10 November, 2014

One of the main arguments against extrapolation of the Women's Health Initiative (WHI) study data to the whole postmenopausal population was that it actually focused on the 60+ year-old women who were treatment-naïve until then [1], whereas in real life most hormone users are 45–55 years old at initiation of therapy. The Kronos Early Estrogen Prevention Study (KEEPS) was designed to provide information on the effects of hormone therapy (HT) in recently menopausal women. Results from KEEPS are now published in the literature [2]. The main aim of KEEPS was to assess atherosclerosis progression and cardiovascular risk factors after HT initiation. The study enrolled 727 healthy menopausal women aged 42–58 years (mean 52.7 years), between 6 and 36 months from last menses, without prior cardiovascular disease events, who had a coronary artery calcium (CAC) score less than 50 Agatston units and had not received estrogen or lipid-lowering therapy for at least 90 days. Study medications included oral conjugated equine estrogens (o-CEE), 0.45 mg/day, or transdermal 17β-estradiol (t-E2), 50 μg/day, each with 200 mg of oral progesterone for 12 days per month, or placebo for 48 months.

The primary endpoint was annual change in carotid artery intima-media thickness (CIMT). Secondary endpoints included changes in markers of cardiovascular disease risk. Of 727 randomly assigned women, 89.3% had at least one follow-up CIMT and 79.8% had CIMT at 48 months. Mean CIMT increases of 0.007 mm/year were similar across groups. The percentages of participants in whom the CAC score increased did not differ significantly across groups. No changes in blood pressure were observed with o-CEE or t-E2. Low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol levels improved and levels of C-reactive protein and sex hormone binding globulin but not interleukin-6 increased with o-CEE. Insulin resistance decreased with t-E2. Serious adverse events did not differ by treatment. Power to compare clinical events was insufficient. Thus 4 years of early HT did not affect progression of atherosclerosis despite improving some markers of cardiovascular disease risk.

Comment

Comment from Amos Pines

KEEPS was the first randomized, double-blind, placebo-controlled study which investigated the cardiovascular protective effects of HT in the early postmenopause [2]. Except for the age factor, KEEPS was also looking at differences between the oral and the transdermal routes of hormone therapy, and the dosage used by women was lower than the standard dose used in the WHI. Because of the young age of the cohort, and very low incidence of cardiovascular events expected, KEEPS investigators looked at CIMT and CAC as non-invasive parameters of coronary atherosclerosis. The value of these tests as predictors of cardiovascular disease has been well established [3]. At first glance, the KEEPS results were frustrating, since many expected to see clear cardioprotective outcomes in the hormone users, which was apparently not the case. However, despite the relatively small sample size (around 200+ women in each of the study arms), and lack of power to compare clinical events, KEEPS is a solid proof that HT in recently menopausal women is not associated with serious adverse events during the first 4 years of use. Women and health-care providers needed this reassuring data to rebuild confidence in the safety of HT, which was much damaged by the mis-interpretation and extrapolation of WHI results to the young, healthy peri- and postmenopausal population. Unlike the WHI patient characteristics, which indicated that many might already have occult coronary artery disease [1], the KEEPS cohort was selected to include only those with insignificant basal CAC and CIMT values, and no history of clinical cardiovascular events or use of lipid-lowering drugs [2]. Also, mean blood pressure and cholesterol levels were within normal limits, and almost all were not current smokers. The KEEPS results are therefore not a surprise, as they reflect the expected almost nil progression of atherosclerosis during 4 years of follow-up in healthy, recently menopausal women having no atherosclerotic burden at baseline.

Previous randomized trials which demonstrated favorable outcomes in hormone users actually had entirely different cohorts: the EPAT study [4] included healthy women at a mean age of 62 years, with a mean LDL cholesterol level of 4.2 mmol/l, and basal CIMTs of 0.776 mm and 0.752 mm (placebo and hormone groups, respectively). EPAT allowed lipid-lowering therapy, which was taken by 61% of participants. The hormone used in EPAT was micronized estradiol at 1 mg/day, as an unopposed therapy and study duration was 2 years. In women who did not receive lipid-lowering medication, CIMT changed by 0.0134 mm/year in placebo recipients and by 0.0013 mm/year in estradiol recipients (p = 0.002). There was no additional effect of HT in those who used statins as well. In the earlier ACAPS study [5], patients were randomized to placebo or statin, and about one-third of them were taking HT. In the placebo group, CIMT tended to progress among HT non-users but to regress among HT users: the mean covariate-adjusted progression rates were 0.015 mm/year versus –0.012 mm/year, respectively (p = 0.05). As already mentioned above, the reciprocal parameters at KEEPS were mean age 53 years, mean LDL cholesterol 2.4 mmol/l and mean basal CIMT score of 0.720 mm. The hormonal preparations were either oral CEE or transdermal estradiol, combined with oral progesterone for 12 days per month. The estimated changes in CIMT were in the range of 0.007–0.008 mm/year in all study groups.

It seems therefore that estrogen may have an impact on progression of coronary atherosclerosis only when there is already some existing arterial plaque formation. Perhaps the WHI CACS study [6] provides a good support for this assumption. WHI CACS included hysterectomized women below age 60 who were assigned to the WHI estrogen-alone trial, thus receiving either CEE at 0.625 mg/day or placebo for about 7 years. Those women underwent CAC measurements some time after study completion, namely some 8–9 years post-randomization. The mean CAC score after trial completion was lower among women receiving estrogen (83.1 Agatston units) than among those receiving placebo (123.1 Agatston units) (p = 0.02 by rank test). This beneficial effect was more prominent in adherent women. Also, a stepwise better consequence of estrogen therapy was detected when Agatston score categories (0, 10 or more, 100 or more, 300 or more units) were compared: the percentage of estrogen users among the total number at a certain category was gradually smaller as Agatson scores ranged higher.

Comment from Fred Naftolin

The lesson is clear: healthy early menopausal women, defined by several indices including lack of smoking, hypertension, elevated lipids, obesity, diabetes/metabolic syndrome, absence of atherosclerosis levels of calcified plaque and greater than normal CIMT, showed typical improvements of menopausal symptoms, atherosclerosis risk factors, bone health, etc. after using constant low-dose cyclic CEE + cyclic oral progesterone treatment over 4 years [2]. There was no excess of cases of venous thromboembolism. There were differences between oral and transdermal treatment but, as with all randomized, controlled trials, these cannot be generalized to other populations or HT regimens.

There was not confirmation of previous results showing that HT users have less calcified plaque and narrower CIMT [7]. However, the risk factors for atherosclerosis improved, so the lack of an apparent effect on the atherosclerosis-surrogate imaging tests remains unexplained.

KEEPS is important because it refutes many of the allegations of null or ill effects made by first-pass interpretations of the WHI hormone treatment groups [8]. It has played an important role in re-establishing the appropriateness and safety of properly administered HT. Hopefully, the results from KEEPS will drive further research into the many salutary effects of menopausal hormone therapy, including cardioprotection.

Comment from JoAnn E. Manson

KEEPS was a very small randomized trial (727 participants in total) and was not powered to look at clinical events (only a handful of clinical outcomes such as myocardial infarctions, strokes, breast cancers, etc.). The goal of KEEPS was to look at surrogate imaging markers of atherosclerosis progression. Even for these, its power was limited (especially for progression of CAC) [2].

I do not think we can say with confidence that KEEPS proves that HT is safe or unsafe – it really wasn't powered to look at the question of safety, which requires power to look at clinical events. Consider the difference in the size of KEEPS and WHI, even for younger women. WHI (the two trials combined) had 30 times as many participants as KEEPS and, even among women below age 60, had ~8 times as many participants.

In the WHI CEE-alone trial, a reduction in myocardial infarction and in CAC score was demonstrated with CEE-alone in the women aged 50–59 years. In the WHI CEE + medroxyprogesterone acetate (MPA) trial, women < 10 years since menopause had no increase in myocardial infarction or coronary heart disease events, while women > 10 years past menopause had elevated risk with CEE+MPA. In addition, absolute risks of adverse events on HT were much lower in the younger women in the WHI.

Thus, WHI showed clearly that women < 10 years since the onset of menopause and/or ages 50–59 had much lower risks from HT than older women – and with CEE-alone, showed evidence for reduced risk of coronary heart disease/myocardial infarction and level of CAC compared to placebo.

Comment from Roger Lobo

KEEPS provided a unique opportunity for a group of investigators to come together in an effort to determine the effects of different preparations of estrogen on coronary health in recently menopausal women, at a time when all clinical research in postmenopausal women had essentially stopped in the aftermath of the WHI.

We hoped to show a benefit of estrogen, compared to placebo, in intermediate markers of coronary atherosclerosis, as was suggested by other data such as EPAT and subgroup analyses from the WHI. In this regard, our findings were a disappointment. It is likely that, because our participants were very healthy women, our study was underpowered to show any differences over the short duration of intervention. It was never the intent of KEEPS to assess risks associated with therapy.

Nevertheless, we have 3 years of prospective data using two different preparations and routes of administration on many different outcomes. While the beneficial effects of estrogen on various symptoms of menopause are well known, there are no long-term data comparing oral and transdermal estrogen. We hope, and anticipate, that KEEPS will be able to provide important new information on various symptoms, as well as metabolic and other endpoints.

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
and
Fred Naftolin
Professor of Obstetrics and Gynecology, and Environmental Medicine, Director, Reproductive Biology Research, Co-Director, NYU Interdisciplinary Program in Menopause Medicine, New York University, New York, USA
and
JoAnn E. Manson
Chief, Division of Preventive Medicine, Brigham and Women's Hospital, Professor of Medicine and the Michael and Lee Bell Professor of Women's Health, Harvard Medical School, Boston, Massachusetts, USA
and
Roger Lobo
Department of Obstetrics & Gynecology, Columbia University, New York, New York, USA

References

1. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-33.
http://www.ncbi.nlm.nih.gov/pubmed/12117397

2. Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med 2014 Jul 29. Epub ahead of print.
http://www.ncbi.nlm.nih.gov/pubmed/25069991

3. Folsom AR, Kronmal RA, Detrano RC, et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern Med 2008;168:1333-9.
http://www.ncbi.nlm.nih.gov/pubmed/18574091

4. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939-53.
http://www.ncbi.nlm.nih.gov/pubmed/11730394

5. Espeland MA, Applegate W, Furberg CD, Lefkowitz D, Rice L, Hunninghake D. Estrogen replacement therapy and progression of intimal-medial thickness in the carotid arteries of postmenopausal women. ACAPS Investigators. Asymptomatic Carotid Atherosclerosis Progression Study. Am J Epidemiol 1995;142:1011-19.
http://www.ncbi.nlm.nih.gov/pubmed/7485045

6. Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med 2007;356:2591-602.
http://www.ncbi.nlm.nih.gov/pubmed/17582069

7. Ge Q, Tian Q, Tseng H, Naftolin F. Development of low-dose reproductive hormone therapies in China. Gynecol Endocrinol 2006;22:636-45
http://www.ncbi.nlm.nih.gov/pubmed/17145650

8. Tan O, Harman SM, Naftolin F. What can we learn from design faults in the Women's Health Initiative randomized clinical trial? Bull NYU Hosp Jt Dis 2009;67:226-9
http://www.ncbi.nlm.nih.gov/pubmed/19583558

Content updated 10 November 2014