July 28th, 2014
No Reduction in Atherosclerosis Progression With Menopausal Hormone Therapy
Larry Husten, PHD
More than a decade ago the Women’s Health Study produced surprising and important results when it showed that broad use of hormone replacement therapy did not reduce cardiovascular risk in postmenopausal women. However, the study also led to speculation that hormone therapy might be beneficial when delivered closer to the time of menopause. Now a study published in Annals of Internal Medicine shows that menopausal hormone therapy (MHT) may have some favorable effects on some cardiovascular risk factors but it does not reduce the progression of atherosclerosis.
In the study, called KEEPS (Kronos Early Estrogen Prevention Study), 727 menopausal women were randomized to placebo or one of two forms of low-dose MHT (oral conjugated equine estrogens or transdermal 17β- estradiol). After four years there was no difference between the groups in the primary endpoint of the study, which was the progression of atherosclerosis as measured by carotid artery intima–media thickness (CIMT). There was also no difference in the coronary artery calcium scores. Women in the equine estrogen group had improvements in their lipid profiles (decrease in LDL and increase in HDL) while women in the transdermal group had improved insulin sensitivity. There was no difference in the incidence of serious adverse events.
The investigators offered several explanations for the findings, including a study population at low risk for athersosclerosis, a relatively short study duration, and the use of low-dose but not high-dose estrogen. “To the extent that these imaging methods predict CVD events, our findings suggest that MHT neither is a risk nor is protective in the population studied,” they wrote. The study was not powered to look at clinical events.
Andrew Kaunitz, a specialist in women’s health and menopause at the University of Florida, said that although it still remains unclear what the long-term effects of MHT will be on cardiovascular events, the study “does not support using hormone therapy to prevent CVD events.”
One Response to “No Reduction in Atherosclerosis Progression With Menopausal Hormone Therapy”
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Before we jump to conclusions, we need to look at these endpoints. We seem to keep using serial CIMT as a surrogate endpoint despite the dearth of evidence correlating serial CIMT with hard cardiovascular events. The initial CIMT has an incremental predictive value as demonstrated in a Framingham offspring study while MESA demonstrated that the baseline CIMT predicted cardiovascular risk about twice as powerfully as combined conventional risk factors. Although it seems logical that serial CIMT should predict incremental risk, the data does not support that conclusion.
Costanzo (Federico II University, Naples, Italy)et. al. November 29, 2010 Journal of the American College of Cardiology did a meta analysis of over 18,000 subjects and found that while the interventions studied provided improvement in coronary events and survival, there was no change in the CIMT with each intervention as compared to placebo. There was a small correlation between serial CIMT change and coronary events among those who had a small initial CIMT and were not on statin therapy. However among those on statin therapy, there was no correlation between CIMT change and coronary events. In addition, those with higher baseline CIMT demonstrated no correlation between progression and coronary events whether or not statins were used.
I have not reviewed this article yet however I cannot tell from Larry’s notes above if they looked at serial Calcium scores or just any significant difference in a static calcium score after 4 years of therapy v placebo.
If they are looking at differences in Calcium scores, it is important that they used the correct technology. If using EBT or 256 slice dual source technology, the comparisons can be made after 12 months. If 64 slice or lower technology was used, the comparisons cannot be made sooner than 36 months without having the scan to scan variability blunt any meaningful calcium change.
If they are only looking at one calcium score, this result is meaningless as related to therapy.
And finally they stated that there was no significant difference in serious adverse events. With a study this small, I cannot imagine a circumstance where a difference in serious adverse events could ever reach statistical significance. Jupiter barely demonstrated significance with a direct comparison of one intervention vs placebo in a study of 17,800. Here we have a 3 way study with placebo and two study options with a cohort of 727 subjects of uncertain pretreatment cardiovascular risk.
In conclusion, while this is interesting reading, as a study, these results truly mean nothing.