positive effects of testosterone occur at much lower doses in men and women who are hypogonadal but, in this particular population, exercise is the key and the major recommendation.
“Testosterone has been overprescribed and overadvertised for essentially a lifetime of sedentary living, and it’s advertised as a way to get all that back without having to work for it,” he said. “Exercise has a profound and positive effect on control of blood pressure, function, and strength, and testosterone may only affect in people who are sick, people who have really low levels.”
The study was funded by the Heart Foundation of Australia. Lawley Pharmaceuticals provided the study medication and placebo. Dr. Yeap has received speaker honoraria and conference support from Bayer, Eli Lilly, and Besins Healthcare; research support from Bayer, Lily, and Lawley; and served as an adviser for Lily, Besins Healthcare, Ferring, and Lawley. Dr. Shalender reports consultation or advisement for GTx, Pfizer, and TAP; grant or other research support from Solvay and GlaxoSmithKline; and honoraria from Solvay and Auxilium. Dr. Evans reported having no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Exercise training – but not testosterone therapy – improved vascular health in aging men with widening midsections and low to normal testosterone, new research suggests.
“Previous studies have suggested that men with higher levels of testosterone, who were more physically active, might have better health outcomes,” Bu Beng Yeap, MBBS, PhD, University of Western Australia, Perth, said in an interview. “We formulated the hypothesis that the combination of testosterone treatment and exercise training would improve the health of arteries more than either alone.”
To test this hypothesis, the investigators randomly assigned 80 men, aged 50-70 years, to 12 weeks of 5% testosterone cream 2 mL applied daily or placebo plus a supervised exercise program that included machine-based resistance and aerobic (cycling) exercises two to three times a week or no additional exercise.
The men (mean age, 59 years) had low-normal testosterone (6-14 nmol/L), a waist circumference of at least 95 cm (37.4 inches), and no known cardiovascular disease (CVD), type 1 diabetes, or other clinically significant illnesses. Current smokers and men on testosterone or medications that would alter testosterone levels were also excluded.
High-resolution ultrasound of the brachial artery was used to assess flow-mediated dilation (FMD) and sublingual glyceryl trinitrate (GTN) responses. FMD has been shown to be predictive of CVD risk, with a 1% increase in FMD associated with a 9%-13% decrease in future CVD events.
Based on participants’ daily dairies, testosterone adherence was 97.6%. Exercise adherence was 96.5% for twice-weekly attendance and 80.0% for thrice-weekly attendance, with no between-group differences.
As reported Feb. 22, 2021, in Hypertension, testosterone levels increased, on average, 3.0 nmol/L in both testosterone groups by week 12 (P = .003). In all, 62% of these men had levels of the hormone exceeding 14 nmol/L, compared with 29% of those receiving placebo.
Testosterone levels improved with exercise training plus placebo by 0.9 nmol/L, but fell with no exercise and placebo by 0.9 nmol/L.
In terms of vascular function, exercise training increased FMD when expressed as both the delta change (mm; P = .004) and relative rise from baseline diameter (%; P = .033).
There was no effect of exercise on GTN%, which is generally in line with exercise literature indicating that shear-mediated adaptations in response to episodic exercise occur largely in endothelial cells, the authors noted.
Testosterone did not affect any measures of FMD nor was there an effect on GTN response, despite previous evidence that lower testosterone doses might enhance smooth muscle function.
“Our main finding was that testosterone – at this dose over this duration of treatment – did not have a beneficial effect on artery health, nor did it enhance the effect of exercise,” said Dr. Yeap, who is also president of the Endocrine Society of Australia. “For middle-aged and older men wanting to improve the health of their arteries, exercise is better than testosterone!”
Shalender Bhasin, MBBS, director of research programs in men’s health, aging, and metabolism at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston, said the study is interesting from a mechanistic perspective and adds to the overall body of evidence on how testosterone affects performance, but was narrowly focused.
“They looked at very specific markers and what they’re showing is that this is not the mechanism by which testosterone improves performance,” he said. “That may be so, but it doesn’t negate the finding that testosterone improves endurance and has other vascular effects: it increases capillarity, increases blood flow to the tissues, and improves myocardial function.”
Although well done, the study doesn’t get at the larger question of whether testosterone increases cardiovascular risk, observed Dr. Bhasin. “None of the randomized studies have been large enough or long enough to determine the effect on cardiovascular events rates. There’s a lot of argument on both sides but we need some data to address that.”
The 6,000-patient TRAVERSE trial is specifically looking at long-term major cardiovascular events with topical testosterone, compared with placebo, in hypogonadal men aged 45-80 years age who have evidence of or are at increased risk for CVD. The study, which is set to be completed in April 2022, should also provide information on fracture risk in these men, said Dr. Bhasin, one of the trial’s principal investigators and lead author of the Endocrine Society’s 2018 clinical practice guideline on testosterone therapy for hypogonadism in men.
William Evans, MD, adjunct professor of human nutrition, University of California, Berkley, said in an interview that the positive effects of testosterone occur at much lower doses in men and women who are hypogonadal but, in this particular population, exercise is the key and the major recommendation.
“Testosterone has been overprescribed and overadvertised for essentially a lifetime of sedentary living, and it’s advertised as a way to get all that back without having to work for it,” he said. “Exercise has a profound and positive effect on control of blood pressure, function, and strength, and testosterone may only affect in people who are sick, people who have really low levels.”
The study was funded by the Heart Foundation of Australia. Lawley Pharmaceuticals provided the study medication and placebo. Dr. Yeap has received speaker honoraria and conference support from Bayer, Eli Lilly, and Besins Healthcare; research support from Bayer, Lily, and Lawley; and served as an adviser for Lily, Besins Healthcare, Ferring, and Lawley. Dr. Shalender reports consultation or advisement for GTx, Pfizer, and TAP; grant or other research support from Solvay and GlaxoSmithKline; and honoraria from Solvay and Auxilium. Dr. Evans reported having no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Big data ‘clinch’ link between high glycemic index diets and CVD
People who mostly ate foods with a low glycemic index had a lower likelihood of premature death and major cardiovascular disease (CVD) events, compared with those whose diet included more “poor-quality” food with a high glycemic index.
The results from the global PURE study of nearly 120,000 people provide evidence that helps cement glycemic index as a key measure of dietary health.
This new analysis from PURE (Prospective Urban and Rural Epidemiological Study) – a massive prospective epidemiologic study – shows people with a diet in the highest quintile of glycemic index had a significant 25% higher rate of combined total deaths and major CVD events during a median follow-up of nearly 10 years, compared with those with a diet in the lowest glycemic index quintile, in the report published online on Feb. 24, 2021, in the New England Journal of Medicine.
David J.A. Jenkins, MD, PhD, DSc, lead author, said people do not necessarily need to closely track the glycemic index of what they eat to follow the guidance that lower is better.
The link between lower glycemic load and fewer CVD events was even stronger among people with an established history of CVD at study entry. In this subset, which included 9% of the total cohort, people in the highest quintile for glycemic index consumption had a 51% higher rate of the composite primary endpoint, compared with those in the lowest quintile, in an analysis that adjusted for several potential confounders.
A simple but accurate and effective public health message is to follow existing dietary recommendations to eat better-quality food – more unprocessed fruits, vegetables, legumes, and whole grains – Dr. Jenkins advised. Those who prefer a more detailed approach could use the comprehensive glycemic index tables compiled by researchers at the University of Sydney.
‘All carbohydrates are not the same’
“What we’re saying is that all carbohydrates are not the same. Some seem to increase the risk for CVD, and others seem protective. This is not new, but worth restating in an era of low-carb and no-carb diets,” said Dr. Jenkins.
Low-glycemic-index foods are generally unprocessed foods in their native state, including fruits, vegetables, legumes, and unrefined whole grains. High-glycemic-index foods contain processed and refined carbohydrates that deliver jolts of glucose soon after eating, as the sugar in these carbohydrates quickly moves from the gut to the bloodstream.
An association between a diet with a lower glycemic index and better outcomes had appeared in prior reports from other studies, but not as unambiguously as in the new data from PURE, likely because of fewer study participants in previous studies.
Another feature of PURE that adds to the generalizability of the findings is the diversity of adults included in the study, from 20 countries on five continents.
“This clinches it,” Dr. Jenkins declared in an interview.
New PURE data tip the evidence balance
The NEJM article includes a new meta-analysis that adds the PURE findings to data from two large prior reports that were each less conclusive. The new calculation with the PURE numbers helps establish a clearer association between a diet with a higher glycemic index and the endpoint of CVD death, showing an overall 26% increase in the outcome.
The PURE data are especially informative because the investigators collected additional information on a range of potential confounders they incorporated into their analyses.
“We were able to include a lot of documentation on many potential confounders. That’s a strength of our data,” noted Dr. Jenkins, a professor of nutritional science and medicine at the University of Toronto.
“The present data, along with prior publications from PURE and several other studies, emphasize that consumption of poor quality carbohydrates is likely to be more adverse than the consumption of most fats in the diet,” said senior author Salim Yusuf, MD, DPhil, professor of medicine and executive director of the Population Health Research Institute at McMaster University, Hamilton, Ont.
“This calls for a fundamental shift in our thinking of what types of diet are likely to be harmful and what types neutral or beneficial,” Dr. Yusuf said in a statement from his institution.
Higher BMI associated with greater glycemic index effect
Another important analysis in the new report calculated the impact of a higher glycemic index diet among people with a body mass index (BMI) of less than 25 kg/m2 as well as higher BMIs.
Among people in the lower BMI subgroup, greater intake of high-glycemic-index foods showed slightly more incident primary outcome events. In contrast, people with a BMI of 25 or greater showed a steady increment in primary outcome events as the glycemic index of their diet increased.
People with higher BMIs in the quartile that ate the greatest amount of high-glycemic =-index foods had a significant 38% higher rate of primary outcome events, compared with people with similar BMIs in the lowest quartile for high-glycemic-index intake.
However, the study showed no impact on the primary association of high glycemic index and increased adverse outcomes by exercise habits, smoking, use of blood pressure medications, or use of statins.
The new report complements a separate analysis from PURE published just a few weeks earlier in the BMJ that established a significant association between increased consumption of whole grains and fewer CVD events, compared with people who had more refined grains in their diet, as reported by this news organization.
This prior report on whole versus refined grains, which Dr. Jenkins coauthored, looked at carbohydrate quality using a two-pronged approach, while glycemic index is a continuous variable that provides more nuance and takes into account carbohydrates from sources other than grains, Dr. Jenkins said.
PURE enrolled roughly 225,000 people aged 35-70 years at entry. The glycemic index analysis focused on 119,575 people who had data available for the primary outcome. During a median follow-up of 9.5 years, these people had 14,075 primary outcome events, including 8,780 deaths.
Analyses that looked at the individual outcomes that comprised the composite endpoint showed significant associations between a high-glycemic-index diet and total mortality, CVD death, non-CVD death, and stroke, but showed no significant link with myocardial infarction or heart failure. These findings are consistent with prior results of other studies that showed a stronger link between stroke and a high glycemic index diet, compared with other nonfatal CVD events.
Dr. Jenkins suggested that the significant excess of non-CVD deaths linked with a high-glycemic-index diet may stem from the impact of this type of diet on cancer-associated mortality.
PURE received partial funding through unrestricted grants from several drug companies. Dr. Jenkins has reported receiving gifts from several food-related trade associations and food companies, as well as research grants from two legume-oriented trade associations.
A version of this article first appeared on Medscape.com.
People who mostly ate foods with a low glycemic index had a lower likelihood of premature death and major cardiovascular disease (CVD) events, compared with those whose diet included more “poor-quality” food with a high glycemic index.
The results from the global PURE study of nearly 120,000 people provide evidence that helps cement glycemic index as a key measure of dietary health.
This new analysis from PURE (Prospective Urban and Rural Epidemiological Study) – a massive prospective epidemiologic study – shows people with a diet in the highest quintile of glycemic index had a significant 25% higher rate of combined total deaths and major CVD events during a median follow-up of nearly 10 years, compared with those with a diet in the lowest glycemic index quintile, in the report published online on Feb. 24, 2021, in the New England Journal of Medicine.
David J.A. Jenkins, MD, PhD, DSc, lead author, said people do not necessarily need to closely track the glycemic index of what they eat to follow the guidance that lower is better.
The link between lower glycemic load and fewer CVD events was even stronger among people with an established history of CVD at study entry. In this subset, which included 9% of the total cohort, people in the highest quintile for glycemic index consumption had a 51% higher rate of the composite primary endpoint, compared with those in the lowest quintile, in an analysis that adjusted for several potential confounders.
A simple but accurate and effective public health message is to follow existing dietary recommendations to eat better-quality food – more unprocessed fruits, vegetables, legumes, and whole grains – Dr. Jenkins advised. Those who prefer a more detailed approach could use the comprehensive glycemic index tables compiled by researchers at the University of Sydney.
‘All carbohydrates are not the same’
“What we’re saying is that all carbohydrates are not the same. Some seem to increase the risk for CVD, and others seem protective. This is not new, but worth restating in an era of low-carb and no-carb diets,” said Dr. Jenkins.
Low-glycemic-index foods are generally unprocessed foods in their native state, including fruits, vegetables, legumes, and unrefined whole grains. High-glycemic-index foods contain processed and refined carbohydrates that deliver jolts of glucose soon after eating, as the sugar in these carbohydrates quickly moves from the gut to the bloodstream.
An association between a diet with a lower glycemic index and better outcomes had appeared in prior reports from other studies, but not as unambiguously as in the new data from PURE, likely because of fewer study participants in previous studies.
Another feature of PURE that adds to the generalizability of the findings is the diversity of adults included in the study, from 20 countries on five continents.
“This clinches it,” Dr. Jenkins declared in an interview.
New PURE data tip the evidence balance
The NEJM article includes a new meta-analysis that adds the PURE findings to data from two large prior reports that were each less conclusive. The new calculation with the PURE numbers helps establish a clearer association between a diet with a higher glycemic index and the endpoint of CVD death, showing an overall 26% increase in the outcome.
The PURE data are especially informative because the investigators collected additional information on a range of potential confounders they incorporated into their analyses.
“We were able to include a lot of documentation on many potential confounders. That’s a strength of our data,” noted Dr. Jenkins, a professor of nutritional science and medicine at the University of Toronto.
“The present data, along with prior publications from PURE and several other studies, emphasize that consumption of poor quality carbohydrates is likely to be more adverse than the consumption of most fats in the diet,” said senior author Salim Yusuf, MD, DPhil, professor of medicine and executive director of the Population Health Research Institute at McMaster University, Hamilton, Ont.
“This calls for a fundamental shift in our thinking of what types of diet are likely to be harmful and what types neutral or beneficial,” Dr. Yusuf said in a statement from his institution.
Higher BMI associated with greater glycemic index effect
Another important analysis in the new report calculated the impact of a higher glycemic index diet among people with a body mass index (BMI) of less than 25 kg/m2 as well as higher BMIs.
Among people in the lower BMI subgroup, greater intake of high-glycemic-index foods showed slightly more incident primary outcome events. In contrast, people with a BMI of 25 or greater showed a steady increment in primary outcome events as the glycemic index of their diet increased.
People with higher BMIs in the quartile that ate the greatest amount of high-glycemic =-index foods had a significant 38% higher rate of primary outcome events, compared with people with similar BMIs in the lowest quartile for high-glycemic-index intake.
However, the study showed no impact on the primary association of high glycemic index and increased adverse outcomes by exercise habits, smoking, use of blood pressure medications, or use of statins.
The new report complements a separate analysis from PURE published just a few weeks earlier in the BMJ that established a significant association between increased consumption of whole grains and fewer CVD events, compared with people who had more refined grains in their diet, as reported by this news organization.
This prior report on whole versus refined grains, which Dr. Jenkins coauthored, looked at carbohydrate quality using a two-pronged approach, while glycemic index is a continuous variable that provides more nuance and takes into account carbohydrates from sources other than grains, Dr. Jenkins said.
PURE enrolled roughly 225,000 people aged 35-70 years at entry. The glycemic index analysis focused on 119,575 people who had data available for the primary outcome. During a median follow-up of 9.5 years, these people had 14,075 primary outcome events, including 8,780 deaths.
Analyses that looked at the individual outcomes that comprised the composite endpoint showed significant associations between a high-glycemic-index diet and total mortality, CVD death, non-CVD death, and stroke, but showed no significant link with myocardial infarction or heart failure. These findings are consistent with prior results of other studies that showed a stronger link between stroke and a high glycemic index diet, compared with other nonfatal CVD events.
Dr. Jenkins suggested that the significant excess of non-CVD deaths linked with a high-glycemic-index diet may stem from the impact of this type of diet on cancer-associated mortality.
PURE received partial funding through unrestricted grants from several drug companies. Dr. Jenkins has reported receiving gifts from several food-related trade associations and food companies, as well as research grants from two legume-oriented trade associations.
A version of this article first appeared on Medscape.com.
People who mostly ate foods with a low glycemic index had a lower likelihood of premature death and major cardiovascular disease (CVD) events, compared with those whose diet included more “poor-quality” food with a high glycemic index.
The results from the global PURE study of nearly 120,000 people provide evidence that helps cement glycemic index as a key measure of dietary health.
This new analysis from PURE (Prospective Urban and Rural Epidemiological Study) – a massive prospective epidemiologic study – shows people with a diet in the highest quintile of glycemic index had a significant 25% higher rate of combined total deaths and major CVD events during a median follow-up of nearly 10 years, compared with those with a diet in the lowest glycemic index quintile, in the report published online on Feb. 24, 2021, in the New England Journal of Medicine.
David J.A. Jenkins, MD, PhD, DSc, lead author, said people do not necessarily need to closely track the glycemic index of what they eat to follow the guidance that lower is better.
The link between lower glycemic load and fewer CVD events was even stronger among people with an established history of CVD at study entry. In this subset, which included 9% of the total cohort, people in the highest quintile for glycemic index consumption had a 51% higher rate of the composite primary endpoint, compared with those in the lowest quintile, in an analysis that adjusted for several potential confounders.
A simple but accurate and effective public health message is to follow existing dietary recommendations to eat better-quality food – more unprocessed fruits, vegetables, legumes, and whole grains – Dr. Jenkins advised. Those who prefer a more detailed approach could use the comprehensive glycemic index tables compiled by researchers at the University of Sydney.
‘All carbohydrates are not the same’
“What we’re saying is that all carbohydrates are not the same. Some seem to increase the risk for CVD, and others seem protective. This is not new, but worth restating in an era of low-carb and no-carb diets,” said Dr. Jenkins.
Low-glycemic-index foods are generally unprocessed foods in their native state, including fruits, vegetables, legumes, and unrefined whole grains. High-glycemic-index foods contain processed and refined carbohydrates that deliver jolts of glucose soon after eating, as the sugar in these carbohydrates quickly moves from the gut to the bloodstream.
An association between a diet with a lower glycemic index and better outcomes had appeared in prior reports from other studies, but not as unambiguously as in the new data from PURE, likely because of fewer study participants in previous studies.
Another feature of PURE that adds to the generalizability of the findings is the diversity of adults included in the study, from 20 countries on five continents.
“This clinches it,” Dr. Jenkins declared in an interview.
New PURE data tip the evidence balance
The NEJM article includes a new meta-analysis that adds the PURE findings to data from two large prior reports that were each less conclusive. The new calculation with the PURE numbers helps establish a clearer association between a diet with a higher glycemic index and the endpoint of CVD death, showing an overall 26% increase in the outcome.
The PURE data are especially informative because the investigators collected additional information on a range of potential confounders they incorporated into their analyses.
“We were able to include a lot of documentation on many potential confounders. That’s a strength of our data,” noted Dr. Jenkins, a professor of nutritional science and medicine at the University of Toronto.
“The present data, along with prior publications from PURE and several other studies, emphasize that consumption of poor quality carbohydrates is likely to be more adverse than the consumption of most fats in the diet,” said senior author Salim Yusuf, MD, DPhil, professor of medicine and executive director of the Population Health Research Institute at McMaster University, Hamilton, Ont.
“This calls for a fundamental shift in our thinking of what types of diet are likely to be harmful and what types neutral or beneficial,” Dr. Yusuf said in a statement from his institution.
Higher BMI associated with greater glycemic index effect
Another important analysis in the new report calculated the impact of a higher glycemic index diet among people with a body mass index (BMI) of less than 25 kg/m2 as well as higher BMIs.
Among people in the lower BMI subgroup, greater intake of high-glycemic-index foods showed slightly more incident primary outcome events. In contrast, people with a BMI of 25 or greater showed a steady increment in primary outcome events as the glycemic index of their diet increased.
People with higher BMIs in the quartile that ate the greatest amount of high-glycemic =-index foods had a significant 38% higher rate of primary outcome events, compared with people with similar BMIs in the lowest quartile for high-glycemic-index intake.
However, the study showed no impact on the primary association of high glycemic index and increased adverse outcomes by exercise habits, smoking, use of blood pressure medications, or use of statins.
The new report complements a separate analysis from PURE published just a few weeks earlier in the BMJ that established a significant association between increased consumption of whole grains and fewer CVD events, compared with people who had more refined grains in their diet, as reported by this news organization.
This prior report on whole versus refined grains, which Dr. Jenkins coauthored, looked at carbohydrate quality using a two-pronged approach, while glycemic index is a continuous variable that provides more nuance and takes into account carbohydrates from sources other than grains, Dr. Jenkins said.
PURE enrolled roughly 225,000 people aged 35-70 years at entry. The glycemic index analysis focused on 119,575 people who had data available for the primary outcome. During a median follow-up of 9.5 years, these people had 14,075 primary outcome events, including 8,780 deaths.
Analyses that looked at the individual outcomes that comprised the composite endpoint showed significant associations between a high-glycemic-index diet and total mortality, CVD death, non-CVD death, and stroke, but showed no significant link with myocardial infarction or heart failure. These findings are consistent with prior results of other studies that showed a stronger link between stroke and a high glycemic index diet, compared with other nonfatal CVD events.
Dr. Jenkins suggested that the significant excess of non-CVD deaths linked with a high-glycemic-index diet may stem from the impact of this type of diet on cancer-associated mortality.
PURE received partial funding through unrestricted grants from several drug companies. Dr. Jenkins has reported receiving gifts from several food-related trade associations and food companies, as well as research grants from two legume-oriented trade associations.
A version of this article first appeared on Medscape.com.
How to convince patients muscle pain isn’t a statin Achilles heel: StatinWISE
Another randomized trial, on the heels of the recently published SAMSON, has concluded – many would say confirmed – that .
Affected patients who sorely doubt that conclusion might possibly embrace statins, researchers say, if the new trial’s creative methodology could somehow be applied to them in clinical practice.
The recent SAMSON trial made waves in November 2020 by concluding, with some caveats, that about 90% of the burden of muscle symptoms reported by patients on statins may be attributable to a nocebo effect; that is, they are attributed to the drugs – perhaps because of negative expectations – but not actually caused by them.
The new trial, StatinWISE (Statin Web-based Investigation of Side Effects), triple the size but similar in design and conducted parallel to SAMSON, similarly saw no important differences in patient-reported muscle symptom prevalence or severity during administration of atorvastatin 20 mg/day or placebo, in withdrawal from the study because of such symptoms, or in patient quality of life.
The findings also support years of observational evidence that argues against a statin effect on muscle symptoms except in rare cases of confirmed myopathy, as well as results from randomized trials like ODYSSEY ALTERNATIVE and GAUSS-3, in which significant muscle symptoms in “statin-intolerant” patients were unusual, note StatinWISE investigators in their report, published online Feb. 24 in BMJ, with lead author Emily Herrett, MSc, PhD, London School of Hygiene and Tropical Medicine.
“I’m hoping it can change minds a bit and reassure people. That was part of the reason we did it, to inform this debate about harms and benefits of statins,” principal investigator Liam Smeeth, MBChB, MSc, PhD, from the same institution, said during a virtual press conference on the trial conducted by the U.K. nonprofit Science Media Centre.
“In thinking through whether to take a statin or not, people can be reassured that these muscle symptoms are rare; they aren’t common. Aches and pains are common, but are not caused by statins,” said Dr. Smeeth, who is senior author on the trial publication.
Another goal of the 200-patient study, he said, was to explore whether patients who had experienced muscle symptoms on a statin but were willing to explore whether the statin was to blame could be convinced – depending on what they learned in the trial – to stay on the drugs.
It seemed to work; two-thirds of the participants who finished the study “decided that they would actually want to try starting statins again, which was quite amazing.”
But there was a “slight caveat,” Dr. Smeeth observed. “To join our trial, yes, you had to have had a bad experience with statins, but you probably had to be a little bit open to the idea of trying them again. So, I can’t claim that that two-thirds would apply to everybody in the population.”
Because StatinWISE entered only patients who had reported severe muscle symptoms on a statin but hadn’t showed significant enzymatic evidence of myopathy, all had either taken themselves off the statin or were “considering” it. And the study had excluded anyone with “persistent, generalized, unexplained muscle pain” regardless of any statin therapy.
“This was very deliberately a select group of people who had serious problems taking statins. This was not a random sample by any means,” Dr. Smeeth said.
“The patients in the study were willing to participate and take statins again,” suggesting they “may not be completely representative of all those who believe they experience side effects with statins, as anyone who refused to take statins ever again would not have been recruited,” observed Tim Chico, MBChB, MD, University of Sheffield (England) in a Science Media Centre press release on StatinWISE.
Still, even among this “supersaturated group of people” selected for having had muscle symptoms on statins, Dr. Smeeth said at the briefing, “in almost all cases, their pains and aches were no worse on statins than they were on placebo. We’re not saying that anyone is making up their aches and pains. These are real aches and pains. What we’re showing very clearly is that those aches and pains are no worse on statins than they are on placebo.”
Rechallenge is possible
Some people are more likely than others to experience adverse reactions to any drug, “and that’s true of statins,” Neil J. Stone, MD, Northwestern University, Chicago, told this news organization. But StatinWISE underscores that many patients with muscle symptoms on the drugs can be convinced to continue with them rather than stop them entirely.
“The study didn’t say that everybody who has symptoms on a statin is having a nocebo effect,” said Dr. Stone, vice chair for the multisociety 2018 Guideline on the Management of Blood Cholesterol, who was not involved with StatinWISE.
“It simply said,” allowing for some caveats, “that a significant number of patients may have symptoms that don’t preclude them from being rechallenged with a statin again, once they understand what this nocebo effect is.”
And, Dr. Stone said, “it amplifies the 2018 guidelines, with their emphasis on the clinician-patient discussion before starting therapy,” by showing that statin-associated muscle pain isn’t necessarily caused by the drugs and isn’t a reason to stop them.
“That there is a second study confirming SAMSON is helpful, and the results are helpful because they say many of these patients, once they are shown the results, can be rechallenged and will then tolerate statins,” Steven E. Nissen, MD, Cleveland Clinic, said in an interview.
“They were able to get two-thirds of those completing the trial into long-term treatment, which I think is obviously very admirable and very important,” said Dr. Nissen, who was GAUSS-3 principal investigator but not associated with StatinWISE.
“I think it is important, however, that we not completely dismiss patients who complain of adverse effects. Because, in fact, there probably are some people who do have muscle-related symptoms,” he said. “But you know, to really call somebody statin intolerant, they really should fail three statins, which would be a very good standard.”
In his experience, said Patrick M. Moriarty, MD, who directs the Atherosclerosis & Lipoprotein-Apheresis Center at the University of Kansas Medical Center, Kansas City, perhaps 80%-90% of patients who believe they are statin intolerant because of muscle symptoms are actually not statin intolerant at all.
“I think a massive amount of it is supratentorial,” Dr. Moriarty, who was not part of StatinWISE, told this news organization. It comes directly from “what they heard, what they read, or what they were told – and at their age, they’re going to have aches and pains.”
Value of the n-of-1 trial
Dr. Smeeth and colleagues framed StatinWISE in part as a test of a strategy for overcoming nocebo-based aversion to statins. One goal was to see whether these methods might be helpful in practice for convincing patients who want to reject statins because of muscle symptoms to give the drugs another chance.
In StatinWISE, patients were individually assigned to take atorvastatin or placebo in randomized order with multiple blinding during each of six successive 2-month periods, so that they were on one or the other agent half the time. They rated their symptoms at the end of each period.
So the trial in composite was, as the publication states, “a series of randomized, placebo-controlled n-of-1 trials.” SAMSON followed a similar scheme, except – as previously reported – it had specified 4 months of atorvastatin, 4 months of placebo, and 4 months with patients on neither statin nor placebo.
StatinWISE “provides a useful approach (the n = 1 study) that could be used in real life to help patients understand the cause of their own possible side effects, which could also be applied to medications other than statins,” Dr. Chico added in the Science Media Centre release.
“I often encounter people who have a firmly held view that statins cause muscle pains, even when they haven’t taken these medications themselves, and I hope that this study may help change this view and make them willing to try such an ‘experiment,’ ” he said.
Others aren’t sure an experiment resembling an n-of-1 trial would be practical or effective when conducted in routine practice.
More efficient and useful, Dr. Moriarty noted, would be for physicians to nurture a close relationship with patients, one that could help transform their negative feelings about statins into a willingness to accept the drugs. “This is a trust you have to build; these are human beings.”
He said getting the patient’s confidence is critical. “You have to explain the pluses and minuses of getting treatment, of the 30% reduction in cardiovascular events that occur with the statin. You don’t go ‘testing this and that.’ I think it’s more about getting them on board.”
No statin effect on muscle symptoms
Patients in StatinWISE were recruited from 50 primary care practices in England and Wales from December 2016 to April 2018, the report notes; their mean age was 69 years, and 58% were men. Of the 200 patients, 151 recorded muscle-symptom scores for at least one statin period and one placebo period, and so were included in the primary-endpoint assessment.
The mean muscle symptom score was lower on statin therapy than on placebo (1.68 vs. 2.57), but there was no significant difference in adjusted analysis (mean difference, –0.11 (95% confidence interval, –0.36 to 0.14; P = .40).
Statins showed no significant effect on development of muscle symptoms overall, it was reported, with an odds ratio of 1.11 (99% confidence interval, 0.62-1.99). Nor was there an effect on “muscle symptoms that could not be attributed to another cause,” (OR, 1.22; 95% CI, 0.77-1.94).
Of the 80 withdrawals during the study for any reason, 43% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Of those, 33 were because of “intolerable muscle symptoms,” says the report. But withdrawal occurred about as often on statin therapy as off the drug – 9% and 7%, respectively – throughout the 1-year study.
“This study provides further evidence through the lived experience of individuals that muscle pains often attributed to statins are not due to the drug,” said Sir Nilesh J. Samani, MBChB, MD, medical director for the British Heart Foundation, as quoted in the Science Media Centre press release.
“The use of each patient as their own control in the trial provides a powerful way of distinguishing the effect of a statin from that of taking a pill,” he said. “The findings should give confidence to patients who may be concerned about taking statins.”
StatinWISE was funded by the National Institute for Health Research-Health Technology Program and sponsored by the London School of Hygiene and Tropical Medicine. The authors declare that they have “no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.” Dr. Smeeth reports receiving grants from GlaxoSmithKline, and personal fees for advisory work from AstraZeneca and GlaxoSmithKline. Dr. Stone reports no industry relationships or other disclosures. Dr. Nissen reports that his center has received funding for clinical trials from AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Orexigen, Pfizer, Takeda, The Medicines Company, and Silence Therapeutics; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction. Dr. Chico had no conflicts. Dr. Moriarty declared no relevant conflicts of interest. Dr. Samani had no disclosures.
A version of this article first appeared on Medscape.com.
Another randomized trial, on the heels of the recently published SAMSON, has concluded – many would say confirmed – that .
Affected patients who sorely doubt that conclusion might possibly embrace statins, researchers say, if the new trial’s creative methodology could somehow be applied to them in clinical practice.
The recent SAMSON trial made waves in November 2020 by concluding, with some caveats, that about 90% of the burden of muscle symptoms reported by patients on statins may be attributable to a nocebo effect; that is, they are attributed to the drugs – perhaps because of negative expectations – but not actually caused by them.
The new trial, StatinWISE (Statin Web-based Investigation of Side Effects), triple the size but similar in design and conducted parallel to SAMSON, similarly saw no important differences in patient-reported muscle symptom prevalence or severity during administration of atorvastatin 20 mg/day or placebo, in withdrawal from the study because of such symptoms, or in patient quality of life.
The findings also support years of observational evidence that argues against a statin effect on muscle symptoms except in rare cases of confirmed myopathy, as well as results from randomized trials like ODYSSEY ALTERNATIVE and GAUSS-3, in which significant muscle symptoms in “statin-intolerant” patients were unusual, note StatinWISE investigators in their report, published online Feb. 24 in BMJ, with lead author Emily Herrett, MSc, PhD, London School of Hygiene and Tropical Medicine.
“I’m hoping it can change minds a bit and reassure people. That was part of the reason we did it, to inform this debate about harms and benefits of statins,” principal investigator Liam Smeeth, MBChB, MSc, PhD, from the same institution, said during a virtual press conference on the trial conducted by the U.K. nonprofit Science Media Centre.
“In thinking through whether to take a statin or not, people can be reassured that these muscle symptoms are rare; they aren’t common. Aches and pains are common, but are not caused by statins,” said Dr. Smeeth, who is senior author on the trial publication.
Another goal of the 200-patient study, he said, was to explore whether patients who had experienced muscle symptoms on a statin but were willing to explore whether the statin was to blame could be convinced – depending on what they learned in the trial – to stay on the drugs.
It seemed to work; two-thirds of the participants who finished the study “decided that they would actually want to try starting statins again, which was quite amazing.”
But there was a “slight caveat,” Dr. Smeeth observed. “To join our trial, yes, you had to have had a bad experience with statins, but you probably had to be a little bit open to the idea of trying them again. So, I can’t claim that that two-thirds would apply to everybody in the population.”
Because StatinWISE entered only patients who had reported severe muscle symptoms on a statin but hadn’t showed significant enzymatic evidence of myopathy, all had either taken themselves off the statin or were “considering” it. And the study had excluded anyone with “persistent, generalized, unexplained muscle pain” regardless of any statin therapy.
“This was very deliberately a select group of people who had serious problems taking statins. This was not a random sample by any means,” Dr. Smeeth said.
“The patients in the study were willing to participate and take statins again,” suggesting they “may not be completely representative of all those who believe they experience side effects with statins, as anyone who refused to take statins ever again would not have been recruited,” observed Tim Chico, MBChB, MD, University of Sheffield (England) in a Science Media Centre press release on StatinWISE.
Still, even among this “supersaturated group of people” selected for having had muscle symptoms on statins, Dr. Smeeth said at the briefing, “in almost all cases, their pains and aches were no worse on statins than they were on placebo. We’re not saying that anyone is making up their aches and pains. These are real aches and pains. What we’re showing very clearly is that those aches and pains are no worse on statins than they are on placebo.”
Rechallenge is possible
Some people are more likely than others to experience adverse reactions to any drug, “and that’s true of statins,” Neil J. Stone, MD, Northwestern University, Chicago, told this news organization. But StatinWISE underscores that many patients with muscle symptoms on the drugs can be convinced to continue with them rather than stop them entirely.
“The study didn’t say that everybody who has symptoms on a statin is having a nocebo effect,” said Dr. Stone, vice chair for the multisociety 2018 Guideline on the Management of Blood Cholesterol, who was not involved with StatinWISE.
“It simply said,” allowing for some caveats, “that a significant number of patients may have symptoms that don’t preclude them from being rechallenged with a statin again, once they understand what this nocebo effect is.”
And, Dr. Stone said, “it amplifies the 2018 guidelines, with their emphasis on the clinician-patient discussion before starting therapy,” by showing that statin-associated muscle pain isn’t necessarily caused by the drugs and isn’t a reason to stop them.
“That there is a second study confirming SAMSON is helpful, and the results are helpful because they say many of these patients, once they are shown the results, can be rechallenged and will then tolerate statins,” Steven E. Nissen, MD, Cleveland Clinic, said in an interview.
“They were able to get two-thirds of those completing the trial into long-term treatment, which I think is obviously very admirable and very important,” said Dr. Nissen, who was GAUSS-3 principal investigator but not associated with StatinWISE.
“I think it is important, however, that we not completely dismiss patients who complain of adverse effects. Because, in fact, there probably are some people who do have muscle-related symptoms,” he said. “But you know, to really call somebody statin intolerant, they really should fail three statins, which would be a very good standard.”
In his experience, said Patrick M. Moriarty, MD, who directs the Atherosclerosis & Lipoprotein-Apheresis Center at the University of Kansas Medical Center, Kansas City, perhaps 80%-90% of patients who believe they are statin intolerant because of muscle symptoms are actually not statin intolerant at all.
“I think a massive amount of it is supratentorial,” Dr. Moriarty, who was not part of StatinWISE, told this news organization. It comes directly from “what they heard, what they read, or what they were told – and at their age, they’re going to have aches and pains.”
Value of the n-of-1 trial
Dr. Smeeth and colleagues framed StatinWISE in part as a test of a strategy for overcoming nocebo-based aversion to statins. One goal was to see whether these methods might be helpful in practice for convincing patients who want to reject statins because of muscle symptoms to give the drugs another chance.
In StatinWISE, patients were individually assigned to take atorvastatin or placebo in randomized order with multiple blinding during each of six successive 2-month periods, so that they were on one or the other agent half the time. They rated their symptoms at the end of each period.
So the trial in composite was, as the publication states, “a series of randomized, placebo-controlled n-of-1 trials.” SAMSON followed a similar scheme, except – as previously reported – it had specified 4 months of atorvastatin, 4 months of placebo, and 4 months with patients on neither statin nor placebo.
StatinWISE “provides a useful approach (the n = 1 study) that could be used in real life to help patients understand the cause of their own possible side effects, which could also be applied to medications other than statins,” Dr. Chico added in the Science Media Centre release.
“I often encounter people who have a firmly held view that statins cause muscle pains, even when they haven’t taken these medications themselves, and I hope that this study may help change this view and make them willing to try such an ‘experiment,’ ” he said.
Others aren’t sure an experiment resembling an n-of-1 trial would be practical or effective when conducted in routine practice.
More efficient and useful, Dr. Moriarty noted, would be for physicians to nurture a close relationship with patients, one that could help transform their negative feelings about statins into a willingness to accept the drugs. “This is a trust you have to build; these are human beings.”
He said getting the patient’s confidence is critical. “You have to explain the pluses and minuses of getting treatment, of the 30% reduction in cardiovascular events that occur with the statin. You don’t go ‘testing this and that.’ I think it’s more about getting them on board.”
No statin effect on muscle symptoms
Patients in StatinWISE were recruited from 50 primary care practices in England and Wales from December 2016 to April 2018, the report notes; their mean age was 69 years, and 58% were men. Of the 200 patients, 151 recorded muscle-symptom scores for at least one statin period and one placebo period, and so were included in the primary-endpoint assessment.
The mean muscle symptom score was lower on statin therapy than on placebo (1.68 vs. 2.57), but there was no significant difference in adjusted analysis (mean difference, –0.11 (95% confidence interval, –0.36 to 0.14; P = .40).
Statins showed no significant effect on development of muscle symptoms overall, it was reported, with an odds ratio of 1.11 (99% confidence interval, 0.62-1.99). Nor was there an effect on “muscle symptoms that could not be attributed to another cause,” (OR, 1.22; 95% CI, 0.77-1.94).
Of the 80 withdrawals during the study for any reason, 43% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Of those, 33 were because of “intolerable muscle symptoms,” says the report. But withdrawal occurred about as often on statin therapy as off the drug – 9% and 7%, respectively – throughout the 1-year study.
“This study provides further evidence through the lived experience of individuals that muscle pains often attributed to statins are not due to the drug,” said Sir Nilesh J. Samani, MBChB, MD, medical director for the British Heart Foundation, as quoted in the Science Media Centre press release.
“The use of each patient as their own control in the trial provides a powerful way of distinguishing the effect of a statin from that of taking a pill,” he said. “The findings should give confidence to patients who may be concerned about taking statins.”
StatinWISE was funded by the National Institute for Health Research-Health Technology Program and sponsored by the London School of Hygiene and Tropical Medicine. The authors declare that they have “no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.” Dr. Smeeth reports receiving grants from GlaxoSmithKline, and personal fees for advisory work from AstraZeneca and GlaxoSmithKline. Dr. Stone reports no industry relationships or other disclosures. Dr. Nissen reports that his center has received funding for clinical trials from AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Orexigen, Pfizer, Takeda, The Medicines Company, and Silence Therapeutics; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction. Dr. Chico had no conflicts. Dr. Moriarty declared no relevant conflicts of interest. Dr. Samani had no disclosures.
A version of this article first appeared on Medscape.com.
Another randomized trial, on the heels of the recently published SAMSON, has concluded – many would say confirmed – that .
Affected patients who sorely doubt that conclusion might possibly embrace statins, researchers say, if the new trial’s creative methodology could somehow be applied to them in clinical practice.
The recent SAMSON trial made waves in November 2020 by concluding, with some caveats, that about 90% of the burden of muscle symptoms reported by patients on statins may be attributable to a nocebo effect; that is, they are attributed to the drugs – perhaps because of negative expectations – but not actually caused by them.
The new trial, StatinWISE (Statin Web-based Investigation of Side Effects), triple the size but similar in design and conducted parallel to SAMSON, similarly saw no important differences in patient-reported muscle symptom prevalence or severity during administration of atorvastatin 20 mg/day or placebo, in withdrawal from the study because of such symptoms, or in patient quality of life.
The findings also support years of observational evidence that argues against a statin effect on muscle symptoms except in rare cases of confirmed myopathy, as well as results from randomized trials like ODYSSEY ALTERNATIVE and GAUSS-3, in which significant muscle symptoms in “statin-intolerant” patients were unusual, note StatinWISE investigators in their report, published online Feb. 24 in BMJ, with lead author Emily Herrett, MSc, PhD, London School of Hygiene and Tropical Medicine.
“I’m hoping it can change minds a bit and reassure people. That was part of the reason we did it, to inform this debate about harms and benefits of statins,” principal investigator Liam Smeeth, MBChB, MSc, PhD, from the same institution, said during a virtual press conference on the trial conducted by the U.K. nonprofit Science Media Centre.
“In thinking through whether to take a statin or not, people can be reassured that these muscle symptoms are rare; they aren’t common. Aches and pains are common, but are not caused by statins,” said Dr. Smeeth, who is senior author on the trial publication.
Another goal of the 200-patient study, he said, was to explore whether patients who had experienced muscle symptoms on a statin but were willing to explore whether the statin was to blame could be convinced – depending on what they learned in the trial – to stay on the drugs.
It seemed to work; two-thirds of the participants who finished the study “decided that they would actually want to try starting statins again, which was quite amazing.”
But there was a “slight caveat,” Dr. Smeeth observed. “To join our trial, yes, you had to have had a bad experience with statins, but you probably had to be a little bit open to the idea of trying them again. So, I can’t claim that that two-thirds would apply to everybody in the population.”
Because StatinWISE entered only patients who had reported severe muscle symptoms on a statin but hadn’t showed significant enzymatic evidence of myopathy, all had either taken themselves off the statin or were “considering” it. And the study had excluded anyone with “persistent, generalized, unexplained muscle pain” regardless of any statin therapy.
“This was very deliberately a select group of people who had serious problems taking statins. This was not a random sample by any means,” Dr. Smeeth said.
“The patients in the study were willing to participate and take statins again,” suggesting they “may not be completely representative of all those who believe they experience side effects with statins, as anyone who refused to take statins ever again would not have been recruited,” observed Tim Chico, MBChB, MD, University of Sheffield (England) in a Science Media Centre press release on StatinWISE.
Still, even among this “supersaturated group of people” selected for having had muscle symptoms on statins, Dr. Smeeth said at the briefing, “in almost all cases, their pains and aches were no worse on statins than they were on placebo. We’re not saying that anyone is making up their aches and pains. These are real aches and pains. What we’re showing very clearly is that those aches and pains are no worse on statins than they are on placebo.”
Rechallenge is possible
Some people are more likely than others to experience adverse reactions to any drug, “and that’s true of statins,” Neil J. Stone, MD, Northwestern University, Chicago, told this news organization. But StatinWISE underscores that many patients with muscle symptoms on the drugs can be convinced to continue with them rather than stop them entirely.
“The study didn’t say that everybody who has symptoms on a statin is having a nocebo effect,” said Dr. Stone, vice chair for the multisociety 2018 Guideline on the Management of Blood Cholesterol, who was not involved with StatinWISE.
“It simply said,” allowing for some caveats, “that a significant number of patients may have symptoms that don’t preclude them from being rechallenged with a statin again, once they understand what this nocebo effect is.”
And, Dr. Stone said, “it amplifies the 2018 guidelines, with their emphasis on the clinician-patient discussion before starting therapy,” by showing that statin-associated muscle pain isn’t necessarily caused by the drugs and isn’t a reason to stop them.
“That there is a second study confirming SAMSON is helpful, and the results are helpful because they say many of these patients, once they are shown the results, can be rechallenged and will then tolerate statins,” Steven E. Nissen, MD, Cleveland Clinic, said in an interview.
“They were able to get two-thirds of those completing the trial into long-term treatment, which I think is obviously very admirable and very important,” said Dr. Nissen, who was GAUSS-3 principal investigator but not associated with StatinWISE.
“I think it is important, however, that we not completely dismiss patients who complain of adverse effects. Because, in fact, there probably are some people who do have muscle-related symptoms,” he said. “But you know, to really call somebody statin intolerant, they really should fail three statins, which would be a very good standard.”
In his experience, said Patrick M. Moriarty, MD, who directs the Atherosclerosis & Lipoprotein-Apheresis Center at the University of Kansas Medical Center, Kansas City, perhaps 80%-90% of patients who believe they are statin intolerant because of muscle symptoms are actually not statin intolerant at all.
“I think a massive amount of it is supratentorial,” Dr. Moriarty, who was not part of StatinWISE, told this news organization. It comes directly from “what they heard, what they read, or what they were told – and at their age, they’re going to have aches and pains.”
Value of the n-of-1 trial
Dr. Smeeth and colleagues framed StatinWISE in part as a test of a strategy for overcoming nocebo-based aversion to statins. One goal was to see whether these methods might be helpful in practice for convincing patients who want to reject statins because of muscle symptoms to give the drugs another chance.
In StatinWISE, patients were individually assigned to take atorvastatin or placebo in randomized order with multiple blinding during each of six successive 2-month periods, so that they were on one or the other agent half the time. They rated their symptoms at the end of each period.
So the trial in composite was, as the publication states, “a series of randomized, placebo-controlled n-of-1 trials.” SAMSON followed a similar scheme, except – as previously reported – it had specified 4 months of atorvastatin, 4 months of placebo, and 4 months with patients on neither statin nor placebo.
StatinWISE “provides a useful approach (the n = 1 study) that could be used in real life to help patients understand the cause of their own possible side effects, which could also be applied to medications other than statins,” Dr. Chico added in the Science Media Centre release.
“I often encounter people who have a firmly held view that statins cause muscle pains, even when they haven’t taken these medications themselves, and I hope that this study may help change this view and make them willing to try such an ‘experiment,’ ” he said.
Others aren’t sure an experiment resembling an n-of-1 trial would be practical or effective when conducted in routine practice.
More efficient and useful, Dr. Moriarty noted, would be for physicians to nurture a close relationship with patients, one that could help transform their negative feelings about statins into a willingness to accept the drugs. “This is a trust you have to build; these are human beings.”
He said getting the patient’s confidence is critical. “You have to explain the pluses and minuses of getting treatment, of the 30% reduction in cardiovascular events that occur with the statin. You don’t go ‘testing this and that.’ I think it’s more about getting them on board.”
No statin effect on muscle symptoms
Patients in StatinWISE were recruited from 50 primary care practices in England and Wales from December 2016 to April 2018, the report notes; their mean age was 69 years, and 58% were men. Of the 200 patients, 151 recorded muscle-symptom scores for at least one statin period and one placebo period, and so were included in the primary-endpoint assessment.
The mean muscle symptom score was lower on statin therapy than on placebo (1.68 vs. 2.57), but there was no significant difference in adjusted analysis (mean difference, –0.11 (95% confidence interval, –0.36 to 0.14; P = .40).
Statins showed no significant effect on development of muscle symptoms overall, it was reported, with an odds ratio of 1.11 (99% confidence interval, 0.62-1.99). Nor was there an effect on “muscle symptoms that could not be attributed to another cause,” (OR, 1.22; 95% CI, 0.77-1.94).
Of the 80 withdrawals during the study for any reason, 43% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Of those, 33 were because of “intolerable muscle symptoms,” says the report. But withdrawal occurred about as often on statin therapy as off the drug – 9% and 7%, respectively – throughout the 1-year study.
“This study provides further evidence through the lived experience of individuals that muscle pains often attributed to statins are not due to the drug,” said Sir Nilesh J. Samani, MBChB, MD, medical director for the British Heart Foundation, as quoted in the Science Media Centre press release.
“The use of each patient as their own control in the trial provides a powerful way of distinguishing the effect of a statin from that of taking a pill,” he said. “The findings should give confidence to patients who may be concerned about taking statins.”
StatinWISE was funded by the National Institute for Health Research-Health Technology Program and sponsored by the London School of Hygiene and Tropical Medicine. The authors declare that they have “no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.” Dr. Smeeth reports receiving grants from GlaxoSmithKline, and personal fees for advisory work from AstraZeneca and GlaxoSmithKline. Dr. Stone reports no industry relationships or other disclosures. Dr. Nissen reports that his center has received funding for clinical trials from AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Orexigen, Pfizer, Takeda, The Medicines Company, and Silence Therapeutics; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction. Dr. Chico had no conflicts. Dr. Moriarty declared no relevant conflicts of interest. Dr. Samani had no disclosures.
A version of this article first appeared on Medscape.com.
Myocardial injury seen on MRI in 54% of recovered COVID-19 patients
About half of 148 patients hospitalized with COVID-19 infection and elevated troponin levels had at least some evidence of myocardial injury on cardiac magnetic resonance (CMR) imaging 2 months later, a new study shows.
“Our results demonstrate that in this subset of patients surviving severe COVID-19 and with troponin elevation, ongoing localized myocardial inflammation, whilst less frequent than previously reported, remains present in a proportion of patients and may represent an emerging issue of clinical relevance,” wrote Marianna Fontana, MD, PhD, of University College London, and colleagues.
The cardiac abnormalities identified were classified as nonischemic (including “myocarditis-like” late gadolinium enhancement [LGE]) in 26% of the cohort; as related to ischemic heart disease (infarction or inducible ischemia) in 22%; and as dual pathology in 6%.
Left ventricular (LV) function was normal in 89% of the 148 patients. In the 17 patients (11%) with LV dysfunction, only four had an ejection fraction below 35%. Of the nine patients whose LV dysfunction was related to myocardial infarction, six had a known history of ischemic heart disease.
No patients with “myocarditis-pattern” LGE had regional wall motion abnormalities, and neither admission nor peak troponin values were predictive of the diagnosis of myocarditis.
The results were published online Feb. 18 in the European Heart Journal.
Glass half full
Taking a “glass half full” approach, co–senior author Graham D. Cole, MD, PhD, noted on Twitter that nearly half the patients had no major cardiac abnormalities on CMR just 2 months after a bout with troponin-positive COVID-19.
“We think this is important: Even in a group who had been very sick with raised troponin, it was common to find no evidence of heart damage,” said Dr. Cole, of the Royal Free London NHS Foundation Trust.
“We believe our data challenge the hypothesis that chronic inflammation, diffuse fibrosis, or long-term LV dysfunction is a dominant feature in those surviving COVID-19,” the investigators concluded in their report.
In an interview, Dr. Fontana explained further: “It has been reported in an early ‘pathfinder’ study that two-thirds of patients recovered from COVID-19 had CMR evidence of abnormal findings with a high incidence of elevated T1 and T2 in keeping with diffuse fibrosis and edema. Our findings with a larger, multicenter study and better controls show low rates of heart impairment and much less ongoing inflammation, which is reassuring.”
She also noted that the different patterns of injury suggest that different mechanisms are at play, including the possibility that “at least some of the found damage might have been preexisting, because people with heart damage are more likely to get severe disease.”
The investigators, including first author Tushar Kotecha, MBChB, PhD, of the Royal Free London NHS Foundation Trust, also noted that myocarditis-like injury was limited to three or fewer myocardial segments in 88% of cases with no associated ventricular dysfunction, and that biventricular function was no different than in those without myocarditis.
“We use the word ‘myocarditis-like’ but we don’t have histology,” Dr. Fontana said. “Our group actually suspects a lot of this will be microvascular clotting (microangiopathic thrombosis). This is exciting, as newer anticoagulation strategies – for example, those being tried in RECOVERY – may have benefit.”
Aloke V. Finn, MD, of the CVPath Institute in Gaithersburg, Md., wishes researchers would stop using the term myocarditis altogether to describe clinical or imaging findings in COVID-19.
“MRI can’t diagnose myocarditis. It is a specific diagnosis that requires, ideally, histology, as the investigators acknowledged,” Dr. Finn said in an interview.
His group at CVPath recently published data showing pathologic evidence of myocarditis after SARS-CoV-2 infection, as reported by theheart.org | Medscape Cardiology.
“As a clinician, when I think of myocarditis, I look at the echo and an LV gram, and I see if there is a wall motion abnormality and troponin elevation, but with normal coronary arteries. And if all that is there, then I think about myocarditis in my differential diagnosis,” he said. “But in most of these cases, as the authors rightly point out, most patients did not have what is necessary to really entertain a diagnosis of myocarditis.”
He agreed with Dr. Fontana’s suggestion that what the CMR might be picking up in these survivors is microthrombi, as his group saw in their recent autopsy study.
“It’s very possible these findings are concordant with the recent autopsy studies done by my group and others in terms of detecting the presence of microthrombi, but we don’t know this for certain because no one has ever studied this entity before in the clinic and we don’t really know how microthrombi might appear on CMR.”
Largest study to date
The 148 participants (mean age, 64 years; 70% male) in the largest study to date to investigate convalescing COVID-19 patients who had elevated troponins – something identified early in the pandemic as a risk factor for worse outcomes in COVID-19 – were treated at one of six hospitals in London.
Patients who had abnormal troponin levels were offered an MRI scan of the heart after discharge and were compared with those from a control group of patients who had not had COVID-19 and with 40 healthy volunteers.
Median length of stay was 9 days, and 32% of patients required ventilatory support in the intensive care unit.
Just over half the patients (57%) had hypertension, 7% had had a previous myocardial infarction, 34% had diabetes, 46% had hypercholesterolemia, and 24% were smokers. Mean body mass index was 28.5 kg/m2.
CMR follow-up was conducted a median of 68 days after confirmation of a COVID-19 diagnosis.
On Twitter, Dr. Cole noted that the findings are subject to both survivor bias and referral bias. “We didn’t scan frail patients where the clinician felt [CMR] was unlikely to inform management.”
The findings, said Dr. Fontana, “say nothing about what happens to people who are not hospitalized with COVID, or those who are hospitalized but without elevated troponin.”
What they do offer, particularly if replicated, is a way forward in identifying patients at higher or lower risk for long-term sequelae and inform strategies that could improve outcomes, she added.
A version of this article first appeared on Medscape.com.
About half of 148 patients hospitalized with COVID-19 infection and elevated troponin levels had at least some evidence of myocardial injury on cardiac magnetic resonance (CMR) imaging 2 months later, a new study shows.
“Our results demonstrate that in this subset of patients surviving severe COVID-19 and with troponin elevation, ongoing localized myocardial inflammation, whilst less frequent than previously reported, remains present in a proportion of patients and may represent an emerging issue of clinical relevance,” wrote Marianna Fontana, MD, PhD, of University College London, and colleagues.
The cardiac abnormalities identified were classified as nonischemic (including “myocarditis-like” late gadolinium enhancement [LGE]) in 26% of the cohort; as related to ischemic heart disease (infarction or inducible ischemia) in 22%; and as dual pathology in 6%.
Left ventricular (LV) function was normal in 89% of the 148 patients. In the 17 patients (11%) with LV dysfunction, only four had an ejection fraction below 35%. Of the nine patients whose LV dysfunction was related to myocardial infarction, six had a known history of ischemic heart disease.
No patients with “myocarditis-pattern” LGE had regional wall motion abnormalities, and neither admission nor peak troponin values were predictive of the diagnosis of myocarditis.
The results were published online Feb. 18 in the European Heart Journal.
Glass half full
Taking a “glass half full” approach, co–senior author Graham D. Cole, MD, PhD, noted on Twitter that nearly half the patients had no major cardiac abnormalities on CMR just 2 months after a bout with troponin-positive COVID-19.
“We think this is important: Even in a group who had been very sick with raised troponin, it was common to find no evidence of heart damage,” said Dr. Cole, of the Royal Free London NHS Foundation Trust.
“We believe our data challenge the hypothesis that chronic inflammation, diffuse fibrosis, or long-term LV dysfunction is a dominant feature in those surviving COVID-19,” the investigators concluded in their report.
In an interview, Dr. Fontana explained further: “It has been reported in an early ‘pathfinder’ study that two-thirds of patients recovered from COVID-19 had CMR evidence of abnormal findings with a high incidence of elevated T1 and T2 in keeping with diffuse fibrosis and edema. Our findings with a larger, multicenter study and better controls show low rates of heart impairment and much less ongoing inflammation, which is reassuring.”
She also noted that the different patterns of injury suggest that different mechanisms are at play, including the possibility that “at least some of the found damage might have been preexisting, because people with heart damage are more likely to get severe disease.”
The investigators, including first author Tushar Kotecha, MBChB, PhD, of the Royal Free London NHS Foundation Trust, also noted that myocarditis-like injury was limited to three or fewer myocardial segments in 88% of cases with no associated ventricular dysfunction, and that biventricular function was no different than in those without myocarditis.
“We use the word ‘myocarditis-like’ but we don’t have histology,” Dr. Fontana said. “Our group actually suspects a lot of this will be microvascular clotting (microangiopathic thrombosis). This is exciting, as newer anticoagulation strategies – for example, those being tried in RECOVERY – may have benefit.”
Aloke V. Finn, MD, of the CVPath Institute in Gaithersburg, Md., wishes researchers would stop using the term myocarditis altogether to describe clinical or imaging findings in COVID-19.
“MRI can’t diagnose myocarditis. It is a specific diagnosis that requires, ideally, histology, as the investigators acknowledged,” Dr. Finn said in an interview.
His group at CVPath recently published data showing pathologic evidence of myocarditis after SARS-CoV-2 infection, as reported by theheart.org | Medscape Cardiology.
“As a clinician, when I think of myocarditis, I look at the echo and an LV gram, and I see if there is a wall motion abnormality and troponin elevation, but with normal coronary arteries. And if all that is there, then I think about myocarditis in my differential diagnosis,” he said. “But in most of these cases, as the authors rightly point out, most patients did not have what is necessary to really entertain a diagnosis of myocarditis.”
He agreed with Dr. Fontana’s suggestion that what the CMR might be picking up in these survivors is microthrombi, as his group saw in their recent autopsy study.
“It’s very possible these findings are concordant with the recent autopsy studies done by my group and others in terms of detecting the presence of microthrombi, but we don’t know this for certain because no one has ever studied this entity before in the clinic and we don’t really know how microthrombi might appear on CMR.”
Largest study to date
The 148 participants (mean age, 64 years; 70% male) in the largest study to date to investigate convalescing COVID-19 patients who had elevated troponins – something identified early in the pandemic as a risk factor for worse outcomes in COVID-19 – were treated at one of six hospitals in London.
Patients who had abnormal troponin levels were offered an MRI scan of the heart after discharge and were compared with those from a control group of patients who had not had COVID-19 and with 40 healthy volunteers.
Median length of stay was 9 days, and 32% of patients required ventilatory support in the intensive care unit.
Just over half the patients (57%) had hypertension, 7% had had a previous myocardial infarction, 34% had diabetes, 46% had hypercholesterolemia, and 24% were smokers. Mean body mass index was 28.5 kg/m2.
CMR follow-up was conducted a median of 68 days after confirmation of a COVID-19 diagnosis.
On Twitter, Dr. Cole noted that the findings are subject to both survivor bias and referral bias. “We didn’t scan frail patients where the clinician felt [CMR] was unlikely to inform management.”
The findings, said Dr. Fontana, “say nothing about what happens to people who are not hospitalized with COVID, or those who are hospitalized but without elevated troponin.”
What they do offer, particularly if replicated, is a way forward in identifying patients at higher or lower risk for long-term sequelae and inform strategies that could improve outcomes, she added.
A version of this article first appeared on Medscape.com.
About half of 148 patients hospitalized with COVID-19 infection and elevated troponin levels had at least some evidence of myocardial injury on cardiac magnetic resonance (CMR) imaging 2 months later, a new study shows.
“Our results demonstrate that in this subset of patients surviving severe COVID-19 and with troponin elevation, ongoing localized myocardial inflammation, whilst less frequent than previously reported, remains present in a proportion of patients and may represent an emerging issue of clinical relevance,” wrote Marianna Fontana, MD, PhD, of University College London, and colleagues.
The cardiac abnormalities identified were classified as nonischemic (including “myocarditis-like” late gadolinium enhancement [LGE]) in 26% of the cohort; as related to ischemic heart disease (infarction or inducible ischemia) in 22%; and as dual pathology in 6%.
Left ventricular (LV) function was normal in 89% of the 148 patients. In the 17 patients (11%) with LV dysfunction, only four had an ejection fraction below 35%. Of the nine patients whose LV dysfunction was related to myocardial infarction, six had a known history of ischemic heart disease.
No patients with “myocarditis-pattern” LGE had regional wall motion abnormalities, and neither admission nor peak troponin values were predictive of the diagnosis of myocarditis.
The results were published online Feb. 18 in the European Heart Journal.
Glass half full
Taking a “glass half full” approach, co–senior author Graham D. Cole, MD, PhD, noted on Twitter that nearly half the patients had no major cardiac abnormalities on CMR just 2 months after a bout with troponin-positive COVID-19.
“We think this is important: Even in a group who had been very sick with raised troponin, it was common to find no evidence of heart damage,” said Dr. Cole, of the Royal Free London NHS Foundation Trust.
“We believe our data challenge the hypothesis that chronic inflammation, diffuse fibrosis, or long-term LV dysfunction is a dominant feature in those surviving COVID-19,” the investigators concluded in their report.
In an interview, Dr. Fontana explained further: “It has been reported in an early ‘pathfinder’ study that two-thirds of patients recovered from COVID-19 had CMR evidence of abnormal findings with a high incidence of elevated T1 and T2 in keeping with diffuse fibrosis and edema. Our findings with a larger, multicenter study and better controls show low rates of heart impairment and much less ongoing inflammation, which is reassuring.”
She also noted that the different patterns of injury suggest that different mechanisms are at play, including the possibility that “at least some of the found damage might have been preexisting, because people with heart damage are more likely to get severe disease.”
The investigators, including first author Tushar Kotecha, MBChB, PhD, of the Royal Free London NHS Foundation Trust, also noted that myocarditis-like injury was limited to three or fewer myocardial segments in 88% of cases with no associated ventricular dysfunction, and that biventricular function was no different than in those without myocarditis.
“We use the word ‘myocarditis-like’ but we don’t have histology,” Dr. Fontana said. “Our group actually suspects a lot of this will be microvascular clotting (microangiopathic thrombosis). This is exciting, as newer anticoagulation strategies – for example, those being tried in RECOVERY – may have benefit.”
Aloke V. Finn, MD, of the CVPath Institute in Gaithersburg, Md., wishes researchers would stop using the term myocarditis altogether to describe clinical or imaging findings in COVID-19.
“MRI can’t diagnose myocarditis. It is a specific diagnosis that requires, ideally, histology, as the investigators acknowledged,” Dr. Finn said in an interview.
His group at CVPath recently published data showing pathologic evidence of myocarditis after SARS-CoV-2 infection, as reported by theheart.org | Medscape Cardiology.
“As a clinician, when I think of myocarditis, I look at the echo and an LV gram, and I see if there is a wall motion abnormality and troponin elevation, but with normal coronary arteries. And if all that is there, then I think about myocarditis in my differential diagnosis,” he said. “But in most of these cases, as the authors rightly point out, most patients did not have what is necessary to really entertain a diagnosis of myocarditis.”
He agreed with Dr. Fontana’s suggestion that what the CMR might be picking up in these survivors is microthrombi, as his group saw in their recent autopsy study.
“It’s very possible these findings are concordant with the recent autopsy studies done by my group and others in terms of detecting the presence of microthrombi, but we don’t know this for certain because no one has ever studied this entity before in the clinic and we don’t really know how microthrombi might appear on CMR.”
Largest study to date
The 148 participants (mean age, 64 years; 70% male) in the largest study to date to investigate convalescing COVID-19 patients who had elevated troponins – something identified early in the pandemic as a risk factor for worse outcomes in COVID-19 – were treated at one of six hospitals in London.
Patients who had abnormal troponin levels were offered an MRI scan of the heart after discharge and were compared with those from a control group of patients who had not had COVID-19 and with 40 healthy volunteers.
Median length of stay was 9 days, and 32% of patients required ventilatory support in the intensive care unit.
Just over half the patients (57%) had hypertension, 7% had had a previous myocardial infarction, 34% had diabetes, 46% had hypercholesterolemia, and 24% were smokers. Mean body mass index was 28.5 kg/m2.
CMR follow-up was conducted a median of 68 days after confirmation of a COVID-19 diagnosis.
On Twitter, Dr. Cole noted that the findings are subject to both survivor bias and referral bias. “We didn’t scan frail patients where the clinician felt [CMR] was unlikely to inform management.”
The findings, said Dr. Fontana, “say nothing about what happens to people who are not hospitalized with COVID, or those who are hospitalized but without elevated troponin.”
What they do offer, particularly if replicated, is a way forward in identifying patients at higher or lower risk for long-term sequelae and inform strategies that could improve outcomes, she added.
A version of this article first appeared on Medscape.com.
FDA approves orphan drug evinacumab-dgnb for homozygous FH
The Food and Drug Administration has approved the fully human monoclonal antibody evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals) for use on top of other cholesterol-modifying medication in patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH), the agency and Regeneron have announced.
Evinacumab had received orphan drug designation and underwent priority regulatory review based primarily on the phase 3 ELIPSE trial, presented at a meeting in March 2020 and published in August 2020 in the New England Journal of Medicine (doi: 10.1056/NEJMoa2004215).
In the trial with 65 patients with HoFH on guideline-based lipid-modifying therapy, those who also received evinacumab 15 mg/kg intravenously every 4 weeks showed a nearly 50% drop in LDL cholesterol levels after 24 weeks, compared with patients given a placebo. Only 2% of patients in both groups discontinued therapy because of adverse reactions.
The drug blocks angiopoietin-like 3, itself an inhibitor of lipoprotein lipase and endothelial lipase. It therefore lowers LDL cholesterol levels by mechanisms that don’t directly involve the LDL receptor.
Regeneron estimates that about 1300 people in the United States have the homozygous genetic disorder, which can lead to LDL cholesterol levels of a 1,000 mg/dL or higher, advanced premature atherosclerosis, and extreme risk for cardiovascular events.
The drug’s average wholesale acquisition cost per patient in the United States is expected to be about $450,000 per year, the company said, adding that it has a financial support program to help qualified patients with out-of-pocket costs.
Regeneron’s announcement included a comment from dyslipidemia-therapy expert Daniel J. Rader, MD, University of Pennsylvania, Philadelphia, who called evinacumab “a potentially transformational new treatment for people with HoFH.”
The drug is currently under regulatory review for the same indication in Europe, the company said.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved the fully human monoclonal antibody evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals) for use on top of other cholesterol-modifying medication in patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH), the agency and Regeneron have announced.
Evinacumab had received orphan drug designation and underwent priority regulatory review based primarily on the phase 3 ELIPSE trial, presented at a meeting in March 2020 and published in August 2020 in the New England Journal of Medicine (doi: 10.1056/NEJMoa2004215).
In the trial with 65 patients with HoFH on guideline-based lipid-modifying therapy, those who also received evinacumab 15 mg/kg intravenously every 4 weeks showed a nearly 50% drop in LDL cholesterol levels after 24 weeks, compared with patients given a placebo. Only 2% of patients in both groups discontinued therapy because of adverse reactions.
The drug blocks angiopoietin-like 3, itself an inhibitor of lipoprotein lipase and endothelial lipase. It therefore lowers LDL cholesterol levels by mechanisms that don’t directly involve the LDL receptor.
Regeneron estimates that about 1300 people in the United States have the homozygous genetic disorder, which can lead to LDL cholesterol levels of a 1,000 mg/dL or higher, advanced premature atherosclerosis, and extreme risk for cardiovascular events.
The drug’s average wholesale acquisition cost per patient in the United States is expected to be about $450,000 per year, the company said, adding that it has a financial support program to help qualified patients with out-of-pocket costs.
Regeneron’s announcement included a comment from dyslipidemia-therapy expert Daniel J. Rader, MD, University of Pennsylvania, Philadelphia, who called evinacumab “a potentially transformational new treatment for people with HoFH.”
The drug is currently under regulatory review for the same indication in Europe, the company said.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved the fully human monoclonal antibody evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals) for use on top of other cholesterol-modifying medication in patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH), the agency and Regeneron have announced.
Evinacumab had received orphan drug designation and underwent priority regulatory review based primarily on the phase 3 ELIPSE trial, presented at a meeting in March 2020 and published in August 2020 in the New England Journal of Medicine (doi: 10.1056/NEJMoa2004215).
In the trial with 65 patients with HoFH on guideline-based lipid-modifying therapy, those who also received evinacumab 15 mg/kg intravenously every 4 weeks showed a nearly 50% drop in LDL cholesterol levels after 24 weeks, compared with patients given a placebo. Only 2% of patients in both groups discontinued therapy because of adverse reactions.
The drug blocks angiopoietin-like 3, itself an inhibitor of lipoprotein lipase and endothelial lipase. It therefore lowers LDL cholesterol levels by mechanisms that don’t directly involve the LDL receptor.
Regeneron estimates that about 1300 people in the United States have the homozygous genetic disorder, which can lead to LDL cholesterol levels of a 1,000 mg/dL or higher, advanced premature atherosclerosis, and extreme risk for cardiovascular events.
The drug’s average wholesale acquisition cost per patient in the United States is expected to be about $450,000 per year, the company said, adding that it has a financial support program to help qualified patients with out-of-pocket costs.
Regeneron’s announcement included a comment from dyslipidemia-therapy expert Daniel J. Rader, MD, University of Pennsylvania, Philadelphia, who called evinacumab “a potentially transformational new treatment for people with HoFH.”
The drug is currently under regulatory review for the same indication in Europe, the company said.
A version of this article first appeared on Medscape.com.
Menopause transition affects heart health risks
Menopause is a key time to monitor women for the development or increase of cardiovascular risk factors, according to a new consensus statement developed by the Task Force on Gender of the European Society of Cardiology and a multidisciplinary ESC working group on Women’s Health in Menopause.
“After menopause, traditional cardiovascular risk factors are adversely affected – particularly hypertension,” wrote Angela H.E.M. Maas, MD, of Radboud University Medical Center, Nijmegen, Netherlands, and colleagues.
“Since the first ESC consensus paper on the management of cardiovascular risk in perimenopausal women was published in 2007, we have a greater understanding on the role of female-specific risk factors for cardiovascular disease (CVD),” they said.
In a consensus statement published in the European Heart Journal, the authors presented clinical guidance for diagnosis and management of cardiovascular risk factors during the menopause transition. The transition to menopause increases a woman’s risk for developing several CVD risk factors, including central adiposity, increased insulin resistance, a proatherogenic lipid profile, and autonomic dysfunction that can contribute to increased heart rate variability, according to the statement.
Estrogen changes may affect ischemic disease
In general, obstructive coronary artery disease (CAD) strikes women later than men, but coronary vasomotor conditions are a common cause of ischemic heart disease in women with or without CAD, the authors noted.
“Lower estrogen levels after menopause are related to altered vascular function, enhanced inflammation, and up-regulation of other hormonal systems such as the renin–angiotensin–aldosterone system, the sympathetic nervous system, and reduced nitric oxide–dependent vasodilation,” they wrote. They recommended use of the coronary artery calcium score for screening middle-aged women who are symptomatic or at intermediate cardiovascular risk.
The transition to menopause causes changes in lipid profiles, and a rise in blood pressure in particular “may be both a direct effect of hormonal changes on the vasculature and metabolic changes with aging,” but hypertension in early post menopause is “often poorly managed,” the authors noted.
Compared with asymptomatic women, women who suffer from severe menopausal symptoms often have increased cardiovascular disease risk factors. For example, the Women’s Health Initiative (WHI) study showed a 48% increased risk of incident diabetes at follow-up in women with severe symptoms of hot flashes and night sweats, the authors wrote. Clinicians should also be aware of the increased immune reactivity that occurs during and after menopause and the increased CVD risk associated with autoimmune and endocrine disorders, they said.
Multiple strategies to reduce risk
Strategies to address the cardiovascular risk in menopause include assessing glucose, lipid levels, and blood pressure during the transition to menopause, according to the statement.
In addition, they recommended increasing employer awareness of menopause, as changes may interfere with working ability. A healthy lifestyle including healthy diet and regular exercise can help reduce cardiovascular risks and relieve symptoms. Menopausal hormone therapy (MHT) may be indicated to relieve symptoms, including symptoms of depression, and provide cardioprotection for younger women around the time of menopause, according to the statement.
However, “MHT is not recommended in women at high CV risk and after a previous CVD event,” and all women should be assessed for cardiovascular risk factors before starting MHT, they emphasized.
Results raise awareness of cardiovascular health and menopause link
“Over the past 20 years, our knowledge of how menopause might contribute to cardiovascular disease has dramatically evolved,” said Samar El Khoudary, MD, of the University of Pittsburg, in an interview.
“We have accumulated data that consistently point to the menopause transition as a time of change in cardiovascular health. As such, there is a compelling need to discuss the implications of the accumulating body of literature on this topic,” she said. “The goal is to raise awareness for both health care providers and women of the significant adverse cardiovascular health changes accompanying the menopause transition and to point out the importance of adopting prevention strategies early during this stage,” she explained.
The impact of the hormonal changes of menopause on CVD risk “is very complex,” Dr. El Khoudary said. “Until now, we could not prove that using estrogen therapy is cardioprotective,” she emphasized. “Studies point to the need to consider the timing of hormone use, as well as types and route of administration,” she noted. “The truth is that, although the menopause transition is associated with an acceleration in CVD risk, the exact mechanism still is not completely clear. Hormone changes contribute, but they are not the ultimate contributor,” she added.
Research gaps include data on lifestyle and behavioral interventions
“Irrespective of the accumulating findings showing adverse changes in multiple cardiovascular health parameters, as women transition through menopause, we do not have data documenting current status of ideal cardiovascular health components during the menopause transition among women,” said Dr. El Khoudary. “The limited data we have [suggest] that a very small proportion of women transitioning through menopause eat a healthy diet (less than 20%) or practice physical activity (about7.2%) at a level that matches the current recommendations,” she noted.
“Lifestyle and behavioral interventions are critical to maintain a healthy heart and reduce heart disease; we do not have adequate randomized clinical trials testing these interventions specifically during the menopause transition,” she said.
“Similarly, we are in need of randomized clinical trials of therapeutic interventions such as lipid-lowering medications and menopause hormone therapy in women transitioning through menopause,” said Dr. El Khoudary. “This high-risk population has not been the focus of previous clinical trials, leaving us with questions of how the results from these studies might apply to women during the menopause transition,” she said.
Consensus invites collaboration
“I commend the group for putting together a statement that crosses practice and specialty boundaries,” said Lubna Pal, MD, of Yale School of Medicine, New Haven, Conn., in an interview. Although the statement does not present novel information, it “has the power of unifying the various providers by bringing focus on the individual elements spanning a woman’s life that cumulatively determine her lifetime health risk,” she said. Preeclampsia may be a risk factor for cardiovascular disease later in life, and events in reproductive age may determine a woman’s trajectory during the transition to menopause and beyond, Dr. Pal noted.
“The consensus statement will likely be read by internists and family medicine providers as well as ob.gyns.; it encourages all those involved in caring for female patients to take on the responsibility of ‘passing on the baton,’ such that all women who are deemed at an enhanced risk for cardiovascular disease are assured due diligence in care through stringent surveillance and timely interventions,” said Dr. Pal. “It is a call for the various providers who care for women at distinct stages of life to work together toward a shared goal of optimizing every woman’s health across her lifespan,” she said.
“More research is needed for us to better understand the mechanisms at play” in the development of cardiovascular risk and in understanding the continuity of changes across women’s lifespans, Dr. Pal said. “We have associations, but not much information about causation,” she emphasized. However, the statement promotes the dissemination of information about women’s health and sensitizes providers to the potential and the power of preventive care. “We should be much more liberal and loud in holding conversations about risk quantification and risk reduction, and this statement is a resounding effort toward identifying and mitigating long-term cardiovascular risk, even if only through promoting a healthier lifestyle in those deemed at risk,” she added.
The statement received no outside funding. Lead author Dr. Maas had no financial conflicts to disclose. Dr. El Khoudary had no financial conflicts to disclose. Dr. Pal had no relevant financial conflicts to disclose.
Menopause is a key time to monitor women for the development or increase of cardiovascular risk factors, according to a new consensus statement developed by the Task Force on Gender of the European Society of Cardiology and a multidisciplinary ESC working group on Women’s Health in Menopause.
“After menopause, traditional cardiovascular risk factors are adversely affected – particularly hypertension,” wrote Angela H.E.M. Maas, MD, of Radboud University Medical Center, Nijmegen, Netherlands, and colleagues.
“Since the first ESC consensus paper on the management of cardiovascular risk in perimenopausal women was published in 2007, we have a greater understanding on the role of female-specific risk factors for cardiovascular disease (CVD),” they said.
In a consensus statement published in the European Heart Journal, the authors presented clinical guidance for diagnosis and management of cardiovascular risk factors during the menopause transition. The transition to menopause increases a woman’s risk for developing several CVD risk factors, including central adiposity, increased insulin resistance, a proatherogenic lipid profile, and autonomic dysfunction that can contribute to increased heart rate variability, according to the statement.
Estrogen changes may affect ischemic disease
In general, obstructive coronary artery disease (CAD) strikes women later than men, but coronary vasomotor conditions are a common cause of ischemic heart disease in women with or without CAD, the authors noted.
“Lower estrogen levels after menopause are related to altered vascular function, enhanced inflammation, and up-regulation of other hormonal systems such as the renin–angiotensin–aldosterone system, the sympathetic nervous system, and reduced nitric oxide–dependent vasodilation,” they wrote. They recommended use of the coronary artery calcium score for screening middle-aged women who are symptomatic or at intermediate cardiovascular risk.
The transition to menopause causes changes in lipid profiles, and a rise in blood pressure in particular “may be both a direct effect of hormonal changes on the vasculature and metabolic changes with aging,” but hypertension in early post menopause is “often poorly managed,” the authors noted.
Compared with asymptomatic women, women who suffer from severe menopausal symptoms often have increased cardiovascular disease risk factors. For example, the Women’s Health Initiative (WHI) study showed a 48% increased risk of incident diabetes at follow-up in women with severe symptoms of hot flashes and night sweats, the authors wrote. Clinicians should also be aware of the increased immune reactivity that occurs during and after menopause and the increased CVD risk associated with autoimmune and endocrine disorders, they said.
Multiple strategies to reduce risk
Strategies to address the cardiovascular risk in menopause include assessing glucose, lipid levels, and blood pressure during the transition to menopause, according to the statement.
In addition, they recommended increasing employer awareness of menopause, as changes may interfere with working ability. A healthy lifestyle including healthy diet and regular exercise can help reduce cardiovascular risks and relieve symptoms. Menopausal hormone therapy (MHT) may be indicated to relieve symptoms, including symptoms of depression, and provide cardioprotection for younger women around the time of menopause, according to the statement.
However, “MHT is not recommended in women at high CV risk and after a previous CVD event,” and all women should be assessed for cardiovascular risk factors before starting MHT, they emphasized.
Results raise awareness of cardiovascular health and menopause link
“Over the past 20 years, our knowledge of how menopause might contribute to cardiovascular disease has dramatically evolved,” said Samar El Khoudary, MD, of the University of Pittsburg, in an interview.
“We have accumulated data that consistently point to the menopause transition as a time of change in cardiovascular health. As such, there is a compelling need to discuss the implications of the accumulating body of literature on this topic,” she said. “The goal is to raise awareness for both health care providers and women of the significant adverse cardiovascular health changes accompanying the menopause transition and to point out the importance of adopting prevention strategies early during this stage,” she explained.
The impact of the hormonal changes of menopause on CVD risk “is very complex,” Dr. El Khoudary said. “Until now, we could not prove that using estrogen therapy is cardioprotective,” she emphasized. “Studies point to the need to consider the timing of hormone use, as well as types and route of administration,” she noted. “The truth is that, although the menopause transition is associated with an acceleration in CVD risk, the exact mechanism still is not completely clear. Hormone changes contribute, but they are not the ultimate contributor,” she added.
Research gaps include data on lifestyle and behavioral interventions
“Irrespective of the accumulating findings showing adverse changes in multiple cardiovascular health parameters, as women transition through menopause, we do not have data documenting current status of ideal cardiovascular health components during the menopause transition among women,” said Dr. El Khoudary. “The limited data we have [suggest] that a very small proportion of women transitioning through menopause eat a healthy diet (less than 20%) or practice physical activity (about7.2%) at a level that matches the current recommendations,” she noted.
“Lifestyle and behavioral interventions are critical to maintain a healthy heart and reduce heart disease; we do not have adequate randomized clinical trials testing these interventions specifically during the menopause transition,” she said.
“Similarly, we are in need of randomized clinical trials of therapeutic interventions such as lipid-lowering medications and menopause hormone therapy in women transitioning through menopause,” said Dr. El Khoudary. “This high-risk population has not been the focus of previous clinical trials, leaving us with questions of how the results from these studies might apply to women during the menopause transition,” she said.
Consensus invites collaboration
“I commend the group for putting together a statement that crosses practice and specialty boundaries,” said Lubna Pal, MD, of Yale School of Medicine, New Haven, Conn., in an interview. Although the statement does not present novel information, it “has the power of unifying the various providers by bringing focus on the individual elements spanning a woman’s life that cumulatively determine her lifetime health risk,” she said. Preeclampsia may be a risk factor for cardiovascular disease later in life, and events in reproductive age may determine a woman’s trajectory during the transition to menopause and beyond, Dr. Pal noted.
“The consensus statement will likely be read by internists and family medicine providers as well as ob.gyns.; it encourages all those involved in caring for female patients to take on the responsibility of ‘passing on the baton,’ such that all women who are deemed at an enhanced risk for cardiovascular disease are assured due diligence in care through stringent surveillance and timely interventions,” said Dr. Pal. “It is a call for the various providers who care for women at distinct stages of life to work together toward a shared goal of optimizing every woman’s health across her lifespan,” she said.
“More research is needed for us to better understand the mechanisms at play” in the development of cardiovascular risk and in understanding the continuity of changes across women’s lifespans, Dr. Pal said. “We have associations, but not much information about causation,” she emphasized. However, the statement promotes the dissemination of information about women’s health and sensitizes providers to the potential and the power of preventive care. “We should be much more liberal and loud in holding conversations about risk quantification and risk reduction, and this statement is a resounding effort toward identifying and mitigating long-term cardiovascular risk, even if only through promoting a healthier lifestyle in those deemed at risk,” she added.
The statement received no outside funding. Lead author Dr. Maas had no financial conflicts to disclose. Dr. El Khoudary had no financial conflicts to disclose. Dr. Pal had no relevant financial conflicts to disclose.
Menopause is a key time to monitor women for the development or increase of cardiovascular risk factors, according to a new consensus statement developed by the Task Force on Gender of the European Society of Cardiology and a multidisciplinary ESC working group on Women’s Health in Menopause.
“After menopause, traditional cardiovascular risk factors are adversely affected – particularly hypertension,” wrote Angela H.E.M. Maas, MD, of Radboud University Medical Center, Nijmegen, Netherlands, and colleagues.
“Since the first ESC consensus paper on the management of cardiovascular risk in perimenopausal women was published in 2007, we have a greater understanding on the role of female-specific risk factors for cardiovascular disease (CVD),” they said.
In a consensus statement published in the European Heart Journal, the authors presented clinical guidance for diagnosis and management of cardiovascular risk factors during the menopause transition. The transition to menopause increases a woman’s risk for developing several CVD risk factors, including central adiposity, increased insulin resistance, a proatherogenic lipid profile, and autonomic dysfunction that can contribute to increased heart rate variability, according to the statement.
Estrogen changes may affect ischemic disease
In general, obstructive coronary artery disease (CAD) strikes women later than men, but coronary vasomotor conditions are a common cause of ischemic heart disease in women with or without CAD, the authors noted.
“Lower estrogen levels after menopause are related to altered vascular function, enhanced inflammation, and up-regulation of other hormonal systems such as the renin–angiotensin–aldosterone system, the sympathetic nervous system, and reduced nitric oxide–dependent vasodilation,” they wrote. They recommended use of the coronary artery calcium score for screening middle-aged women who are symptomatic or at intermediate cardiovascular risk.
The transition to menopause causes changes in lipid profiles, and a rise in blood pressure in particular “may be both a direct effect of hormonal changes on the vasculature and metabolic changes with aging,” but hypertension in early post menopause is “often poorly managed,” the authors noted.
Compared with asymptomatic women, women who suffer from severe menopausal symptoms often have increased cardiovascular disease risk factors. For example, the Women’s Health Initiative (WHI) study showed a 48% increased risk of incident diabetes at follow-up in women with severe symptoms of hot flashes and night sweats, the authors wrote. Clinicians should also be aware of the increased immune reactivity that occurs during and after menopause and the increased CVD risk associated with autoimmune and endocrine disorders, they said.
Multiple strategies to reduce risk
Strategies to address the cardiovascular risk in menopause include assessing glucose, lipid levels, and blood pressure during the transition to menopause, according to the statement.
In addition, they recommended increasing employer awareness of menopause, as changes may interfere with working ability. A healthy lifestyle including healthy diet and regular exercise can help reduce cardiovascular risks and relieve symptoms. Menopausal hormone therapy (MHT) may be indicated to relieve symptoms, including symptoms of depression, and provide cardioprotection for younger women around the time of menopause, according to the statement.
However, “MHT is not recommended in women at high CV risk and after a previous CVD event,” and all women should be assessed for cardiovascular risk factors before starting MHT, they emphasized.
Results raise awareness of cardiovascular health and menopause link
“Over the past 20 years, our knowledge of how menopause might contribute to cardiovascular disease has dramatically evolved,” said Samar El Khoudary, MD, of the University of Pittsburg, in an interview.
“We have accumulated data that consistently point to the menopause transition as a time of change in cardiovascular health. As such, there is a compelling need to discuss the implications of the accumulating body of literature on this topic,” she said. “The goal is to raise awareness for both health care providers and women of the significant adverse cardiovascular health changes accompanying the menopause transition and to point out the importance of adopting prevention strategies early during this stage,” she explained.
The impact of the hormonal changes of menopause on CVD risk “is very complex,” Dr. El Khoudary said. “Until now, we could not prove that using estrogen therapy is cardioprotective,” she emphasized. “Studies point to the need to consider the timing of hormone use, as well as types and route of administration,” she noted. “The truth is that, although the menopause transition is associated with an acceleration in CVD risk, the exact mechanism still is not completely clear. Hormone changes contribute, but they are not the ultimate contributor,” she added.
Research gaps include data on lifestyle and behavioral interventions
“Irrespective of the accumulating findings showing adverse changes in multiple cardiovascular health parameters, as women transition through menopause, we do not have data documenting current status of ideal cardiovascular health components during the menopause transition among women,” said Dr. El Khoudary. “The limited data we have [suggest] that a very small proportion of women transitioning through menopause eat a healthy diet (less than 20%) or practice physical activity (about7.2%) at a level that matches the current recommendations,” she noted.
“Lifestyle and behavioral interventions are critical to maintain a healthy heart and reduce heart disease; we do not have adequate randomized clinical trials testing these interventions specifically during the menopause transition,” she said.
“Similarly, we are in need of randomized clinical trials of therapeutic interventions such as lipid-lowering medications and menopause hormone therapy in women transitioning through menopause,” said Dr. El Khoudary. “This high-risk population has not been the focus of previous clinical trials, leaving us with questions of how the results from these studies might apply to women during the menopause transition,” she said.
Consensus invites collaboration
“I commend the group for putting together a statement that crosses practice and specialty boundaries,” said Lubna Pal, MD, of Yale School of Medicine, New Haven, Conn., in an interview. Although the statement does not present novel information, it “has the power of unifying the various providers by bringing focus on the individual elements spanning a woman’s life that cumulatively determine her lifetime health risk,” she said. Preeclampsia may be a risk factor for cardiovascular disease later in life, and events in reproductive age may determine a woman’s trajectory during the transition to menopause and beyond, Dr. Pal noted.
“The consensus statement will likely be read by internists and family medicine providers as well as ob.gyns.; it encourages all those involved in caring for female patients to take on the responsibility of ‘passing on the baton,’ such that all women who are deemed at an enhanced risk for cardiovascular disease are assured due diligence in care through stringent surveillance and timely interventions,” said Dr. Pal. “It is a call for the various providers who care for women at distinct stages of life to work together toward a shared goal of optimizing every woman’s health across her lifespan,” she said.
“More research is needed for us to better understand the mechanisms at play” in the development of cardiovascular risk and in understanding the continuity of changes across women’s lifespans, Dr. Pal said. “We have associations, but not much information about causation,” she emphasized. However, the statement promotes the dissemination of information about women’s health and sensitizes providers to the potential and the power of preventive care. “We should be much more liberal and loud in holding conversations about risk quantification and risk reduction, and this statement is a resounding effort toward identifying and mitigating long-term cardiovascular risk, even if only through promoting a healthier lifestyle in those deemed at risk,” she added.
The statement received no outside funding. Lead author Dr. Maas had no financial conflicts to disclose. Dr. El Khoudary had no financial conflicts to disclose. Dr. Pal had no relevant financial conflicts to disclose.
FROM THE EUROPEAN HEART JOURNAL
Women and ACS: Focus on typical symptoms to improve outcomes
There are some differences in how women relative to men report symptoms of an acute coronary syndrome (ACS), but they should not be permitted to get in the way of prompt diagnosis and treatment, according to an expert review at the virtual Going Back to the Heart of Cardiology meeting.
“We need to get away from the idea that symptoms of a myocardial infarction in women are atypical, because women are also having typical symptoms,” said Martha Gulati, MD, chief of cardiology at the University of Arizona, Phoenix.
Sexes share key symptoms, but not treatment
Although “women are more likely to report additional symptoms,” chest pain “is pretty much equal between men and women” presenting with an ACS, according to Dr. Gulati.
There are several studies that have shown this, including the Variation in Recovery: Role of Gender on Outcomes of Young AMI patients (VIRGO). In VIRGO, which looked at ACS symptom presentation in younger patients (ages 18-55 years), 87.0% of women versus 89.5% of men presented with chest pain defined as pain, pressure, tightness, or discomfort.
Even among those who recognize that more women die of cardiovascular disease (CVD) disease than any other cause, nothing seems to erase the bias that women in an ED are less likely than men to be having a heart attack. About 60 million women in the United States have CVD, so no threat imposes a higher toll in morbidity and mortality.
In comparison, there are only about 3.5 million women with breast cancer. Even though this is a major cause of morbidity and mortality in women, it is dwarfed by CVD, according to statistics cited by Dr. Gulati. Yet, the data show women get inferior care by guideline-based standards.
“After a myocardial infarction, women relative to men are less likely to get aspirin or beta-blockers within 24 hours, they are less likely to undergo any type of invasive procedure, and they are less likely to meet the door-to-balloon time or receive any reperfusion therapy,” Dr. Gulati said. After a CVD event, “the only thing women do better is to die.”
Additional symptoms may muddy the diagnostic waters
In the setting of ACS, the problem is not that women fail to report symptoms that should lead clinicians to consider CVD, but that they report additional symptoms. For the clinician less inclined to consider CVD in women, particularly younger women, there is a greater risk of going down the wrong diagnostic pathway.
In other words, women report symptoms consistent with CVD, “but it is a question of whether we are hearing it,” Dr. Gulati said.
In the VIRGO study, 61.9% of women versus 54.8% of men (P < .001) presented three or more symptoms in addition to chest pain, such as epigastric symptoms, discomfort in the arms or neck, or palpitations. Women were more likely than men to attribute the symptoms to stress or anxiety (20.9% vs. 11.8%; P < .001), while less likely to consider them a result of muscle pain (15.4% vs. 21.2%; P = .029).
There are other gender differences for ACS. For example, women are more likely than men to presented ischemia without obstruction, but Dr. Gulati emphasized that lack of obstruction is not a reason to dismiss the potential for an underlying CV cause.
‘Yentl syndrome’ persists
“Women should not need to present exactly like men to be taken seriously,” she said, describing the “Yentl syndrome,” which now has its own Wikipedia page. A cardiovascular version of this syndrome was first described 30 years ago. Based on a movie of a woman who cross dresses in order to be allowed to undertake Jewish studies, the term captures the societal failure to adapt care for women who do not present disease the same way that men do.
Overall, inadequate urgency to pursue potential symptoms of ACS in women is just another manifestation of the “bikini approach to women’s health,” according to Dr. Gulati. This describes the focus on the breast and reproductive system to the exclusion or other organs and anatomy. Dr. Gulati speculated that this might be the reason that clinicians have failed to apply ACS guidelines to women with the same rigor that they apply to men.
This is hardly a new issue. Calls for improving cardiovascular care in women have been increasing in volume for more than past 20 years, but the issue has proven persistent, according to Dr. Gulati. As an example, she noted that the same types of gaps in care and in outcome reported in a 2008 registry study had not much changed in an article published 8 years later.
The solution is not complex, according to Dr. Gulati. In the ED, guideline-directed diagnostic tests should be offered to any man or woman, including younger women, who present with chest pain, ignoring gender bias that threatens misinterpretation of patient history and symptoms. Once CVD is diagnosed as promptly in women as it is in men, guideline-directed intervention would be expected to reduce the gender gap in outcomes.
“By applying standardized protocols, it will help us to the same for women as we do for men,” Dr. Gulati said.
The meeting was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
There are some differences in how women relative to men report symptoms of an acute coronary syndrome (ACS), but they should not be permitted to get in the way of prompt diagnosis and treatment, according to an expert review at the virtual Going Back to the Heart of Cardiology meeting.
“We need to get away from the idea that symptoms of a myocardial infarction in women are atypical, because women are also having typical symptoms,” said Martha Gulati, MD, chief of cardiology at the University of Arizona, Phoenix.
Sexes share key symptoms, but not treatment
Although “women are more likely to report additional symptoms,” chest pain “is pretty much equal between men and women” presenting with an ACS, according to Dr. Gulati.
There are several studies that have shown this, including the Variation in Recovery: Role of Gender on Outcomes of Young AMI patients (VIRGO). In VIRGO, which looked at ACS symptom presentation in younger patients (ages 18-55 years), 87.0% of women versus 89.5% of men presented with chest pain defined as pain, pressure, tightness, or discomfort.
Even among those who recognize that more women die of cardiovascular disease (CVD) disease than any other cause, nothing seems to erase the bias that women in an ED are less likely than men to be having a heart attack. About 60 million women in the United States have CVD, so no threat imposes a higher toll in morbidity and mortality.
In comparison, there are only about 3.5 million women with breast cancer. Even though this is a major cause of morbidity and mortality in women, it is dwarfed by CVD, according to statistics cited by Dr. Gulati. Yet, the data show women get inferior care by guideline-based standards.
“After a myocardial infarction, women relative to men are less likely to get aspirin or beta-blockers within 24 hours, they are less likely to undergo any type of invasive procedure, and they are less likely to meet the door-to-balloon time or receive any reperfusion therapy,” Dr. Gulati said. After a CVD event, “the only thing women do better is to die.”
Additional symptoms may muddy the diagnostic waters
In the setting of ACS, the problem is not that women fail to report symptoms that should lead clinicians to consider CVD, but that they report additional symptoms. For the clinician less inclined to consider CVD in women, particularly younger women, there is a greater risk of going down the wrong diagnostic pathway.
In other words, women report symptoms consistent with CVD, “but it is a question of whether we are hearing it,” Dr. Gulati said.
In the VIRGO study, 61.9% of women versus 54.8% of men (P < .001) presented three or more symptoms in addition to chest pain, such as epigastric symptoms, discomfort in the arms or neck, or palpitations. Women were more likely than men to attribute the symptoms to stress or anxiety (20.9% vs. 11.8%; P < .001), while less likely to consider them a result of muscle pain (15.4% vs. 21.2%; P = .029).
There are other gender differences for ACS. For example, women are more likely than men to presented ischemia without obstruction, but Dr. Gulati emphasized that lack of obstruction is not a reason to dismiss the potential for an underlying CV cause.
‘Yentl syndrome’ persists
“Women should not need to present exactly like men to be taken seriously,” she said, describing the “Yentl syndrome,” which now has its own Wikipedia page. A cardiovascular version of this syndrome was first described 30 years ago. Based on a movie of a woman who cross dresses in order to be allowed to undertake Jewish studies, the term captures the societal failure to adapt care for women who do not present disease the same way that men do.
Overall, inadequate urgency to pursue potential symptoms of ACS in women is just another manifestation of the “bikini approach to women’s health,” according to Dr. Gulati. This describes the focus on the breast and reproductive system to the exclusion or other organs and anatomy. Dr. Gulati speculated that this might be the reason that clinicians have failed to apply ACS guidelines to women with the same rigor that they apply to men.
This is hardly a new issue. Calls for improving cardiovascular care in women have been increasing in volume for more than past 20 years, but the issue has proven persistent, according to Dr. Gulati. As an example, she noted that the same types of gaps in care and in outcome reported in a 2008 registry study had not much changed in an article published 8 years later.
The solution is not complex, according to Dr. Gulati. In the ED, guideline-directed diagnostic tests should be offered to any man or woman, including younger women, who present with chest pain, ignoring gender bias that threatens misinterpretation of patient history and symptoms. Once CVD is diagnosed as promptly in women as it is in men, guideline-directed intervention would be expected to reduce the gender gap in outcomes.
“By applying standardized protocols, it will help us to the same for women as we do for men,” Dr. Gulati said.
The meeting was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
There are some differences in how women relative to men report symptoms of an acute coronary syndrome (ACS), but they should not be permitted to get in the way of prompt diagnosis and treatment, according to an expert review at the virtual Going Back to the Heart of Cardiology meeting.
“We need to get away from the idea that symptoms of a myocardial infarction in women are atypical, because women are also having typical symptoms,” said Martha Gulati, MD, chief of cardiology at the University of Arizona, Phoenix.
Sexes share key symptoms, but not treatment
Although “women are more likely to report additional symptoms,” chest pain “is pretty much equal between men and women” presenting with an ACS, according to Dr. Gulati.
There are several studies that have shown this, including the Variation in Recovery: Role of Gender on Outcomes of Young AMI patients (VIRGO). In VIRGO, which looked at ACS symptom presentation in younger patients (ages 18-55 years), 87.0% of women versus 89.5% of men presented with chest pain defined as pain, pressure, tightness, or discomfort.
Even among those who recognize that more women die of cardiovascular disease (CVD) disease than any other cause, nothing seems to erase the bias that women in an ED are less likely than men to be having a heart attack. About 60 million women in the United States have CVD, so no threat imposes a higher toll in morbidity and mortality.
In comparison, there are only about 3.5 million women with breast cancer. Even though this is a major cause of morbidity and mortality in women, it is dwarfed by CVD, according to statistics cited by Dr. Gulati. Yet, the data show women get inferior care by guideline-based standards.
“After a myocardial infarction, women relative to men are less likely to get aspirin or beta-blockers within 24 hours, they are less likely to undergo any type of invasive procedure, and they are less likely to meet the door-to-balloon time or receive any reperfusion therapy,” Dr. Gulati said. After a CVD event, “the only thing women do better is to die.”
Additional symptoms may muddy the diagnostic waters
In the setting of ACS, the problem is not that women fail to report symptoms that should lead clinicians to consider CVD, but that they report additional symptoms. For the clinician less inclined to consider CVD in women, particularly younger women, there is a greater risk of going down the wrong diagnostic pathway.
In other words, women report symptoms consistent with CVD, “but it is a question of whether we are hearing it,” Dr. Gulati said.
In the VIRGO study, 61.9% of women versus 54.8% of men (P < .001) presented three or more symptoms in addition to chest pain, such as epigastric symptoms, discomfort in the arms or neck, or palpitations. Women were more likely than men to attribute the symptoms to stress or anxiety (20.9% vs. 11.8%; P < .001), while less likely to consider them a result of muscle pain (15.4% vs. 21.2%; P = .029).
There are other gender differences for ACS. For example, women are more likely than men to presented ischemia without obstruction, but Dr. Gulati emphasized that lack of obstruction is not a reason to dismiss the potential for an underlying CV cause.
‘Yentl syndrome’ persists
“Women should not need to present exactly like men to be taken seriously,” she said, describing the “Yentl syndrome,” which now has its own Wikipedia page. A cardiovascular version of this syndrome was first described 30 years ago. Based on a movie of a woman who cross dresses in order to be allowed to undertake Jewish studies, the term captures the societal failure to adapt care for women who do not present disease the same way that men do.
Overall, inadequate urgency to pursue potential symptoms of ACS in women is just another manifestation of the “bikini approach to women’s health,” according to Dr. Gulati. This describes the focus on the breast and reproductive system to the exclusion or other organs and anatomy. Dr. Gulati speculated that this might be the reason that clinicians have failed to apply ACS guidelines to women with the same rigor that they apply to men.
This is hardly a new issue. Calls for improving cardiovascular care in women have been increasing in volume for more than past 20 years, but the issue has proven persistent, according to Dr. Gulati. As an example, she noted that the same types of gaps in care and in outcome reported in a 2008 registry study had not much changed in an article published 8 years later.
The solution is not complex, according to Dr. Gulati. In the ED, guideline-directed diagnostic tests should be offered to any man or woman, including younger women, who present with chest pain, ignoring gender bias that threatens misinterpretation of patient history and symptoms. Once CVD is diagnosed as promptly in women as it is in men, guideline-directed intervention would be expected to reduce the gender gap in outcomes.
“By applying standardized protocols, it will help us to the same for women as we do for men,” Dr. Gulati said.
The meeting was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
FROM GOING BACK TO THE HEART OF CARDIOLOGY
Coffee lowers heart failure risk in unique study
Higher coffee consumption is associated with a lower risk of heart failure, according to a machine learning–based algorithm that analyzed data from three large observational trials.
“Coffee consumption actually was predictive on top of known risk factors originally identified from those three trials.” The study is significant because it underscores the potential of big data for individualizing patient management, lead investigator David Kao, MD, said in an interview. “We in fact adjusted for the scores that are commonly used to predict heart disease, and coffee consumption remained a predictor even on top of that.”
The study used supervised machine learning to analyze data on diet and other variables from three well-known observational studies: Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and ARIC (Atherosclerosis Risk in Communities). The goal of the study, published online on Feb. 9, 2021*, was to identify potential novel risk factors for incident coronary heart disease, stroke, and heart failure.
“The main difference of the relationship between coffee and heart disease, compared with prior analyses, is that we’re able to find it in these well-known and well-accepted studies that have helped us find risk factors before,” Dr. Kao said
The study included 2,732 FHS participants aged 30-62 years, 3,704 CHS patients aged 65 and older, and 14,925 ARIC subjects aged 45-64, all of whom had no history of cardiovascular disease events when they enrolled. Primary outcomes for the machine-learning study were times to incident coronary heart disease, heart failure, and stroke.
Mathematics, not hypotheses
To compensate for variations in methodologies between the three observational trials, the study used 204 data measurements collected at the first FHS exam, including 16 dietary variables and for which similar data were collected for the other two studies.
The machine-learning model used what’s known as a random forest analysis to identify the leading potential risk factors from among the 204 variables. To confirm findings between studies, the authors used a technique called “data harmonization” to smooth variations in the methodologies of the trials, not only with participant age and duration and date of the trials, but also in how data on coffee consumption were gathered. For example, FHS collected that data as cups per day, whereas CHS and ARIC collected that as monthly, weekly, and daily consumption. The study converted the coffee consumption data from CHS and ARIC to cups per day to conform to FHS data.
Random forest analysis is a type of machine learning that randomly creates a cluster of decision trees – the “forest” – to determine which variables, such as dietary factors, are important in predicting a result. The analysis uses mathematics, not hypotheses, to identify important variables.
Heart failure and risk reduced
In this study, the analysis determined that each cup of caffeinated coffee daily was linked with a 5% reduction in the risk of heart failure (hazard ratio, 0.95; P = .02) and 6% reduction in stroke risk (HR, 0.94; P = .02), but had no significant impact on risk for coronary heart disease or cardiovascular disease.
When the data were adjusted for the FHS CVD risk score, increasing coffee consumption remained significantly associated with an identical lower risk of heart failure (P = .03) but not stroke (P = .33).
While the study supports an association between coffee consumption and heart failure risk, it doesn’t establish causation, noted Alice H. Lichtenstein, DSc, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston. “The authors could not rule out the possibility that caffeinated coffee intake was a proxy for other heart-healthy lifestyle behaviors,” Dr. Lichtenstein said. “Perhaps the best message from the study is that there appears to be no adverse effects of drinking moderate amounts of caffeinated coffee, and there may be benefits.”
She added a note of caution. “This result does not suggest coffee intake should be increased, nor does it give license to increasing coffee drinks with a lot of added cream and sugar.”
Machine learning mines observational trials
Dr. Kao explained the rationale for applying a machine-learning algorithm to the three observational trials. “When these trials were designed in general, they had an idea of what they were looking for in terms of what might be a risk factor,” said Dr. Kao, of the University of Colorado at Denver, Aurora. “What we were interested in doing was to look for risk factors that nobody really thought about ahead of time and let the data show us what might be a predictor without any bias of what we imagined to be true.”
He described the role of machine learning in extracting and “filtering” data from the trials. “Machine learning allows us to look at a very large number of factors or variables and identify the most important ones in predicting a specific outcome,” he said. This study evaluated the 204 variables and focused on dietary factors because they’re modifiable.
“We looked at them in these different studies where we could, and coffee was the one that was reproducible in all of them,” he said. “Machine learning helped filter down these very large numbers of variables in ways you can’t do with traditional statistics. It’s useful in studies like this because they gather thousands and thousands of variables that generally nobody uses, but these methods allow you to actually do something with them – to determine which ones are most important.”
He added: “These methods I think will take us toward personalized medicine where you’re really individualizing a plan for keeping a patient healthy. We still have a lot of work to do, but there’s a lot of promise for really helping each of us to figure out the ways we can become the healthiest that we can be.”
The study was supported with funding from the National Heart, Lung, and Blood Institute and the American Heart Association. Dr. Kao and coauthors, as well as Dr. Lichtenstein, had no relevant financial relationships to disclose.
*Correction, 2/10/21: An earlier version of this article misstated the study's publication date.
Higher coffee consumption is associated with a lower risk of heart failure, according to a machine learning–based algorithm that analyzed data from three large observational trials.
“Coffee consumption actually was predictive on top of known risk factors originally identified from those three trials.” The study is significant because it underscores the potential of big data for individualizing patient management, lead investigator David Kao, MD, said in an interview. “We in fact adjusted for the scores that are commonly used to predict heart disease, and coffee consumption remained a predictor even on top of that.”
The study used supervised machine learning to analyze data on diet and other variables from three well-known observational studies: Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and ARIC (Atherosclerosis Risk in Communities). The goal of the study, published online on Feb. 9, 2021*, was to identify potential novel risk factors for incident coronary heart disease, stroke, and heart failure.
“The main difference of the relationship between coffee and heart disease, compared with prior analyses, is that we’re able to find it in these well-known and well-accepted studies that have helped us find risk factors before,” Dr. Kao said
The study included 2,732 FHS participants aged 30-62 years, 3,704 CHS patients aged 65 and older, and 14,925 ARIC subjects aged 45-64, all of whom had no history of cardiovascular disease events when they enrolled. Primary outcomes for the machine-learning study were times to incident coronary heart disease, heart failure, and stroke.
Mathematics, not hypotheses
To compensate for variations in methodologies between the three observational trials, the study used 204 data measurements collected at the first FHS exam, including 16 dietary variables and for which similar data were collected for the other two studies.
The machine-learning model used what’s known as a random forest analysis to identify the leading potential risk factors from among the 204 variables. To confirm findings between studies, the authors used a technique called “data harmonization” to smooth variations in the methodologies of the trials, not only with participant age and duration and date of the trials, but also in how data on coffee consumption were gathered. For example, FHS collected that data as cups per day, whereas CHS and ARIC collected that as monthly, weekly, and daily consumption. The study converted the coffee consumption data from CHS and ARIC to cups per day to conform to FHS data.
Random forest analysis is a type of machine learning that randomly creates a cluster of decision trees – the “forest” – to determine which variables, such as dietary factors, are important in predicting a result. The analysis uses mathematics, not hypotheses, to identify important variables.
Heart failure and risk reduced
In this study, the analysis determined that each cup of caffeinated coffee daily was linked with a 5% reduction in the risk of heart failure (hazard ratio, 0.95; P = .02) and 6% reduction in stroke risk (HR, 0.94; P = .02), but had no significant impact on risk for coronary heart disease or cardiovascular disease.
When the data were adjusted for the FHS CVD risk score, increasing coffee consumption remained significantly associated with an identical lower risk of heart failure (P = .03) but not stroke (P = .33).
While the study supports an association between coffee consumption and heart failure risk, it doesn’t establish causation, noted Alice H. Lichtenstein, DSc, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston. “The authors could not rule out the possibility that caffeinated coffee intake was a proxy for other heart-healthy lifestyle behaviors,” Dr. Lichtenstein said. “Perhaps the best message from the study is that there appears to be no adverse effects of drinking moderate amounts of caffeinated coffee, and there may be benefits.”
She added a note of caution. “This result does not suggest coffee intake should be increased, nor does it give license to increasing coffee drinks with a lot of added cream and sugar.”
Machine learning mines observational trials
Dr. Kao explained the rationale for applying a machine-learning algorithm to the three observational trials. “When these trials were designed in general, they had an idea of what they were looking for in terms of what might be a risk factor,” said Dr. Kao, of the University of Colorado at Denver, Aurora. “What we were interested in doing was to look for risk factors that nobody really thought about ahead of time and let the data show us what might be a predictor without any bias of what we imagined to be true.”
He described the role of machine learning in extracting and “filtering” data from the trials. “Machine learning allows us to look at a very large number of factors or variables and identify the most important ones in predicting a specific outcome,” he said. This study evaluated the 204 variables and focused on dietary factors because they’re modifiable.
“We looked at them in these different studies where we could, and coffee was the one that was reproducible in all of them,” he said. “Machine learning helped filter down these very large numbers of variables in ways you can’t do with traditional statistics. It’s useful in studies like this because they gather thousands and thousands of variables that generally nobody uses, but these methods allow you to actually do something with them – to determine which ones are most important.”
He added: “These methods I think will take us toward personalized medicine where you’re really individualizing a plan for keeping a patient healthy. We still have a lot of work to do, but there’s a lot of promise for really helping each of us to figure out the ways we can become the healthiest that we can be.”
The study was supported with funding from the National Heart, Lung, and Blood Institute and the American Heart Association. Dr. Kao and coauthors, as well as Dr. Lichtenstein, had no relevant financial relationships to disclose.
*Correction, 2/10/21: An earlier version of this article misstated the study's publication date.
Higher coffee consumption is associated with a lower risk of heart failure, according to a machine learning–based algorithm that analyzed data from three large observational trials.
“Coffee consumption actually was predictive on top of known risk factors originally identified from those three trials.” The study is significant because it underscores the potential of big data for individualizing patient management, lead investigator David Kao, MD, said in an interview. “We in fact adjusted for the scores that are commonly used to predict heart disease, and coffee consumption remained a predictor even on top of that.”
The study used supervised machine learning to analyze data on diet and other variables from three well-known observational studies: Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and ARIC (Atherosclerosis Risk in Communities). The goal of the study, published online on Feb. 9, 2021*, was to identify potential novel risk factors for incident coronary heart disease, stroke, and heart failure.
“The main difference of the relationship between coffee and heart disease, compared with prior analyses, is that we’re able to find it in these well-known and well-accepted studies that have helped us find risk factors before,” Dr. Kao said
The study included 2,732 FHS participants aged 30-62 years, 3,704 CHS patients aged 65 and older, and 14,925 ARIC subjects aged 45-64, all of whom had no history of cardiovascular disease events when they enrolled. Primary outcomes for the machine-learning study were times to incident coronary heart disease, heart failure, and stroke.
Mathematics, not hypotheses
To compensate for variations in methodologies between the three observational trials, the study used 204 data measurements collected at the first FHS exam, including 16 dietary variables and for which similar data were collected for the other two studies.
The machine-learning model used what’s known as a random forest analysis to identify the leading potential risk factors from among the 204 variables. To confirm findings between studies, the authors used a technique called “data harmonization” to smooth variations in the methodologies of the trials, not only with participant age and duration and date of the trials, but also in how data on coffee consumption were gathered. For example, FHS collected that data as cups per day, whereas CHS and ARIC collected that as monthly, weekly, and daily consumption. The study converted the coffee consumption data from CHS and ARIC to cups per day to conform to FHS data.
Random forest analysis is a type of machine learning that randomly creates a cluster of decision trees – the “forest” – to determine which variables, such as dietary factors, are important in predicting a result. The analysis uses mathematics, not hypotheses, to identify important variables.
Heart failure and risk reduced
In this study, the analysis determined that each cup of caffeinated coffee daily was linked with a 5% reduction in the risk of heart failure (hazard ratio, 0.95; P = .02) and 6% reduction in stroke risk (HR, 0.94; P = .02), but had no significant impact on risk for coronary heart disease or cardiovascular disease.
When the data were adjusted for the FHS CVD risk score, increasing coffee consumption remained significantly associated with an identical lower risk of heart failure (P = .03) but not stroke (P = .33).
While the study supports an association between coffee consumption and heart failure risk, it doesn’t establish causation, noted Alice H. Lichtenstein, DSc, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston. “The authors could not rule out the possibility that caffeinated coffee intake was a proxy for other heart-healthy lifestyle behaviors,” Dr. Lichtenstein said. “Perhaps the best message from the study is that there appears to be no adverse effects of drinking moderate amounts of caffeinated coffee, and there may be benefits.”
She added a note of caution. “This result does not suggest coffee intake should be increased, nor does it give license to increasing coffee drinks with a lot of added cream and sugar.”
Machine learning mines observational trials
Dr. Kao explained the rationale for applying a machine-learning algorithm to the three observational trials. “When these trials were designed in general, they had an idea of what they were looking for in terms of what might be a risk factor,” said Dr. Kao, of the University of Colorado at Denver, Aurora. “What we were interested in doing was to look for risk factors that nobody really thought about ahead of time and let the data show us what might be a predictor without any bias of what we imagined to be true.”
He described the role of machine learning in extracting and “filtering” data from the trials. “Machine learning allows us to look at a very large number of factors or variables and identify the most important ones in predicting a specific outcome,” he said. This study evaluated the 204 variables and focused on dietary factors because they’re modifiable.
“We looked at them in these different studies where we could, and coffee was the one that was reproducible in all of them,” he said. “Machine learning helped filter down these very large numbers of variables in ways you can’t do with traditional statistics. It’s useful in studies like this because they gather thousands and thousands of variables that generally nobody uses, but these methods allow you to actually do something with them – to determine which ones are most important.”
He added: “These methods I think will take us toward personalized medicine where you’re really individualizing a plan for keeping a patient healthy. We still have a lot of work to do, but there’s a lot of promise for really helping each of us to figure out the ways we can become the healthiest that we can be.”
The study was supported with funding from the National Heart, Lung, and Blood Institute and the American Heart Association. Dr. Kao and coauthors, as well as Dr. Lichtenstein, had no relevant financial relationships to disclose.
*Correction, 2/10/21: An earlier version of this article misstated the study's publication date.
FROM CIRCULATION: HEART FAILURE