Joann E. Manson, MD, DrPH

This transcript has been edited for clarity.

This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent report in JAMA Network Open on the subject of whether statin therapy may be able to offset some of the excess risk for venous thromboembolism (VTE) among women taking menopausal hormone therapy.

It’s an important issue because we know that menopausal hormone therapy, especially oral therapy, is linked to an excess risk for VTE, approximately doubling of risk in the randomized clinical trials. There is also emerging evidence from some randomized trials, such as the Jupiter trial, that step therapy may be linked to a reduction in risk. This may be related to anti-inflammatory or antithrombotic effects of statin therapy.

The authors made use of a very large administrative claims database, Optum Health, to look at more than 15 million annual members. They were able to identify 2000 women with a diagnostic code for VTE treatment. The women were between ages 50 and 64 years, and they were compared with 200,000 controls without VTE, matched in 10-to-1 fashion.

About 50% of the women were taking oral hormone therapy, and about 50% took non-oral transdermal or other non-oral formulations of hormone therapy. The odds ratio for VTE was 1.53 among the women who did not also have prescription records for statin therapy. They were able to look at prescribed prescriptions for both the hormone therapy and the statins. Among the women prescribed hormone therapy and also low- to intermediate-dose statins, the odds ratio was 1.29. So that was quite a mitigation of the elevated risk. Among the women taking high-intensity statins, the odds ratio was 1.06, and there was no significant elevation.

We do need more data and more research on this question. One approach would be a meta-analysis of all of the existing randomized trials of hormone therapy in recent years wherein there was increased uptake of statin therapy to look at this question not only for VTE but also for coronary heart disease, stroke, and other CVD outcomes to see whether statin therapy is associated with some attenuation of the excess risk. We also need a targeted randomized trial of statins vs placebo among women who have clear indications for hormone therapy but may be at some increased risk for VTE. That type of trial would be extremely helpful.

In the interim, there are ways to minimize risk for VTE among women who are clear candidates for menopausal hormone therapy, especially among women at increased risk for VTE. These include choosing a transdermal rather than an oral formulation of hormone therapy and using lower doses of hormone therapy. Also, women who are clear candidates for hormone therapy and also for statins, it’s obvious that statins could be co-prescribed. Even among women who are clear candidates for hormone therapy but only intermediate borderline candidates for statin therapy, the prescription of statins might be considered in that clinical scenario to try to mitigate that excess risk for VTE.

JoAnn E. Manson, MD, DrPH, has disclosed the following relevant financial relationships: Received study pill donation and infrastructure support from: Mars Symbioscience (for the COSMOS trial).

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent report in JAMA Network Open on the subject of whether statin therapy may be able to offset some of the excess risk for venous thromboembolism (VTE) among women taking menopausal hormone therapy.

It’s an important issue because we know that menopausal hormone therapy, especially oral therapy, is linked to an excess risk for VTE, approximately doubling of risk in the randomized clinical trials. There is also emerging evidence from some randomized trials, such as the Jupiter trial, that step therapy may be linked to a reduction in risk. This may be related to anti-inflammatory or antithrombotic effects of statin therapy.

The authors made use of a very large administrative claims database, Optum Health, to look at more than 15 million annual members. They were able to identify 2000 women with a diagnostic code for VTE treatment. The women were between ages 50 and 64 years, and they were compared with 200,000 controls without VTE, matched in 10-to-1 fashion.

About 50% of the women were taking oral hormone therapy, and about 50% took non-oral transdermal or other non-oral formulations of hormone therapy. The odds ratio for VTE was 1.53 among the women who did not also have prescription records for statin therapy. They were able to look at prescribed prescriptions for both the hormone therapy and the statins. Among the women prescribed hormone therapy and also low- to intermediate-dose statins, the odds ratio was 1.29. So that was quite a mitigation of the elevated risk. Among the women taking high-intensity statins, the odds ratio was 1.06, and there was no significant elevation.

We do need more data and more research on this question. One approach would be a meta-analysis of all of the existing randomized trials of hormone therapy in recent years wherein there was increased uptake of statin therapy to look at this question not only for VTE but also for coronary heart disease, stroke, and other CVD outcomes to see whether statin therapy is associated with some attenuation of the excess risk. We also need a targeted randomized trial of statins vs placebo among women who have clear indications for hormone therapy but may be at some increased risk for VTE. That type of trial would be extremely helpful.

In the interim, there are ways to minimize risk for VTE among women who are clear candidates for menopausal hormone therapy, especially among women at increased risk for VTE. These include choosing a transdermal rather than an oral formulation of hormone therapy and using lower doses of hormone therapy. Also, women who are clear candidates for hormone therapy and also for statins, it’s obvious that statins could be co-prescribed. Even among women who are clear candidates for hormone therapy but only intermediate borderline candidates for statin therapy, the prescription of statins might be considered in that clinical scenario to try to mitigate that excess risk for VTE.

JoAnn E. Manson, MD, DrPH, has disclosed the following relevant financial relationships: Received study pill donation and infrastructure support from: Mars Symbioscience (for the COSMOS trial).

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent report in JAMA Network Open on the subject of whether statin therapy may be able to offset some of the excess risk for venous thromboembolism (VTE) among women taking menopausal hormone therapy.

It’s an important issue because we know that menopausal hormone therapy, especially oral therapy, is linked to an excess risk for VTE, approximately doubling of risk in the randomized clinical trials. There is also emerging evidence from some randomized trials, such as the Jupiter trial, that step therapy may be linked to a reduction in risk. This may be related to anti-inflammatory or antithrombotic effects of statin therapy.

The authors made use of a very large administrative claims database, Optum Health, to look at more than 15 million annual members. They were able to identify 2000 women with a diagnostic code for VTE treatment. The women were between ages 50 and 64 years, and they were compared with 200,000 controls without VTE, matched in 10-to-1 fashion.

About 50% of the women were taking oral hormone therapy, and about 50% took non-oral transdermal or other non-oral formulations of hormone therapy. The odds ratio for VTE was 1.53 among the women who did not also have prescription records for statin therapy. They were able to look at prescribed prescriptions for both the hormone therapy and the statins. Among the women prescribed hormone therapy and also low- to intermediate-dose statins, the odds ratio was 1.29. So that was quite a mitigation of the elevated risk. Among the women taking high-intensity statins, the odds ratio was 1.06, and there was no significant elevation.

We do need more data and more research on this question. One approach would be a meta-analysis of all of the existing randomized trials of hormone therapy in recent years wherein there was increased uptake of statin therapy to look at this question not only for VTE but also for coronary heart disease, stroke, and other CVD outcomes to see whether statin therapy is associated with some attenuation of the excess risk. We also need a targeted randomized trial of statins vs placebo among women who have clear indications for hormone therapy but may be at some increased risk for VTE. That type of trial would be extremely helpful.

In the interim, there are ways to minimize risk for VTE among women who are clear candidates for menopausal hormone therapy, especially among women at increased risk for VTE. These include choosing a transdermal rather than an oral formulation of hormone therapy and using lower doses of hormone therapy. Also, women who are clear candidates for hormone therapy and also for statins, it’s obvious that statins could be co-prescribed. Even among women who are clear candidates for hormone therapy but only intermediate borderline candidates for statin therapy, the prescription of statins might be considered in that clinical scenario to try to mitigate that excess risk for VTE.

JoAnn E. Manson, MD, DrPH, has disclosed the following relevant financial relationships: Received study pill donation and infrastructure support from: Mars Symbioscience (for the COSMOS trial).

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk about a recent report in the journal Hypertension that raises questions about whether blood pressure (BP) guidelines should be revisited and whether sex-specific thresholds and targets should be considered. Current BP guidelines are sex-agnostic.

This study was done in the large-scale nationally representative NHANES cohort. It included more than 53,000 US men and women. The average age was about 45 years, with an average duration of follow-up of 9.5 years. During that time, about 2400 cardiovascular (CVD) deaths were documented at baseline. The BP was measured three times, and the results were averaged. About 20% of the cohort were taking antihypertensive medications, and 80% were not.

Sex differences were observed in the association between BP and CVD mortality. The systolic BP associated with the lowest risk for CVD death was 110-119 mm Hg in men and 100-109 mm Hg in women. In men, however, compared with a reference category of systolic BP of 100-109 mm Hg, the risk for CVD death began to increase significantly at a systolic BP ≥ 160 mm Hg, at which point, the hazard ratio was 1.76, or 76% higher risk.

In women, the risk for CVD death began to increase significantly at a lower threshold. Compared with a reference category of systolic BP of 100-109 mm Hg, women whose systolic BP was 130-139 mm Hg had a significant 61% increase in CVD death, and among those with a systolic BP of 140-159 mm Hg, the risk was increased by 75%. With a systolic BP ≥ 160 mm Hg, CVD deaths among women were more than doubled, with a hazard ratio of 2.13.

Overall, these findings suggest sex differences, with women having an increased risk for CVD death beginning at a lower elevation of their systolic BP. For diastolic BP, both men and women showed the typical U-shaped curve and the diastolic BP associated with the lowest risk for CVD death was 70-80 mm Hg.

If these findings can be replicated with additional research and other large-scale cohort studies, and randomized trials show differences in lowering BP, then sex-specific BP guidelines could have advantages and should be seriously considered. Furthermore, some of the CVD risk scores and risk modeling should perhaps use sex-specific blood pressure thresholds.Dr. Manson received study pill donation and infrastructure support from Mars Symbioscience (for the COSMOS trial).

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk about a recent report in the journal Hypertension that raises questions about whether blood pressure (BP) guidelines should be revisited and whether sex-specific thresholds and targets should be considered. Current BP guidelines are sex-agnostic.

This study was done in the large-scale nationally representative NHANES cohort. It included more than 53,000 US men and women. The average age was about 45 years, with an average duration of follow-up of 9.5 years. During that time, about 2400 cardiovascular (CVD) deaths were documented at baseline. The BP was measured three times, and the results were averaged. About 20% of the cohort were taking antihypertensive medications, and 80% were not.

Sex differences were observed in the association between BP and CVD mortality. The systolic BP associated with the lowest risk for CVD death was 110-119 mm Hg in men and 100-109 mm Hg in women. In men, however, compared with a reference category of systolic BP of 100-109 mm Hg, the risk for CVD death began to increase significantly at a systolic BP ≥ 160 mm Hg, at which point, the hazard ratio was 1.76, or 76% higher risk.

In women, the risk for CVD death began to increase significantly at a lower threshold. Compared with a reference category of systolic BP of 100-109 mm Hg, women whose systolic BP was 130-139 mm Hg had a significant 61% increase in CVD death, and among those with a systolic BP of 140-159 mm Hg, the risk was increased by 75%. With a systolic BP ≥ 160 mm Hg, CVD deaths among women were more than doubled, with a hazard ratio of 2.13.

Overall, these findings suggest sex differences, with women having an increased risk for CVD death beginning at a lower elevation of their systolic BP. For diastolic BP, both men and women showed the typical U-shaped curve and the diastolic BP associated with the lowest risk for CVD death was 70-80 mm Hg.

If these findings can be replicated with additional research and other large-scale cohort studies, and randomized trials show differences in lowering BP, then sex-specific BP guidelines could have advantages and should be seriously considered. Furthermore, some of the CVD risk scores and risk modeling should perhaps use sex-specific blood pressure thresholds.Dr. Manson received study pill donation and infrastructure support from Mars Symbioscience (for the COSMOS trial).

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk about a recent report in the journal Hypertension that raises questions about whether blood pressure (BP) guidelines should be revisited and whether sex-specific thresholds and targets should be considered. Current BP guidelines are sex-agnostic.

This study was done in the large-scale nationally representative NHANES cohort. It included more than 53,000 US men and women. The average age was about 45 years, with an average duration of follow-up of 9.5 years. During that time, about 2400 cardiovascular (CVD) deaths were documented at baseline. The BP was measured three times, and the results were averaged. About 20% of the cohort were taking antihypertensive medications, and 80% were not.

Sex differences were observed in the association between BP and CVD mortality. The systolic BP associated with the lowest risk for CVD death was 110-119 mm Hg in men and 100-109 mm Hg in women. In men, however, compared with a reference category of systolic BP of 100-109 mm Hg, the risk for CVD death began to increase significantly at a systolic BP ≥ 160 mm Hg, at which point, the hazard ratio was 1.76, or 76% higher risk.

In women, the risk for CVD death began to increase significantly at a lower threshold. Compared with a reference category of systolic BP of 100-109 mm Hg, women whose systolic BP was 130-139 mm Hg had a significant 61% increase in CVD death, and among those with a systolic BP of 140-159 mm Hg, the risk was increased by 75%. With a systolic BP ≥ 160 mm Hg, CVD deaths among women were more than doubled, with a hazard ratio of 2.13.

Overall, these findings suggest sex differences, with women having an increased risk for CVD death beginning at a lower elevation of their systolic BP. For diastolic BP, both men and women showed the typical U-shaped curve and the diastolic BP associated with the lowest risk for CVD death was 70-80 mm Hg.

If these findings can be replicated with additional research and other large-scale cohort studies, and randomized trials show differences in lowering BP, then sex-specific BP guidelines could have advantages and should be seriously considered. Furthermore, some of the CVD risk scores and risk modeling should perhaps use sex-specific blood pressure thresholds.Dr. Manson received study pill donation and infrastructure support from Mars Symbioscience (for the COSMOS trial).

A version of this article appeared on Medscape.com.

I’d like to talk with you about a recent report from the large-scale Black Women’s Health Study, published in the new journal NEJM Evidence.

This study looked at the association between hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension, and the risk for stroke over the next 20 (median, 22) years. Previous studies have linked hypertensive disorders of pregnancy with an increased risk for stroke. However, most of these studies have been done in White women of European ancestry, and evidence in Black women has been very limited, despite a disproportionately high risk of having a hypertensive disorder of pregnancy and also of stroke.

Manson_JoAnn_E_BOSTON_web.jpg

This study, in more than 40,000 U.S. women, found an increased risk for subsequent stroke among women with a prior history of hypertensive disorder of pregnancy – overall, a 66% increased risk, an 80% increased risk with gestational hypertension, and about a 50% increased risk with preeclampsia.

We know that pregnancy itself can lead to some remodeling of the vascular system, but we don’t know whether a direct causal relationship exists between preeclampsia or gestational hypertension and subsequent stroke. Another potential explanation is that these complications of pregnancy serve as a window into a woman’s future cardiometabolic health and a marker of her cardiovascular risk.

Regardless, the clinical implications are the same. First, we would want to prevent these complications of pregnancy whenever possible. Some women will be candidates for the use of aspirin if they are at high risk for preeclampsia, and certainly for monitoring blood pressure very closely during pregnancy. It will also be important to maintain blood pressure control in the postpartum period and during the subsequent years of adulthood to minimize risk for stroke, because hypertension is such a powerful risk factor for stroke.

It will also be tremendously important to intensify lifestyle modifications such as increasing physical activity and having a heart-healthy diet. These complications of pregnancy have also been linked in other studies to an increased risk for subsequent coronary heart disease events and heart failure.

This transcript has been edited for clarity.

Dr. Manson is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and chief of the division of preventive medicine, Brigham and Women’s Hospital, both in Boston, and past president, North American Menopause Society, 2011-2012. She disclosed receiving study pill donation and infrastructure support from Mars Symbioscience (for the COSMOS trial).

A version of this article appeared on Medscape.com.

I’d like to talk with you about a recent report from the large-scale Black Women’s Health Study, published in the new journal NEJM Evidence.

This study looked at the association between hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension, and the risk for stroke over the next 20 (median, 22) years. Previous studies have linked hypertensive disorders of pregnancy with an increased risk for stroke. However, most of these studies have been done in White women of European ancestry, and evidence in Black women has been very limited, despite a disproportionately high risk of having a hypertensive disorder of pregnancy and also of stroke.

Manson_JoAnn_E_BOSTON_web.jpg

This study, in more than 40,000 U.S. women, found an increased risk for subsequent stroke among women with a prior history of hypertensive disorder of pregnancy – overall, a 66% increased risk, an 80% increased risk with gestational hypertension, and about a 50% increased risk with preeclampsia.

We know that pregnancy itself can lead to some remodeling of the vascular system, but we don’t know whether a direct causal relationship exists between preeclampsia or gestational hypertension and subsequent stroke. Another potential explanation is that these complications of pregnancy serve as a window into a woman’s future cardiometabolic health and a marker of her cardiovascular risk.

Regardless, the clinical implications are the same. First, we would want to prevent these complications of pregnancy whenever possible. Some women will be candidates for the use of aspirin if they are at high risk for preeclampsia, and certainly for monitoring blood pressure very closely during pregnancy. It will also be important to maintain blood pressure control in the postpartum period and during the subsequent years of adulthood to minimize risk for stroke, because hypertension is such a powerful risk factor for stroke.

It will also be tremendously important to intensify lifestyle modifications such as increasing physical activity and having a heart-healthy diet. These complications of pregnancy have also been linked in other studies to an increased risk for subsequent coronary heart disease events and heart failure.

This transcript has been edited for clarity.

Dr. Manson is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and chief of the division of preventive medicine, Brigham and Women’s Hospital, both in Boston, and past president, North American Menopause Society, 2011-2012. She disclosed receiving study pill donation and infrastructure support from Mars Symbioscience (for the COSMOS trial).

A version of this article appeared on Medscape.com.

I’d like to talk with you about a recent report from the large-scale Black Women’s Health Study, published in the new journal NEJM Evidence.

This study looked at the association between hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension, and the risk for stroke over the next 20 (median, 22) years. Previous studies have linked hypertensive disorders of pregnancy with an increased risk for stroke. However, most of these studies have been done in White women of European ancestry, and evidence in Black women has been very limited, despite a disproportionately high risk of having a hypertensive disorder of pregnancy and also of stroke.

Manson_JoAnn_E_BOSTON_web.jpg

This study, in more than 40,000 U.S. women, found an increased risk for subsequent stroke among women with a prior history of hypertensive disorder of pregnancy – overall, a 66% increased risk, an 80% increased risk with gestational hypertension, and about a 50% increased risk with preeclampsia.

We know that pregnancy itself can lead to some remodeling of the vascular system, but we don’t know whether a direct causal relationship exists between preeclampsia or gestational hypertension and subsequent stroke. Another potential explanation is that these complications of pregnancy serve as a window into a woman’s future cardiometabolic health and a marker of her cardiovascular risk.

Regardless, the clinical implications are the same. First, we would want to prevent these complications of pregnancy whenever possible. Some women will be candidates for the use of aspirin if they are at high risk for preeclampsia, and certainly for monitoring blood pressure very closely during pregnancy. It will also be important to maintain blood pressure control in the postpartum period and during the subsequent years of adulthood to minimize risk for stroke, because hypertension is such a powerful risk factor for stroke.

It will also be tremendously important to intensify lifestyle modifications such as increasing physical activity and having a heart-healthy diet. These complications of pregnancy have also been linked in other studies to an increased risk for subsequent coronary heart disease events and heart failure.

This transcript has been edited for clarity.

Dr. Manson is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and chief of the division of preventive medicine, Brigham and Women’s Hospital, both in Boston, and past president, North American Menopause Society, 2011-2012. She disclosed receiving study pill donation and infrastructure support from Mars Symbioscience (for the COSMOS trial).

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent report on the American Heart Association Life’s Essential 8 metric and its association with both life expectancy and health span or life expectancy free of chronic diseases such as cardiovascular disease (CVD), cancer, diabetes, and dementia.

This study leveraged the UK Biobank and included more than 135,000 U.K. adults with a mean age of 55. The AHA metric was defined as including the following lifestyle behavioral factors:

• Not smoking.
• Regular physical activity.
• Healthy weight.
• Healthy diet.
• Healthy sleep (defined as an average of 7-9 hours nightly).
• Blood pressure in a healthy range.
• Blood glucose in a healthy range.
• Non-HDL cholesterol in a healthy range.

This study was just published in JAMA Internal Medicine. I’d like to acknowledge that I’m a coauthor of this study, along with my colleagues at Tulane.

We divided the study population into three groups: those with low, moderate, and high scores on the Life’s Essential 8 metric – low, moderate, and high cardiovascular health. Overall, the average life expectancy free of chronic disease was estimated to be age 50, with 25 additional years in men and 30 additional years in women.

We saw large differences across the Life’s Essential 8 metric group. Men with high cardiovascular health scores tended to have an additional 7 years of life expectancy free of chronic disease, compared with those who had poorer scores. In women, the difference was about 9.5 years between high scores and lower scores. Also, the number of years lived with chronic disease was compressed in those with high cardiovascular health scores. They tended to have fewer years living with those chronic diseases but more years living free of chronic diseases.

We were interested in how these results might differ by socioeconomic status, educational level, and income level, as well as the Townsend deprivation index. We were intrigued by the finding that the gain in life expectancy free of chronic disease was very similar across all socioeconomic strata – those with lower education and lower income gained as much in terms of chronic disease–free life expectancy as those who were in the higher socioeconomic strata.

Overall, the findings make a compelling case for the importance of lifestyle factors in extending health span and years free of chronic disease. It can be motivating to tell our patients that a healthy lifestyle not only extends life expectancy but also extends years of health free of chronic disease.

Nonetheless, we do have many disparities in life expectancy and health span. So it will be very important to population health to narrow those health disparities through education about the importance of lifestyle factors, more research on implementation of lifestyle factors and behaviors, and public policy to make a healthy lifestyle both affordable and accessible to all people across all of these socioeconomic groups.

Thank you so much for your attention.

JoAnn E. Manson, MD, DrPH, is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, Boston.

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

This transcript has been edited for clarity.

This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent report on the American Heart Association Life’s Essential 8 metric and its association with both life expectancy and health span or life expectancy free of chronic diseases such as cardiovascular disease (CVD), cancer, diabetes, and dementia.

This study leveraged the UK Biobank and included more than 135,000 U.K. adults with a mean age of 55. The AHA metric was defined as including the following lifestyle behavioral factors:

• Not smoking.
• Regular physical activity.
• Healthy weight.
• Healthy diet.
• Healthy sleep (defined as an average of 7-9 hours nightly).
• Blood pressure in a healthy range.
• Blood glucose in a healthy range.
• Non-HDL cholesterol in a healthy range.

This study was just published in JAMA Internal Medicine. I’d like to acknowledge that I’m a coauthor of this study, along with my colleagues at Tulane.

We divided the study population into three groups: those with low, moderate, and high scores on the Life’s Essential 8 metric – low, moderate, and high cardiovascular health. Overall, the average life expectancy free of chronic disease was estimated to be age 50, with 25 additional years in men and 30 additional years in women.

We saw large differences across the Life’s Essential 8 metric group. Men with high cardiovascular health scores tended to have an additional 7 years of life expectancy free of chronic disease, compared with those who had poorer scores. In women, the difference was about 9.5 years between high scores and lower scores. Also, the number of years lived with chronic disease was compressed in those with high cardiovascular health scores. They tended to have fewer years living with those chronic diseases but more years living free of chronic diseases.

We were interested in how these results might differ by socioeconomic status, educational level, and income level, as well as the Townsend deprivation index. We were intrigued by the finding that the gain in life expectancy free of chronic disease was very similar across all socioeconomic strata – those with lower education and lower income gained as much in terms of chronic disease–free life expectancy as those who were in the higher socioeconomic strata.

Overall, the findings make a compelling case for the importance of lifestyle factors in extending health span and years free of chronic disease. It can be motivating to tell our patients that a healthy lifestyle not only extends life expectancy but also extends years of health free of chronic disease.

Nonetheless, we do have many disparities in life expectancy and health span. So it will be very important to population health to narrow those health disparities through education about the importance of lifestyle factors, more research on implementation of lifestyle factors and behaviors, and public policy to make a healthy lifestyle both affordable and accessible to all people across all of these socioeconomic groups.

Thank you so much for your attention.

JoAnn E. Manson, MD, DrPH, is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, Boston.

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

This transcript has been edited for clarity.

This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent report on the American Heart Association Life’s Essential 8 metric and its association with both life expectancy and health span or life expectancy free of chronic diseases such as cardiovascular disease (CVD), cancer, diabetes, and dementia.

This study leveraged the UK Biobank and included more than 135,000 U.K. adults with a mean age of 55. The AHA metric was defined as including the following lifestyle behavioral factors:

• Not smoking.
• Regular physical activity.
• Healthy weight.
• Healthy diet.
• Healthy sleep (defined as an average of 7-9 hours nightly).
• Blood pressure in a healthy range.
• Blood glucose in a healthy range.
• Non-HDL cholesterol in a healthy range.

This study was just published in JAMA Internal Medicine. I’d like to acknowledge that I’m a coauthor of this study, along with my colleagues at Tulane.

We divided the study population into three groups: those with low, moderate, and high scores on the Life’s Essential 8 metric – low, moderate, and high cardiovascular health. Overall, the average life expectancy free of chronic disease was estimated to be age 50, with 25 additional years in men and 30 additional years in women.

We saw large differences across the Life’s Essential 8 metric group. Men with high cardiovascular health scores tended to have an additional 7 years of life expectancy free of chronic disease, compared with those who had poorer scores. In women, the difference was about 9.5 years between high scores and lower scores. Also, the number of years lived with chronic disease was compressed in those with high cardiovascular health scores. They tended to have fewer years living with those chronic diseases but more years living free of chronic diseases.

We were interested in how these results might differ by socioeconomic status, educational level, and income level, as well as the Townsend deprivation index. We were intrigued by the finding that the gain in life expectancy free of chronic disease was very similar across all socioeconomic strata – those with lower education and lower income gained as much in terms of chronic disease–free life expectancy as those who were in the higher socioeconomic strata.

Overall, the findings make a compelling case for the importance of lifestyle factors in extending health span and years free of chronic disease. It can be motivating to tell our patients that a healthy lifestyle not only extends life expectancy but also extends years of health free of chronic disease.

Nonetheless, we do have many disparities in life expectancy and health span. So it will be very important to population health to narrow those health disparities through education about the importance of lifestyle factors, more research on implementation of lifestyle factors and behaviors, and public policy to make a healthy lifestyle both affordable and accessible to all people across all of these socioeconomic groups.

Thank you so much for your attention.

JoAnn E. Manson, MD, DrPH, is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, Boston.

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

This transcript has been edited for clarity.

Hello. This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent report in JAMA Cardiology on atrial fibrillation (AF), sex differences, and modifiable risk factors.

We looked at these questions in our vitamin D and omega-3 trial VITAL in an ancillary study called VITAL Rhythm, led by Dr. Christine Albert at Cedars-Sinai. And this particular project was led by Dr. Hasan Siddiqi at Vanderbilt.

As you know, AF is the most common arrhythmia in the world, and it’s burgeoning in numbers, primarily because of the aging of the population. It’s also a major cause of stroke, heart failure, and cardiovascular mortality. Although women are known to have lower rates of AF than men, they’re also known to have a higher risk for cardiovascular complications and sequelae, such as higher risk for stroke and CVD mortality. Therefore, we thought that understanding sex differences in risk and modifiable risk factors for AF that could reduce the burden of disease would be important.

It’s known that greater height is a risk factor for AF, but the extent to which it explains the differences in AF risk between men and women isn’t really known. So we looked at these questions in the VITAL cohort. VITAL has more than 25,000 participants. It’s a large, diverse, nationwide cohort. About 51% are women, and all are aged 50 years or older, with a mean age of 67. All were free of known clinical cardiovascular disease at the start of the study.

AF reports were confirmed by medical records and also supplemented by Medicare CMS linkage for fuller ascertainment of outcomes. We had 900 incident cases of AF in the study, and we did see that women were less likely to be diagnosed with AF. They had a 32% lower risk – strongly statistically significant compared with men, with a P < .001. Women were also more likely to be symptomatic: About 77% of women vs. 63% of men had symptoms prior to or at diagnosis.

It was very interesting that adjustment for height eliminated the lower risk for AF in women compared with men. After accounting for height, there was not only no reduction in risk for AF among the women, there was actually a reversal of the association so that there was a slightly higher risk for AF in the women. Other risk factors for AF in the cohort included older age, higher body mass index, hypertension, and higher consumption of alcohol. We did not see an association between diabetes and higher risk for AF. We also saw no clear association with physical activity, although very strenuous physical activity has been linked to AF in some other studies.

We looked at the interventions of vitamin D (2,000 IU/day) and omega-3 fatty acids (460 mg/day of EPA and 380 mg/day of DHA) and found no association with AF, although some other studies have seen increased risk for AF with higher doses of the marine omega-3s > 1 g/day and certainly at doses of 4 g/day. So overall, the findings highlight the fact that many of the risk factors for AF do seem to be modifiable, and it is really important to identify and try to reduce these risk factors in order to reduce the burden of AF. This may be particularly important in women because women are more likely to have stroke and cardiovascular mortality in these adverse cardiovascular outcomes.

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

This transcript has been edited for clarity.

Hello. This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent report in JAMA Cardiology on atrial fibrillation (AF), sex differences, and modifiable risk factors.

We looked at these questions in our vitamin D and omega-3 trial VITAL in an ancillary study called VITAL Rhythm, led by Dr. Christine Albert at Cedars-Sinai. And this particular project was led by Dr. Hasan Siddiqi at Vanderbilt.

As you know, AF is the most common arrhythmia in the world, and it’s burgeoning in numbers, primarily because of the aging of the population. It’s also a major cause of stroke, heart failure, and cardiovascular mortality. Although women are known to have lower rates of AF than men, they’re also known to have a higher risk for cardiovascular complications and sequelae, such as higher risk for stroke and CVD mortality. Therefore, we thought that understanding sex differences in risk and modifiable risk factors for AF that could reduce the burden of disease would be important.

It’s known that greater height is a risk factor for AF, but the extent to which it explains the differences in AF risk between men and women isn’t really known. So we looked at these questions in the VITAL cohort. VITAL has more than 25,000 participants. It’s a large, diverse, nationwide cohort. About 51% are women, and all are aged 50 years or older, with a mean age of 67. All were free of known clinical cardiovascular disease at the start of the study.

AF reports were confirmed by medical records and also supplemented by Medicare CMS linkage for fuller ascertainment of outcomes. We had 900 incident cases of AF in the study, and we did see that women were less likely to be diagnosed with AF. They had a 32% lower risk – strongly statistically significant compared with men, with a P < .001. Women were also more likely to be symptomatic: About 77% of women vs. 63% of men had symptoms prior to or at diagnosis.

It was very interesting that adjustment for height eliminated the lower risk for AF in women compared with men. After accounting for height, there was not only no reduction in risk for AF among the women, there was actually a reversal of the association so that there was a slightly higher risk for AF in the women. Other risk factors for AF in the cohort included older age, higher body mass index, hypertension, and higher consumption of alcohol. We did not see an association between diabetes and higher risk for AF. We also saw no clear association with physical activity, although very strenuous physical activity has been linked to AF in some other studies.

We looked at the interventions of vitamin D (2,000 IU/day) and omega-3 fatty acids (460 mg/day of EPA and 380 mg/day of DHA) and found no association with AF, although some other studies have seen increased risk for AF with higher doses of the marine omega-3s > 1 g/day and certainly at doses of 4 g/day. So overall, the findings highlight the fact that many of the risk factors for AF do seem to be modifiable, and it is really important to identify and try to reduce these risk factors in order to reduce the burden of AF. This may be particularly important in women because women are more likely to have stroke and cardiovascular mortality in these adverse cardiovascular outcomes.

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

This transcript has been edited for clarity.

Hello. This is Dr. JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about a recent report in JAMA Cardiology on atrial fibrillation (AF), sex differences, and modifiable risk factors.

We looked at these questions in our vitamin D and omega-3 trial VITAL in an ancillary study called VITAL Rhythm, led by Dr. Christine Albert at Cedars-Sinai. And this particular project was led by Dr. Hasan Siddiqi at Vanderbilt.

As you know, AF is the most common arrhythmia in the world, and it’s burgeoning in numbers, primarily because of the aging of the population. It’s also a major cause of stroke, heart failure, and cardiovascular mortality. Although women are known to have lower rates of AF than men, they’re also known to have a higher risk for cardiovascular complications and sequelae, such as higher risk for stroke and CVD mortality. Therefore, we thought that understanding sex differences in risk and modifiable risk factors for AF that could reduce the burden of disease would be important.

It’s known that greater height is a risk factor for AF, but the extent to which it explains the differences in AF risk between men and women isn’t really known. So we looked at these questions in the VITAL cohort. VITAL has more than 25,000 participants. It’s a large, diverse, nationwide cohort. About 51% are women, and all are aged 50 years or older, with a mean age of 67. All were free of known clinical cardiovascular disease at the start of the study.

AF reports were confirmed by medical records and also supplemented by Medicare CMS linkage for fuller ascertainment of outcomes. We had 900 incident cases of AF in the study, and we did see that women were less likely to be diagnosed with AF. They had a 32% lower risk – strongly statistically significant compared with men, with a P < .001. Women were also more likely to be symptomatic: About 77% of women vs. 63% of men had symptoms prior to or at diagnosis.

It was very interesting that adjustment for height eliminated the lower risk for AF in women compared with men. After accounting for height, there was not only no reduction in risk for AF among the women, there was actually a reversal of the association so that there was a slightly higher risk for AF in the women. Other risk factors for AF in the cohort included older age, higher body mass index, hypertension, and higher consumption of alcohol. We did not see an association between diabetes and higher risk for AF. We also saw no clear association with physical activity, although very strenuous physical activity has been linked to AF in some other studies.

We looked at the interventions of vitamin D (2,000 IU/day) and omega-3 fatty acids (460 mg/day of EPA and 380 mg/day of DHA) and found no association with AF, although some other studies have seen increased risk for AF with higher doses of the marine omega-3s > 1 g/day and certainly at doses of 4 g/day. So overall, the findings highlight the fact that many of the risk factors for AF do seem to be modifiable, and it is really important to identify and try to reduce these risk factors in order to reduce the burden of AF. This may be particularly important in women because women are more likely to have stroke and cardiovascular mortality in these adverse cardiovascular outcomes.

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

This transcript has been edited for clarity.

Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about the recent research (particularly randomized clinical trials) of vitamin D supplementation and the implications for clinical practice. As a director of the Vitamin D and Omega-3 trial (VITAL), the largest randomized clinical trial in the world, I’m often asked, “How much vitamin D do we need, and should I take a vitamin D supplement?” I want to review the findings from recent randomized clinical trials and the implications for practice.

For a long time, vitamin D has been perceived as a magic bullet, a panacea, and a cure-all for many chronic health conditions such as cancer, cardiovascular disease, diabetes, bone fractures, cognitive decline, and depression. Many of the findings, though, have been from observational studies where a higher blood level of 25-hydroxy vitamin D has been linked to a lower risk for these health conditions.

We know in epidemiology that correlation doesn’t prove causation. Other factors could be involved; for example, people who have higher blood levels of vitamin D may have healthier diets, or they may be spending more time outdoors, being physically active and exposed to the sun. Some of these other factors could be lowering their risk.

When the randomized trials began to emerge, in many of these large-scale trials, the findings were generally neutral or null for cardiovascular disease, total cancer, diabetes, cognitive decline, depression, and many other health outcomes, including fracture. So, the question was asked, does this mean that vitamin D is not important to health?

To the contrary, these findings suggest that vitamin D is so essential to health that we need only small to moderate amounts of vitamin D. Vitamin D is very tightly regulated in the body – the metabolism and function of vitamin D. Even small to moderate amounts will meet the requirements for vitamin D and bone health and many other outcomes.

This is what the National Academy of Medicine, U.S. Preventive Services Task Force, and many other professional organizations have advised, that widespread screening for vitamin D deficiency and blanket universal supplementation with vitamin D would not be indicated.

The randomized trials of vitamin D, including the VITAL study, have generally not shown reductions in the major health outcomes. We found two exceptions in VITAL. We saw promising signals, including a 22% reduction in autoimmune conditions (rheumatoid arthritis and psoriasis) and a 17% reduction in advanced (metastatic or fatal) cancers. In meta-analyses of other large-scale randomized trials, the findings were a signal for a reduction in advanced cancers, even with very small doses of vitamin D (400-800 IUs daily). We tested 2,000 IUs daily in VITAL.

Overall, it’s recommended that small to moderate amounts of vitamin D are adequate, and among the healthy population, most people do not need screening or supplements.

The reduction in autoimmune diseases suggests that vitamin D may play a role in tamping down inflammation. The question has been raised about whether vitamin D is beneficial in reducing the severity of COVID illness, the need for hospitalization, and long COVID. We are looking at this question in a separate trial called VIVID (Vitamin D for COVID Trial) which tests a higher dose (> 3,000 IUs daily) of vitamin D. Those results will be available at the end of this year or early next year.

In other randomized trials of COVID and vitamin D, the results have been mixed and inconsistent, with no clear answer. During the COVID pandemic, I have generally advised that it’s reasonable to take 1,000-2,000 IUs of vitamin D daily as a form of insurance. This dose is known to be very safe. Over 5.3 years in the VITAL trial we saw that a dose of 2,000 IUs was very safe.

But it’s not essential to take a supplement. And overall, aside from some high-risk groups, most people do not need a supplement. The high-risk groups include patients in nursing homes who may have restricted diets and limited time out of doors. For people with malabsorption conditions such as Crohn’s disease, celiac disease, post–gastric bypass surgery, and those with osteoporosis who are on medications for osteoporosis, it’s still quite reasonable to prescribe calcium and vitamin D.

Recommendations for vitamin D in the generally healthy population really should focus on a healthy diet. The United States has a fortified food supply. Vitamin D is added to many foods, dairy products, and cereals, as well as beverages. Natural sources of vitamin D include fatty fish and wild mushrooms.

We should be looking at food labels (which now include vitamin D content) and try to get adequate vitamin D from our diet, and also do our best to spend time outdoors, being physically active, because it is of great benefit to our health. The general principle is that a dietary supplement will never be a substitute for a healthy diet or healthy lifestyle. And those other behaviors really should be the focus at this time.

Dr. Manson is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and chief of the division of preventive medicine at Brigham and Women’s Hospital, both in Boston. She has received infrastructure support from Mars Symbioscience for the COSMOS trial.

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

This transcript has been edited for clarity.

Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about the recent research (particularly randomized clinical trials) of vitamin D supplementation and the implications for clinical practice. As a director of the Vitamin D and Omega-3 trial (VITAL), the largest randomized clinical trial in the world, I’m often asked, “How much vitamin D do we need, and should I take a vitamin D supplement?” I want to review the findings from recent randomized clinical trials and the implications for practice.

For a long time, vitamin D has been perceived as a magic bullet, a panacea, and a cure-all for many chronic health conditions such as cancer, cardiovascular disease, diabetes, bone fractures, cognitive decline, and depression. Many of the findings, though, have been from observational studies where a higher blood level of 25-hydroxy vitamin D has been linked to a lower risk for these health conditions.

We know in epidemiology that correlation doesn’t prove causation. Other factors could be involved; for example, people who have higher blood levels of vitamin D may have healthier diets, or they may be spending more time outdoors, being physically active and exposed to the sun. Some of these other factors could be lowering their risk.

When the randomized trials began to emerge, in many of these large-scale trials, the findings were generally neutral or null for cardiovascular disease, total cancer, diabetes, cognitive decline, depression, and many other health outcomes, including fracture. So, the question was asked, does this mean that vitamin D is not important to health?

To the contrary, these findings suggest that vitamin D is so essential to health that we need only small to moderate amounts of vitamin D. Vitamin D is very tightly regulated in the body – the metabolism and function of vitamin D. Even small to moderate amounts will meet the requirements for vitamin D and bone health and many other outcomes.

This is what the National Academy of Medicine, U.S. Preventive Services Task Force, and many other professional organizations have advised, that widespread screening for vitamin D deficiency and blanket universal supplementation with vitamin D would not be indicated.

The randomized trials of vitamin D, including the VITAL study, have generally not shown reductions in the major health outcomes. We found two exceptions in VITAL. We saw promising signals, including a 22% reduction in autoimmune conditions (rheumatoid arthritis and psoriasis) and a 17% reduction in advanced (metastatic or fatal) cancers. In meta-analyses of other large-scale randomized trials, the findings were a signal for a reduction in advanced cancers, even with very small doses of vitamin D (400-800 IUs daily). We tested 2,000 IUs daily in VITAL.

Overall, it’s recommended that small to moderate amounts of vitamin D are adequate, and among the healthy population, most people do not need screening or supplements.

The reduction in autoimmune diseases suggests that vitamin D may play a role in tamping down inflammation. The question has been raised about whether vitamin D is beneficial in reducing the severity of COVID illness, the need for hospitalization, and long COVID. We are looking at this question in a separate trial called VIVID (Vitamin D for COVID Trial) which tests a higher dose (> 3,000 IUs daily) of vitamin D. Those results will be available at the end of this year or early next year.

In other randomized trials of COVID and vitamin D, the results have been mixed and inconsistent, with no clear answer. During the COVID pandemic, I have generally advised that it’s reasonable to take 1,000-2,000 IUs of vitamin D daily as a form of insurance. This dose is known to be very safe. Over 5.3 years in the VITAL trial we saw that a dose of 2,000 IUs was very safe.

But it’s not essential to take a supplement. And overall, aside from some high-risk groups, most people do not need a supplement. The high-risk groups include patients in nursing homes who may have restricted diets and limited time out of doors. For people with malabsorption conditions such as Crohn’s disease, celiac disease, post–gastric bypass surgery, and those with osteoporosis who are on medications for osteoporosis, it’s still quite reasonable to prescribe calcium and vitamin D.

Recommendations for vitamin D in the generally healthy population really should focus on a healthy diet. The United States has a fortified food supply. Vitamin D is added to many foods, dairy products, and cereals, as well as beverages. Natural sources of vitamin D include fatty fish and wild mushrooms.

We should be looking at food labels (which now include vitamin D content) and try to get adequate vitamin D from our diet, and also do our best to spend time outdoors, being physically active, because it is of great benefit to our health. The general principle is that a dietary supplement will never be a substitute for a healthy diet or healthy lifestyle. And those other behaviors really should be the focus at this time.

Dr. Manson is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and chief of the division of preventive medicine at Brigham and Women’s Hospital, both in Boston. She has received infrastructure support from Mars Symbioscience for the COSMOS trial.

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

This transcript has been edited for clarity.

Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about the recent research (particularly randomized clinical trials) of vitamin D supplementation and the implications for clinical practice. As a director of the Vitamin D and Omega-3 trial (VITAL), the largest randomized clinical trial in the world, I’m often asked, “How much vitamin D do we need, and should I take a vitamin D supplement?” I want to review the findings from recent randomized clinical trials and the implications for practice.

For a long time, vitamin D has been perceived as a magic bullet, a panacea, and a cure-all for many chronic health conditions such as cancer, cardiovascular disease, diabetes, bone fractures, cognitive decline, and depression. Many of the findings, though, have been from observational studies where a higher blood level of 25-hydroxy vitamin D has been linked to a lower risk for these health conditions.

We know in epidemiology that correlation doesn’t prove causation. Other factors could be involved; for example, people who have higher blood levels of vitamin D may have healthier diets, or they may be spending more time outdoors, being physically active and exposed to the sun. Some of these other factors could be lowering their risk.

When the randomized trials began to emerge, in many of these large-scale trials, the findings were generally neutral or null for cardiovascular disease, total cancer, diabetes, cognitive decline, depression, and many other health outcomes, including fracture. So, the question was asked, does this mean that vitamin D is not important to health?

To the contrary, these findings suggest that vitamin D is so essential to health that we need only small to moderate amounts of vitamin D. Vitamin D is very tightly regulated in the body – the metabolism and function of vitamin D. Even small to moderate amounts will meet the requirements for vitamin D and bone health and many other outcomes.

This is what the National Academy of Medicine, U.S. Preventive Services Task Force, and many other professional organizations have advised, that widespread screening for vitamin D deficiency and blanket universal supplementation with vitamin D would not be indicated.

The randomized trials of vitamin D, including the VITAL study, have generally not shown reductions in the major health outcomes. We found two exceptions in VITAL. We saw promising signals, including a 22% reduction in autoimmune conditions (rheumatoid arthritis and psoriasis) and a 17% reduction in advanced (metastatic or fatal) cancers. In meta-analyses of other large-scale randomized trials, the findings were a signal for a reduction in advanced cancers, even with very small doses of vitamin D (400-800 IUs daily). We tested 2,000 IUs daily in VITAL.

Overall, it’s recommended that small to moderate amounts of vitamin D are adequate, and among the healthy population, most people do not need screening or supplements.

The reduction in autoimmune diseases suggests that vitamin D may play a role in tamping down inflammation. The question has been raised about whether vitamin D is beneficial in reducing the severity of COVID illness, the need for hospitalization, and long COVID. We are looking at this question in a separate trial called VIVID (Vitamin D for COVID Trial) which tests a higher dose (> 3,000 IUs daily) of vitamin D. Those results will be available at the end of this year or early next year.

In other randomized trials of COVID and vitamin D, the results have been mixed and inconsistent, with no clear answer. During the COVID pandemic, I have generally advised that it’s reasonable to take 1,000-2,000 IUs of vitamin D daily as a form of insurance. This dose is known to be very safe. Over 5.3 years in the VITAL trial we saw that a dose of 2,000 IUs was very safe.

But it’s not essential to take a supplement. And overall, aside from some high-risk groups, most people do not need a supplement. The high-risk groups include patients in nursing homes who may have restricted diets and limited time out of doors. For people with malabsorption conditions such as Crohn’s disease, celiac disease, post–gastric bypass surgery, and those with osteoporosis who are on medications for osteoporosis, it’s still quite reasonable to prescribe calcium and vitamin D.

Recommendations for vitamin D in the generally healthy population really should focus on a healthy diet. The United States has a fortified food supply. Vitamin D is added to many foods, dairy products, and cereals, as well as beverages. Natural sources of vitamin D include fatty fish and wild mushrooms.

We should be looking at food labels (which now include vitamin D content) and try to get adequate vitamin D from our diet, and also do our best to spend time outdoors, being physically active, because it is of great benefit to our health. The general principle is that a dietary supplement will never be a substitute for a healthy diet or healthy lifestyle. And those other behaviors really should be the focus at this time.

Dr. Manson is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and chief of the division of preventive medicine at Brigham and Women’s Hospital, both in Boston. She has received infrastructure support from Mars Symbioscience for the COSMOS trial.

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

This recently published study from Finland generated headlines when its authors concluded that stopping HT elevates the risk of mortality from cardiovascular disease (CVD), including cardiac and cerebrovascular events. Using nationwide data, investigators compared the CVD mortality rate among women who discontinued HT during the years 1994 through 2009 (n = 332,202) with expected (not actual) CVD mortality rates in the background population.
Within the first year after HT discontinuation, elevations in death rates from cardiac events and stroke were noted (standardized mortality ratio, 1.26 and 1.63, respectively), while in the subsequent year, reductions in such mortality were observed (P<.05 for all comparisons).
The absolute increased risk of death from cardiac events reported within the first year after discontinuation of HT was 4 deaths per 10,000 woman-years of exposure. The absolute risk of death from stroke was 5 additional events per 10,000 woman-years. This level of risk is considered to be rare.

How these data compare to those of other studiesIn contrast with these Finnish data, findings from the Women’s Health Initiative—the largest randomized trial of menopausal HT—do not indicate an increase in mortality or an increase in coronary heart or stroke events among women stopping HT.^1,2
It seems likely that limitations associated with the Finnish observational data account for this discordance. For example, Mikkola and colleagues did not know why women discontinued HT, raising the possibility that women with symptoms suggestive of CVD or development of new risk factors preferentially stopped HT, potentially introducing important bias into the Finnish analysis.

What this evidence means for practiceWomen and their clinicians should make decisions regarding whether to continue, reduce the dose, or discontinue HT through shared decision making, focusing on individual patient quality of life parameters as well as changing risk concerns related to such entities as cancer, CVD, and osteoporosis.³ Dramatic as they are, findings from this Finnish report should not impact how we counsel women regarding use or discontinuation of HT.
—Andrew M. Kaunitz, MD; JoAnn E. Manson, MD, DrPH; and Cynthia A. Stuenkel, MD

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

This recently published study from Finland generated headlines when its authors concluded that stopping HT elevates the risk of mortality from cardiovascular disease (CVD), including cardiac and cerebrovascular events. Using nationwide data, investigators compared the CVD mortality rate among women who discontinued HT during the years 1994 through 2009 (n = 332,202) with expected (not actual) CVD mortality rates in the background population.
Within the first year after HT discontinuation, elevations in death rates from cardiac events and stroke were noted (standardized mortality ratio, 1.26 and 1.63, respectively), while in the subsequent year, reductions in such mortality were observed (P<.05 for all comparisons).
The absolute increased risk of death from cardiac events reported within the first year after discontinuation of HT was 4 deaths per 10,000 woman-years of exposure. The absolute risk of death from stroke was 5 additional events per 10,000 woman-years. This level of risk is considered to be rare.

How these data compare to those of other studiesIn contrast with these Finnish data, findings from the Women’s Health Initiative—the largest randomized trial of menopausal HT—do not indicate an increase in mortality or an increase in coronary heart or stroke events among women stopping HT.^1,2
It seems likely that limitations associated with the Finnish observational data account for this discordance. For example, Mikkola and colleagues did not know why women discontinued HT, raising the possibility that women with symptoms suggestive of CVD or development of new risk factors preferentially stopped HT, potentially introducing important bias into the Finnish analysis.

What this evidence means for practiceWomen and their clinicians should make decisions regarding whether to continue, reduce the dose, or discontinue HT through shared decision making, focusing on individual patient quality of life parameters as well as changing risk concerns related to such entities as cancer, CVD, and osteoporosis.³ Dramatic as they are, findings from this Finnish report should not impact how we counsel women regarding use or discontinuation of HT.
—Andrew M. Kaunitz, MD; JoAnn E. Manson, MD, DrPH; and Cynthia A. Stuenkel, MD

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

This recently published study from Finland generated headlines when its authors concluded that stopping HT elevates the risk of mortality from cardiovascular disease (CVD), including cardiac and cerebrovascular events. Using nationwide data, investigators compared the CVD mortality rate among women who discontinued HT during the years 1994 through 2009 (n = 332,202) with expected (not actual) CVD mortality rates in the background population.
Within the first year after HT discontinuation, elevations in death rates from cardiac events and stroke were noted (standardized mortality ratio, 1.26 and 1.63, respectively), while in the subsequent year, reductions in such mortality were observed (P<.05 for all comparisons).
The absolute increased risk of death from cardiac events reported within the first year after discontinuation of HT was 4 deaths per 10,000 woman-years of exposure. The absolute risk of death from stroke was 5 additional events per 10,000 woman-years. This level of risk is considered to be rare.

How these data compare to those of other studiesIn contrast with these Finnish data, findings from the Women’s Health Initiative—the largest randomized trial of menopausal HT—do not indicate an increase in mortality or an increase in coronary heart or stroke events among women stopping HT.^1,2
It seems likely that limitations associated with the Finnish observational data account for this discordance. For example, Mikkola and colleagues did not know why women discontinued HT, raising the possibility that women with symptoms suggestive of CVD or development of new risk factors preferentially stopped HT, potentially introducing important bias into the Finnish analysis.

What this evidence means for practiceWomen and their clinicians should make decisions regarding whether to continue, reduce the dose, or discontinue HT through shared decision making, focusing on individual patient quality of life parameters as well as changing risk concerns related to such entities as cancer, CVD, and osteoporosis.³ Dramatic as they are, findings from this Finnish report should not impact how we counsel women regarding use or discontinuation of HT.
—Andrew M. Kaunitz, MD; JoAnn E. Manson, MD, DrPH; and Cynthia A. Stuenkel, MD

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

More than 2 years have passed since we published the results of the Women’s Health Initiative (WHI), which caused a storm of information—and misinformation—about the effect of long-term dietary intervention on disease outcomes in postmenopausal women. Now that the dust has long settled, what have we learned from this landmark study?

The WHI results led to numerous additional analyses of all aspects of the study.^1–7 What are the implications of all the analyses to clinical practice?

In this article, we summarize key aspects of the clinical trial, including study design, interventions, main results, and future plans. We also discuss potential clinical applications and practical considerations for public health efforts.

WHO WAS ELIGIBLE, WHO WAS NOT

A total of 48,835 postmenopausal women were randomly assigned to either no dietary intervention (n = 29,294) or a dietary intervention (n = 19,541) (see below).⁷ Participants were followed at 40 clinical centers between 1993 and 2005.⁴ Their mean age was 62.3 years; 18.6% were members of minorities.

Women were eligible if they were post-menopausal and had a daily dietary fat intake of at least 32% of total calories, based on assessment via a food-frequency questionnaire. They were excluded from the study if they had any of the following: a history of breast cancer, colorectal cancer, or other cancer except skin cancer during the past 10 years; type 1 diabetes; a medical condition in which the predicted survival was less than 3 years; and a potential barrier to adherence to the study regimen, including alcoholism or a lifestyle that involved often eating meals away from home.

THE WHI DIET: LESS FAT, BUT MORE FRUITS, VEGETABLES, GRAINS

The WHI dietary intervention was designed to prevent breast cancer, based on the evidence available when the study was planned. The targets included a total fat intake of less than 20% of energy (in kilocalories), increasing the intake of fruits and vegetables to at least five servings per day, and increasing the intake of grains to at least six servings per day.

Although reduction in saturated fat intake per se was not part of the WHI protocol, we assumed from previous pilot studies⁸ that the reduction of total fat intake would simultaneously produce a reduction in saturated fat intake to 7% of total calories.

A simpler dietary intervention

Unlike the 2006 American Heart Association guidelines and the US Department of Agriculture’s Dietary Guidelines for Americans 2005, the WHI dietary intervention had no specifications for dietary fiber, specific fatty acids (trans-fatty acids, omega-3 fatty acids, conjugated linoleic acid), complex carbohydrates, whole grains, vegetable protein, or other factors that have emerged as potential risk factors for cardiovascular and other chronic diseases since the study began. The WHI intervention also included no specific recommendation for total calorie intake, nor were patients in the intervention group encouraged to lose weight, as this could have confounded the results of the dietary intervention.

Education and encouragement

Those in the intervention group were each assigned a fat-gram goal, calculated on the basis of height. They were taught how to monitor their intake of total fat, fruits, vegetables, and grains. They attended intensive behavioral modification sessions to encourage them to keep to the dietary program: 18 group sessions in the first year and quarterly maintenance sessions thereafter, touching on a wide variety of nutrition- and behavior-related topics.^7,9 Specially trained and certified nutritionists supervised the dietary intervention and the behavioral modification sessions according to the WHI study protocol.

Control-group participants received a copy of the US Department of Agriculture’s Dietary Guidelines for Americans¹⁰ and other health-related materials. They had no contact with the study nutritionists.

Other arms of the study

The WHI trial design included several arms,^4,11–13 and many participants joined more than one arm: 20,592 postmenopausal women (42.2% of the total enrollment) chose dietary modification only, 8,050 (16.5%) chose diet plus hormone replacement therapy, 25,210 (51.6%) chose diet plus calcium and vitamin D supplementation, and 5,017 (10.3%) enrolled in all three.

Length of follow-up

Participants were followed from enrollment until they died, were lost to follow-up, or requested no further contact, or until the trial’s planned completion date, regardless of adherence to the dietary intervention, according to intention-to-treat analysis. All participants were contacted by clinic staff at 6-month intervals to provide updates on their health outcomes.

Factors assessed

Height, weight, waist circumference, and blood pressure were measured at annual visits using standardized procedures. Fasting blood samples were collected at baseline and at year 1 from all participants and from a subsample of 2,816 women (5.8% of the study population) at years 3 and 6. This subsample was randomly chosen with oversampling of minority women, for whom the odds for selection were six times higher than for white women.

Physical activity was assessed at baseline and at years 1, 3, 6, and 9. Walking and participation in sports and hours of activity per week were calculated for each participant. Physical activity was expressed as metabolic equivalent tasks per week for the analyses.

A food-frequency questionnaire⁶ to assess average dietary intake in the past 3 months was given at baseline and at year 1 for all participants. A third of all participants completed the questionnaire each year in a rotating sample. Completion rates were 100% at baseline and 81% thereafter. Follow-up data were collected from years 5 through 7. Also, 4-day food records were provided by all women before randomization.

HOW OUTCOMES WERE ASSESSED

The primary assessments of clinical outcome^1–3 were mammographic screening, a self-reported medical history documented by a review of medical records, and electrocardiograms digitally obtained every 3 years. Mammograms and electrocardiograms were centrally adjudicated. The diagnosis of acute myocardial infarction was based on an algorithm that included cardiac pain, enzyme levels, and electrocardiographic readings.

OVERALL RESULTS

At 8.1 years, the incidence of breast cancer was 9% lower in the intervention group than in the comparison group (95% confidence interval [CI] = 0.83–1.01; P = .07, P = .09 weighted for length of follow-up).³ Subgroup analysis further showed that women who reported higher intakes of total dietary fat at baseline reduced their risk of breast cancer by 22% (95% CI = 0.64–0.96). Whether extended follow-up will show a significant association has yet to be determined.

Colon cancer rates did not differ between groups, but the number of polyps and adenomas reported was significantly lower in the dietary intervention group.¹ The rate of colon cancer will also be included in the extended follow-up study of the WHI.

Risk factors for coronary heart disease in both groups—including levels of serum total cholesterol and serum low-density lipoprotein cholesterol, body weight, body mass index, diastolic blood pressure, and factor VIIc—improved slightly, but at year 3 of the trial, differences in overall rates of coronary heart disease and stroke in the two groups were not statistically significant.² In addition, the low-fat diet intervention was associated with a reduction in blood estradiol concentrations between baseline and year 1.³ At the end of the study, however, differences in rates of breast cancer, colorectal cancer, and heart disease between the two groups were not statistically significant.

RESULTS OF DIETARY MODIFICATIONS

Fat as a percentage of total calories

RTEmagicC_VanHorn_LessonsFromWHIStudy_T1.gif.gif

At the beginning of the WHI, all participants reported consuming an average of 35% of their caloric intake from fat (Table 1). At 1 year from baseline, the fat intake decreased to 24.3% in the intervention group (short of the study goal of 20%); this level had risen again to 26.7% by year 3 and to 28.8% at the end of the study. Stratified by quartile, women who achieved the greatest reductions in saturated and trans-fatty acids or the largest increases in their intake of fruits and vegetables appeared to have a moderate reduction in the risk of coronary heart disease.² Women in the comparison group also decreased their fat intake initially, but to a lesser degree, and gradually increased it again thereafter. The mean net difference in self-reported total fat intake between the intervention group and the comparison group at 6 years was 8.2% (P < .001) (study goal, 13%).^1–3

Intake of fruits, vegetables, and grains

At baseline, fruit and vegetable intake averaged 3.6 servings per day (Table 1). In the intervention group, this increased to 5.1 servings per day at year 1, and to 5.2 servings at year 3, but at the end of the study it had decreased to 4.9 servings.

Women in the intervention group were eating 4.7 servings of grains per day at baseline. This increased to 5.1 servings at year 1 and then decreased to 4.6 servings at year 3 and to 4.3 servings at the end of the study. It seems that as the women grew older their determination to increase servings of these foods diminished.

Proponents of some currently popular diets blame weight gain on a higher intake of carbohydrates, but the women following the WHI low-fat diet did not gain weight.²

Total fat vs saturated fat

Intake of total fat and saturated fat decreased in the intervention group during the study, but the difference between fat intake in the intervention group and that in the comparison group did not reach the degree expected.

At year 1, total fat as a percentage of total caloric intake was 10.8 percentage points below that of the comparison group, whereas the study expected difference was 13.0. At the end of the trial, the difference was only 8.2 percentage points, whereas the expected difference was 11.0.

Intake of all fatty acids (saturated and unsaturated) decreased at year 1, but then went back up slightly by the end of the trial but did not exceed baseline levels, and saturated fatty acids remained well below baseline levels: 9.5% vs 12.5% of caloric intake at baseline.⁴

INTERPRETING THE RESULTS

It might be tempting to dismiss the results of the WHI dietary intervention trial as not significant and therefore not meaningful. This would be unfortunate. The trial had some remarkable accomplishments and offers important lessons for future investigations.

The initial reductions in total fat intake were impressive, and women who had the highest total fat intake at baseline achieved the greatest reduction of total fat (to less than 22% of total calories).³ Nonetheless, the dietary intervention goal of less than 20% of calories from fat was not achieved despite intensive dietary counseling and a highly motivated study population. Thus, this dietary fat target may not be reasonable in the general population.

Also, despite the absence of targeted intervention on specific fatty acids, the observed blood cholesterol levels were as expected based on the well-known formula of Mensink and Katan,¹⁴ which incorporates information on changes in saturated fat, polyunsaturated fat, and dietary cholesterol intake. The predicted reduction in low-density lipoprotein cholesterol was 2.7 mg/dL; the observed reduction was 2.3 mg/dL.² This illustrates that with greater modifications in specific known dietary risk factors for cardiovascular disease, such as saturated fatty acids, cholesterol, and unsaturated fatty acids, blood cholesterol levels respond in a predictable fashion. This was presumably not observed in WHI precisely because no goals and objectives were provided to participants for intake of saturated or polyunsaturated fatty acids.

Recent findings from the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart)¹⁵ further highlight differences in the total cholesterol response to diets of varying macronutrient (carbohydrate, protein, fat) content compared with the WHI dietary intervention.¹⁵ Participants in OmniHeart had reductions in levels of low-density lipoprotein cholesterol that were predictable from the changes reported in intake of saturated fatty acids. Presumably, the results of the WHI intervention would have been similar if the study had included this level of detail.

QUESTIONS REMAIN

Questions from the WHI that need consideration for future clinical applications include whether the study population may have already been “too old” to achieve a benefit from dietary modification, and whether the best timing for dietary intervention might be earlier adulthood with sustained changes in saturated fat, cholesterol, and unsaturated fat intake throughout life. Future subgroup analyses based on age at baseline will need to address these questions. Likewise, a longer follow-up period may be needed for a definitive evaluation of the impact of a regular low-fat diet on different health outcomes.

As reported by Patterson et al,¹⁶ the major contributors to total dietary fat intake at baseline were “added fats” such as sauces, gravies, butter, and margarines (25.1% of fat intake), followed by meats (20.9% of fat intake), and desserts (12.8% of fat intake). These findings highlight target areas for future interventions in women of this age group.

Another issue is how to standardize the dietary intervention from one clinical center to another—ie, to minimize differences in how each clinical center manages the study patients. Such differences were noted in WHI and other studies.¹⁷ Despite standardized training in delivering the dietary intervention, nutritionists encountered regional and cultural differences that required tailoring the dietary intervention to their patients’ needs. Staff turnover, an unavoidable phenomenon in long-term studies, has previously been reported to negatively influence dietary adherence.¹⁸

LIMITATIONS

A major limitation of diet modification research in general is the self-reporting of dietary intake, primarily by a food-frequency questionnaire. Although the use of a questionnaire is the most practical way to obtain dietary data for large studies, systematic biases may exist that obscure true nutrient-outcome relationships.¹⁹ Biomarker studies of energy balance suggest that people who are overweight or obese may under-report energy intake to a greater degree than people who are not overweight.²⁰ Also, we still do not know how to get people to follow a healthy diet, although theories and models abound, such as social learning and cognitive-behavioral theory, and a lack of data limits our understanding of factors related to dietary adherence.^21,22

FUTURE DIRECTIONS IN WHI

The WHI Extension Study is under way and has been funded through the year 2010. Outcomes ascertainment is the primary focus with no ongoing intervention, although the intervention group participants continue to receive a WHI newsletter that simply reiterates the importance of the study and encourages ongoing participation. As of 2006, an estimated 84% of the cohort, including both observational study and clinical trial participants, are involved. Efforts continue to recruit the remaining 16%, but many of these participants now consider themselves too old or too feeble to respond reliably.

In regard to breast cancer, the results published in 2006 are promising, albeit not statistically significant, and definitive statements cannot yet be made. However, postmenopausal women who are eating the diets highest in fat may have the greatest benefit from reductions in total fat.

Other considerations regarding the lack of statistically significant differences between groups may include the possibility that women in the intervention group may have been at lower risk for breast cancer at baseline. Likewise, although the results of the WHI dietary intervention do not include a statistically significant impact on colorectal cancer outcomes, the significant reduction in polyps and adenomas may later translate into a reduction in invasive cancer risk.

Finally, although no significant reduction was seen in the rate of death due to cardiovascular causes, greater reductions in saturated and trans-fatty acid intake were associated with greater reductions in blood cholesterol and cardiovascular risk.

Numerous subgroup analyses and ongoing assessments of the long-term impact of the diet modification are planned. Further associations are expected to emerge. The current and future results will continue to provide new insights that may lead to new clinical and public health recommendations in the future.

The WHI has raised additional issues that warrant further investigation:

• Will earlier dietary intervention, eg, during premenopausal years or even childhood, alter these results?
• Does the low-fat, high-carbohydrate diet used in WHI facilitate weight maintenance or even weight loss, as proposed by Howard et al²³?
• Do quantitative changes in physical activity and weight control attenuate morbidity and mortality rates beyond changes in diet alone?
• Do vitamin and mineral supplements or hormone therapy alter disease outcomes or quality of life?
• Which behavioral approaches are best suited to the recruitment of patients for dietary intervention trials?

More than 2 years have passed since we published the results of the Women’s Health Initiative (WHI), which caused a storm of information—and misinformation—about the effect of long-term dietary intervention on disease outcomes in postmenopausal women. Now that the dust has long settled, what have we learned from this landmark study?

The WHI results led to numerous additional analyses of all aspects of the study.^1–7 What are the implications of all the analyses to clinical practice?

In this article, we summarize key aspects of the clinical trial, including study design, interventions, main results, and future plans. We also discuss potential clinical applications and practical considerations for public health efforts.

WHO WAS ELIGIBLE, WHO WAS NOT

A total of 48,835 postmenopausal women were randomly assigned to either no dietary intervention (n = 29,294) or a dietary intervention (n = 19,541) (see below).⁷ Participants were followed at 40 clinical centers between 1993 and 2005.⁴ Their mean age was 62.3 years; 18.6% were members of minorities.

Women were eligible if they were post-menopausal and had a daily dietary fat intake of at least 32% of total calories, based on assessment via a food-frequency questionnaire. They were excluded from the study if they had any of the following: a history of breast cancer, colorectal cancer, or other cancer except skin cancer during the past 10 years; type 1 diabetes; a medical condition in which the predicted survival was less than 3 years; and a potential barrier to adherence to the study regimen, including alcoholism or a lifestyle that involved often eating meals away from home.

THE WHI DIET: LESS FAT, BUT MORE FRUITS, VEGETABLES, GRAINS

The WHI dietary intervention was designed to prevent breast cancer, based on the evidence available when the study was planned. The targets included a total fat intake of less than 20% of energy (in kilocalories), increasing the intake of fruits and vegetables to at least five servings per day, and increasing the intake of grains to at least six servings per day.

Although reduction in saturated fat intake per se was not part of the WHI protocol, we assumed from previous pilot studies⁸ that the reduction of total fat intake would simultaneously produce a reduction in saturated fat intake to 7% of total calories.

A simpler dietary intervention

Unlike the 2006 American Heart Association guidelines and the US Department of Agriculture’s Dietary Guidelines for Americans 2005, the WHI dietary intervention had no specifications for dietary fiber, specific fatty acids (trans-fatty acids, omega-3 fatty acids, conjugated linoleic acid), complex carbohydrates, whole grains, vegetable protein, or other factors that have emerged as potential risk factors for cardiovascular and other chronic diseases since the study began. The WHI intervention also included no specific recommendation for total calorie intake, nor were patients in the intervention group encouraged to lose weight, as this could have confounded the results of the dietary intervention.

Education and encouragement

Those in the intervention group were each assigned a fat-gram goal, calculated on the basis of height. They were taught how to monitor their intake of total fat, fruits, vegetables, and grains. They attended intensive behavioral modification sessions to encourage them to keep to the dietary program: 18 group sessions in the first year and quarterly maintenance sessions thereafter, touching on a wide variety of nutrition- and behavior-related topics.^7,9 Specially trained and certified nutritionists supervised the dietary intervention and the behavioral modification sessions according to the WHI study protocol.

Control-group participants received a copy of the US Department of Agriculture’s Dietary Guidelines for Americans¹⁰ and other health-related materials. They had no contact with the study nutritionists.

Other arms of the study

The WHI trial design included several arms,^4,11–13 and many participants joined more than one arm: 20,592 postmenopausal women (42.2% of the total enrollment) chose dietary modification only, 8,050 (16.5%) chose diet plus hormone replacement therapy, 25,210 (51.6%) chose diet plus calcium and vitamin D supplementation, and 5,017 (10.3%) enrolled in all three.

Length of follow-up

Participants were followed from enrollment until they died, were lost to follow-up, or requested no further contact, or until the trial’s planned completion date, regardless of adherence to the dietary intervention, according to intention-to-treat analysis. All participants were contacted by clinic staff at 6-month intervals to provide updates on their health outcomes.

Factors assessed

Height, weight, waist circumference, and blood pressure were measured at annual visits using standardized procedures. Fasting blood samples were collected at baseline and at year 1 from all participants and from a subsample of 2,816 women (5.8% of the study population) at years 3 and 6. This subsample was randomly chosen with oversampling of minority women, for whom the odds for selection were six times higher than for white women.

Physical activity was assessed at baseline and at years 1, 3, 6, and 9. Walking and participation in sports and hours of activity per week were calculated for each participant. Physical activity was expressed as metabolic equivalent tasks per week for the analyses.

A food-frequency questionnaire⁶ to assess average dietary intake in the past 3 months was given at baseline and at year 1 for all participants. A third of all participants completed the questionnaire each year in a rotating sample. Completion rates were 100% at baseline and 81% thereafter. Follow-up data were collected from years 5 through 7. Also, 4-day food records were provided by all women before randomization.

HOW OUTCOMES WERE ASSESSED

The primary assessments of clinical outcome^1–3 were mammographic screening, a self-reported medical history documented by a review of medical records, and electrocardiograms digitally obtained every 3 years. Mammograms and electrocardiograms were centrally adjudicated. The diagnosis of acute myocardial infarction was based on an algorithm that included cardiac pain, enzyme levels, and electrocardiographic readings.

OVERALL RESULTS

At 8.1 years, the incidence of breast cancer was 9% lower in the intervention group than in the comparison group (95% confidence interval [CI] = 0.83–1.01; P = .07, P = .09 weighted for length of follow-up).³ Subgroup analysis further showed that women who reported higher intakes of total dietary fat at baseline reduced their risk of breast cancer by 22% (95% CI = 0.64–0.96). Whether extended follow-up will show a significant association has yet to be determined.

Colon cancer rates did not differ between groups, but the number of polyps and adenomas reported was significantly lower in the dietary intervention group.¹ The rate of colon cancer will also be included in the extended follow-up study of the WHI.

Risk factors for coronary heart disease in both groups—including levels of serum total cholesterol and serum low-density lipoprotein cholesterol, body weight, body mass index, diastolic blood pressure, and factor VIIc—improved slightly, but at year 3 of the trial, differences in overall rates of coronary heart disease and stroke in the two groups were not statistically significant.² In addition, the low-fat diet intervention was associated with a reduction in blood estradiol concentrations between baseline and year 1.³ At the end of the study, however, differences in rates of breast cancer, colorectal cancer, and heart disease between the two groups were not statistically significant.

RESULTS OF DIETARY MODIFICATIONS

Fat as a percentage of total calories

RTEmagicC_VanHorn_LessonsFromWHIStudy_T1.gif.gif

At the beginning of the WHI, all participants reported consuming an average of 35% of their caloric intake from fat (Table 1). At 1 year from baseline, the fat intake decreased to 24.3% in the intervention group (short of the study goal of 20%); this level had risen again to 26.7% by year 3 and to 28.8% at the end of the study. Stratified by quartile, women who achieved the greatest reductions in saturated and trans-fatty acids or the largest increases in their intake of fruits and vegetables appeared to have a moderate reduction in the risk of coronary heart disease.² Women in the comparison group also decreased their fat intake initially, but to a lesser degree, and gradually increased it again thereafter. The mean net difference in self-reported total fat intake between the intervention group and the comparison group at 6 years was 8.2% (P < .001) (study goal, 13%).^1–3

Intake of fruits, vegetables, and grains

At baseline, fruit and vegetable intake averaged 3.6 servings per day (Table 1). In the intervention group, this increased to 5.1 servings per day at year 1, and to 5.2 servings at year 3, but at the end of the study it had decreased to 4.9 servings.

Women in the intervention group were eating 4.7 servings of grains per day at baseline. This increased to 5.1 servings at year 1 and then decreased to 4.6 servings at year 3 and to 4.3 servings at the end of the study. It seems that as the women grew older their determination to increase servings of these foods diminished.

Proponents of some currently popular diets blame weight gain on a higher intake of carbohydrates, but the women following the WHI low-fat diet did not gain weight.²

Total fat vs saturated fat

Intake of total fat and saturated fat decreased in the intervention group during the study, but the difference between fat intake in the intervention group and that in the comparison group did not reach the degree expected.

At year 1, total fat as a percentage of total caloric intake was 10.8 percentage points below that of the comparison group, whereas the study expected difference was 13.0. At the end of the trial, the difference was only 8.2 percentage points, whereas the expected difference was 11.0.

Intake of all fatty acids (saturated and unsaturated) decreased at year 1, but then went back up slightly by the end of the trial but did not exceed baseline levels, and saturated fatty acids remained well below baseline levels: 9.5% vs 12.5% of caloric intake at baseline.⁴

INTERPRETING THE RESULTS

It might be tempting to dismiss the results of the WHI dietary intervention trial as not significant and therefore not meaningful. This would be unfortunate. The trial had some remarkable accomplishments and offers important lessons for future investigations.

The initial reductions in total fat intake were impressive, and women who had the highest total fat intake at baseline achieved the greatest reduction of total fat (to less than 22% of total calories).³ Nonetheless, the dietary intervention goal of less than 20% of calories from fat was not achieved despite intensive dietary counseling and a highly motivated study population. Thus, this dietary fat target may not be reasonable in the general population.

Also, despite the absence of targeted intervention on specific fatty acids, the observed blood cholesterol levels were as expected based on the well-known formula of Mensink and Katan,¹⁴ which incorporates information on changes in saturated fat, polyunsaturated fat, and dietary cholesterol intake. The predicted reduction in low-density lipoprotein cholesterol was 2.7 mg/dL; the observed reduction was 2.3 mg/dL.² This illustrates that with greater modifications in specific known dietary risk factors for cardiovascular disease, such as saturated fatty acids, cholesterol, and unsaturated fatty acids, blood cholesterol levels respond in a predictable fashion. This was presumably not observed in WHI precisely because no goals and objectives were provided to participants for intake of saturated or polyunsaturated fatty acids.

Recent findings from the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart)¹⁵ further highlight differences in the total cholesterol response to diets of varying macronutrient (carbohydrate, protein, fat) content compared with the WHI dietary intervention.¹⁵ Participants in OmniHeart had reductions in levels of low-density lipoprotein cholesterol that were predictable from the changes reported in intake of saturated fatty acids. Presumably, the results of the WHI intervention would have been similar if the study had included this level of detail.

QUESTIONS REMAIN

Questions from the WHI that need consideration for future clinical applications include whether the study population may have already been “too old” to achieve a benefit from dietary modification, and whether the best timing for dietary intervention might be earlier adulthood with sustained changes in saturated fat, cholesterol, and unsaturated fat intake throughout life. Future subgroup analyses based on age at baseline will need to address these questions. Likewise, a longer follow-up period may be needed for a definitive evaluation of the impact of a regular low-fat diet on different health outcomes.

As reported by Patterson et al,¹⁶ the major contributors to total dietary fat intake at baseline were “added fats” such as sauces, gravies, butter, and margarines (25.1% of fat intake), followed by meats (20.9% of fat intake), and desserts (12.8% of fat intake). These findings highlight target areas for future interventions in women of this age group.

Another issue is how to standardize the dietary intervention from one clinical center to another—ie, to minimize differences in how each clinical center manages the study patients. Such differences were noted in WHI and other studies.¹⁷ Despite standardized training in delivering the dietary intervention, nutritionists encountered regional and cultural differences that required tailoring the dietary intervention to their patients’ needs. Staff turnover, an unavoidable phenomenon in long-term studies, has previously been reported to negatively influence dietary adherence.¹⁸

LIMITATIONS

A major limitation of diet modification research in general is the self-reporting of dietary intake, primarily by a food-frequency questionnaire. Although the use of a questionnaire is the most practical way to obtain dietary data for large studies, systematic biases may exist that obscure true nutrient-outcome relationships.¹⁹ Biomarker studies of energy balance suggest that people who are overweight or obese may under-report energy intake to a greater degree than people who are not overweight.²⁰ Also, we still do not know how to get people to follow a healthy diet, although theories and models abound, such as social learning and cognitive-behavioral theory, and a lack of data limits our understanding of factors related to dietary adherence.^21,22

FUTURE DIRECTIONS IN WHI

The WHI Extension Study is under way and has been funded through the year 2010. Outcomes ascertainment is the primary focus with no ongoing intervention, although the intervention group participants continue to receive a WHI newsletter that simply reiterates the importance of the study and encourages ongoing participation. As of 2006, an estimated 84% of the cohort, including both observational study and clinical trial participants, are involved. Efforts continue to recruit the remaining 16%, but many of these participants now consider themselves too old or too feeble to respond reliably.

In regard to breast cancer, the results published in 2006 are promising, albeit not statistically significant, and definitive statements cannot yet be made. However, postmenopausal women who are eating the diets highest in fat may have the greatest benefit from reductions in total fat.

Other considerations regarding the lack of statistically significant differences between groups may include the possibility that women in the intervention group may have been at lower risk for breast cancer at baseline. Likewise, although the results of the WHI dietary intervention do not include a statistically significant impact on colorectal cancer outcomes, the significant reduction in polyps and adenomas may later translate into a reduction in invasive cancer risk.

Finally, although no significant reduction was seen in the rate of death due to cardiovascular causes, greater reductions in saturated and trans-fatty acid intake were associated with greater reductions in blood cholesterol and cardiovascular risk.

Numerous subgroup analyses and ongoing assessments of the long-term impact of the diet modification are planned. Further associations are expected to emerge. The current and future results will continue to provide new insights that may lead to new clinical and public health recommendations in the future.

The WHI has raised additional issues that warrant further investigation:

• Will earlier dietary intervention, eg, during premenopausal years or even childhood, alter these results?
• Does the low-fat, high-carbohydrate diet used in WHI facilitate weight maintenance or even weight loss, as proposed by Howard et al²³?
• Do quantitative changes in physical activity and weight control attenuate morbidity and mortality rates beyond changes in diet alone?
• Do vitamin and mineral supplements or hormone therapy alter disease outcomes or quality of life?
• Which behavioral approaches are best suited to the recruitment of patients for dietary intervention trials?

More than 2 years have passed since we published the results of the Women’s Health Initiative (WHI), which caused a storm of information—and misinformation—about the effect of long-term dietary intervention on disease outcomes in postmenopausal women. Now that the dust has long settled, what have we learned from this landmark study?

The WHI results led to numerous additional analyses of all aspects of the study.^1–7 What are the implications of all the analyses to clinical practice?

In this article, we summarize key aspects of the clinical trial, including study design, interventions, main results, and future plans. We also discuss potential clinical applications and practical considerations for public health efforts.

WHO WAS ELIGIBLE, WHO WAS NOT

A total of 48,835 postmenopausal women were randomly assigned to either no dietary intervention (n = 29,294) or a dietary intervention (n = 19,541) (see below).⁷ Participants were followed at 40 clinical centers between 1993 and 2005.⁴ Their mean age was 62.3 years; 18.6% were members of minorities.

Women were eligible if they were post-menopausal and had a daily dietary fat intake of at least 32% of total calories, based on assessment via a food-frequency questionnaire. They were excluded from the study if they had any of the following: a history of breast cancer, colorectal cancer, or other cancer except skin cancer during the past 10 years; type 1 diabetes; a medical condition in which the predicted survival was less than 3 years; and a potential barrier to adherence to the study regimen, including alcoholism or a lifestyle that involved often eating meals away from home.

THE WHI DIET: LESS FAT, BUT MORE FRUITS, VEGETABLES, GRAINS

The WHI dietary intervention was designed to prevent breast cancer, based on the evidence available when the study was planned. The targets included a total fat intake of less than 20% of energy (in kilocalories), increasing the intake of fruits and vegetables to at least five servings per day, and increasing the intake of grains to at least six servings per day.

Although reduction in saturated fat intake per se was not part of the WHI protocol, we assumed from previous pilot studies⁸ that the reduction of total fat intake would simultaneously produce a reduction in saturated fat intake to 7% of total calories.

A simpler dietary intervention

Unlike the 2006 American Heart Association guidelines and the US Department of Agriculture’s Dietary Guidelines for Americans 2005, the WHI dietary intervention had no specifications for dietary fiber, specific fatty acids (trans-fatty acids, omega-3 fatty acids, conjugated linoleic acid), complex carbohydrates, whole grains, vegetable protein, or other factors that have emerged as potential risk factors for cardiovascular and other chronic diseases since the study began. The WHI intervention also included no specific recommendation for total calorie intake, nor were patients in the intervention group encouraged to lose weight, as this could have confounded the results of the dietary intervention.

Education and encouragement

Those in the intervention group were each assigned a fat-gram goal, calculated on the basis of height. They were taught how to monitor their intake of total fat, fruits, vegetables, and grains. They attended intensive behavioral modification sessions to encourage them to keep to the dietary program: 18 group sessions in the first year and quarterly maintenance sessions thereafter, touching on a wide variety of nutrition- and behavior-related topics.^7,9 Specially trained and certified nutritionists supervised the dietary intervention and the behavioral modification sessions according to the WHI study protocol.

Control-group participants received a copy of the US Department of Agriculture’s Dietary Guidelines for Americans¹⁰ and other health-related materials. They had no contact with the study nutritionists.

Other arms of the study

The WHI trial design included several arms,^4,11–13 and many participants joined more than one arm: 20,592 postmenopausal women (42.2% of the total enrollment) chose dietary modification only, 8,050 (16.5%) chose diet plus hormone replacement therapy, 25,210 (51.6%) chose diet plus calcium and vitamin D supplementation, and 5,017 (10.3%) enrolled in all three.

Length of follow-up

Participants were followed from enrollment until they died, were lost to follow-up, or requested no further contact, or until the trial’s planned completion date, regardless of adherence to the dietary intervention, according to intention-to-treat analysis. All participants were contacted by clinic staff at 6-month intervals to provide updates on their health outcomes.

Factors assessed

Height, weight, waist circumference, and blood pressure were measured at annual visits using standardized procedures. Fasting blood samples were collected at baseline and at year 1 from all participants and from a subsample of 2,816 women (5.8% of the study population) at years 3 and 6. This subsample was randomly chosen with oversampling of minority women, for whom the odds for selection were six times higher than for white women.

Physical activity was assessed at baseline and at years 1, 3, 6, and 9. Walking and participation in sports and hours of activity per week were calculated for each participant. Physical activity was expressed as metabolic equivalent tasks per week for the analyses.

A food-frequency questionnaire⁶ to assess average dietary intake in the past 3 months was given at baseline and at year 1 for all participants. A third of all participants completed the questionnaire each year in a rotating sample. Completion rates were 100% at baseline and 81% thereafter. Follow-up data were collected from years 5 through 7. Also, 4-day food records were provided by all women before randomization.

HOW OUTCOMES WERE ASSESSED

The primary assessments of clinical outcome^1–3 were mammographic screening, a self-reported medical history documented by a review of medical records, and electrocardiograms digitally obtained every 3 years. Mammograms and electrocardiograms were centrally adjudicated. The diagnosis of acute myocardial infarction was based on an algorithm that included cardiac pain, enzyme levels, and electrocardiographic readings.

OVERALL RESULTS

At 8.1 years, the incidence of breast cancer was 9% lower in the intervention group than in the comparison group (95% confidence interval [CI] = 0.83–1.01; P = .07, P = .09 weighted for length of follow-up).³ Subgroup analysis further showed that women who reported higher intakes of total dietary fat at baseline reduced their risk of breast cancer by 22% (95% CI = 0.64–0.96). Whether extended follow-up will show a significant association has yet to be determined.

Colon cancer rates did not differ between groups, but the number of polyps and adenomas reported was significantly lower in the dietary intervention group.¹ The rate of colon cancer will also be included in the extended follow-up study of the WHI.

Risk factors for coronary heart disease in both groups—including levels of serum total cholesterol and serum low-density lipoprotein cholesterol, body weight, body mass index, diastolic blood pressure, and factor VIIc—improved slightly, but at year 3 of the trial, differences in overall rates of coronary heart disease and stroke in the two groups were not statistically significant.² In addition, the low-fat diet intervention was associated with a reduction in blood estradiol concentrations between baseline and year 1.³ At the end of the study, however, differences in rates of breast cancer, colorectal cancer, and heart disease between the two groups were not statistically significant.

RESULTS OF DIETARY MODIFICATIONS

Fat as a percentage of total calories

RTEmagicC_VanHorn_LessonsFromWHIStudy_T1.gif.gif

At the beginning of the WHI, all participants reported consuming an average of 35% of their caloric intake from fat (Table 1). At 1 year from baseline, the fat intake decreased to 24.3% in the intervention group (short of the study goal of 20%); this level had risen again to 26.7% by year 3 and to 28.8% at the end of the study. Stratified by quartile, women who achieved the greatest reductions in saturated and trans-fatty acids or the largest increases in their intake of fruits and vegetables appeared to have a moderate reduction in the risk of coronary heart disease.² Women in the comparison group also decreased their fat intake initially, but to a lesser degree, and gradually increased it again thereafter. The mean net difference in self-reported total fat intake between the intervention group and the comparison group at 6 years was 8.2% (P < .001) (study goal, 13%).^1–3

Intake of fruits, vegetables, and grains

At baseline, fruit and vegetable intake averaged 3.6 servings per day (Table 1). In the intervention group, this increased to 5.1 servings per day at year 1, and to 5.2 servings at year 3, but at the end of the study it had decreased to 4.9 servings.

Women in the intervention group were eating 4.7 servings of grains per day at baseline. This increased to 5.1 servings at year 1 and then decreased to 4.6 servings at year 3 and to 4.3 servings at the end of the study. It seems that as the women grew older their determination to increase servings of these foods diminished.

Proponents of some currently popular diets blame weight gain on a higher intake of carbohydrates, but the women following the WHI low-fat diet did not gain weight.²

Total fat vs saturated fat

Intake of total fat and saturated fat decreased in the intervention group during the study, but the difference between fat intake in the intervention group and that in the comparison group did not reach the degree expected.

At year 1, total fat as a percentage of total caloric intake was 10.8 percentage points below that of the comparison group, whereas the study expected difference was 13.0. At the end of the trial, the difference was only 8.2 percentage points, whereas the expected difference was 11.0.

Intake of all fatty acids (saturated and unsaturated) decreased at year 1, but then went back up slightly by the end of the trial but did not exceed baseline levels, and saturated fatty acids remained well below baseline levels: 9.5% vs 12.5% of caloric intake at baseline.⁴

INTERPRETING THE RESULTS

It might be tempting to dismiss the results of the WHI dietary intervention trial as not significant and therefore not meaningful. This would be unfortunate. The trial had some remarkable accomplishments and offers important lessons for future investigations.

The initial reductions in total fat intake were impressive, and women who had the highest total fat intake at baseline achieved the greatest reduction of total fat (to less than 22% of total calories).³ Nonetheless, the dietary intervention goal of less than 20% of calories from fat was not achieved despite intensive dietary counseling and a highly motivated study population. Thus, this dietary fat target may not be reasonable in the general population.

Also, despite the absence of targeted intervention on specific fatty acids, the observed blood cholesterol levels were as expected based on the well-known formula of Mensink and Katan,¹⁴ which incorporates information on changes in saturated fat, polyunsaturated fat, and dietary cholesterol intake. The predicted reduction in low-density lipoprotein cholesterol was 2.7 mg/dL; the observed reduction was 2.3 mg/dL.² This illustrates that with greater modifications in specific known dietary risk factors for cardiovascular disease, such as saturated fatty acids, cholesterol, and unsaturated fatty acids, blood cholesterol levels respond in a predictable fashion. This was presumably not observed in WHI precisely because no goals and objectives were provided to participants for intake of saturated or polyunsaturated fatty acids.

Recent findings from the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart)¹⁵ further highlight differences in the total cholesterol response to diets of varying macronutrient (carbohydrate, protein, fat) content compared with the WHI dietary intervention.¹⁵ Participants in OmniHeart had reductions in levels of low-density lipoprotein cholesterol that were predictable from the changes reported in intake of saturated fatty acids. Presumably, the results of the WHI intervention would have been similar if the study had included this level of detail.

QUESTIONS REMAIN

Questions from the WHI that need consideration for future clinical applications include whether the study population may have already been “too old” to achieve a benefit from dietary modification, and whether the best timing for dietary intervention might be earlier adulthood with sustained changes in saturated fat, cholesterol, and unsaturated fat intake throughout life. Future subgroup analyses based on age at baseline will need to address these questions. Likewise, a longer follow-up period may be needed for a definitive evaluation of the impact of a regular low-fat diet on different health outcomes.

As reported by Patterson et al,¹⁶ the major contributors to total dietary fat intake at baseline were “added fats” such as sauces, gravies, butter, and margarines (25.1% of fat intake), followed by meats (20.9% of fat intake), and desserts (12.8% of fat intake). These findings highlight target areas for future interventions in women of this age group.

Another issue is how to standardize the dietary intervention from one clinical center to another—ie, to minimize differences in how each clinical center manages the study patients. Such differences were noted in WHI and other studies.¹⁷ Despite standardized training in delivering the dietary intervention, nutritionists encountered regional and cultural differences that required tailoring the dietary intervention to their patients’ needs. Staff turnover, an unavoidable phenomenon in long-term studies, has previously been reported to negatively influence dietary adherence.¹⁸

LIMITATIONS

A major limitation of diet modification research in general is the self-reporting of dietary intake, primarily by a food-frequency questionnaire. Although the use of a questionnaire is the most practical way to obtain dietary data for large studies, systematic biases may exist that obscure true nutrient-outcome relationships.¹⁹ Biomarker studies of energy balance suggest that people who are overweight or obese may under-report energy intake to a greater degree than people who are not overweight.²⁰ Also, we still do not know how to get people to follow a healthy diet, although theories and models abound, such as social learning and cognitive-behavioral theory, and a lack of data limits our understanding of factors related to dietary adherence.^21,22

FUTURE DIRECTIONS IN WHI

The WHI Extension Study is under way and has been funded through the year 2010. Outcomes ascertainment is the primary focus with no ongoing intervention, although the intervention group participants continue to receive a WHI newsletter that simply reiterates the importance of the study and encourages ongoing participation. As of 2006, an estimated 84% of the cohort, including both observational study and clinical trial participants, are involved. Efforts continue to recruit the remaining 16%, but many of these participants now consider themselves too old or too feeble to respond reliably.

In regard to breast cancer, the results published in 2006 are promising, albeit not statistically significant, and definitive statements cannot yet be made. However, postmenopausal women who are eating the diets highest in fat may have the greatest benefit from reductions in total fat.

Other considerations regarding the lack of statistically significant differences between groups may include the possibility that women in the intervention group may have been at lower risk for breast cancer at baseline. Likewise, although the results of the WHI dietary intervention do not include a statistically significant impact on colorectal cancer outcomes, the significant reduction in polyps and adenomas may later translate into a reduction in invasive cancer risk.

Finally, although no significant reduction was seen in the rate of death due to cardiovascular causes, greater reductions in saturated and trans-fatty acid intake were associated with greater reductions in blood cholesterol and cardiovascular risk.

Numerous subgroup analyses and ongoing assessments of the long-term impact of the diet modification are planned. Further associations are expected to emerge. The current and future results will continue to provide new insights that may lead to new clinical and public health recommendations in the future.

The WHI has raised additional issues that warrant further investigation:

• Will earlier dietary intervention, eg, during premenopausal years or even childhood, alter these results?
• Does the low-fat, high-carbohydrate diet used in WHI facilitate weight maintenance or even weight loss, as proposed by Howard et al²³?
• Do quantitative changes in physical activity and weight control attenuate morbidity and mortality rates beyond changes in diet alone?
• Do vitamin and mineral supplements or hormone therapy alter disease outcomes or quality of life?
• Which behavioral approaches are best suited to the recruitment of patients for dietary intervention trials?