More Good News from the WHI

Abstract & Commentary

By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: Women age 50-59 treated with estrogen in the WHI had less atherosclerosis.

Source: Manson JE, et al. Estrogen therapy and coronary-artery calcification. New Engl J Med. 2007;356:2591-2602.

The Women's Health Initiative (WHI) Coronary-Artery Calcium Study (WHI-CACS) was an ancillary study of estrogen-only participants in 28 of the 40 WHI centers.1 A total of 1064 women out of the 1742 eligible participants underwent computed tomography (CT) examinations of the heart, on average 1.3 years after the conclusion of the trial, which occurred after a mean 7.4 years of treatment. Coronary-artery calcium scores were measured at a blinded, central reading center (Wake Forest University School of Medicine). Calcification in the coronary arteries is located in atheromas and is correlated with the degree of atherosclerosis. The treatment group (0.625 mg conjugated estrogens daily) and the placebo group did not differ in baseline characteristics, including cardiac risk and lifestyle factors. The average calcium score in the treated women was 83.1, compared with 123.1 in the placebo group. All analyses indicated significant differences, including adjustments for age, race, and ethnic group. The difference was greater in the women adherent to treatment for at least 5 years. The odds ratio for extensive coronary-artery calcification was 61% reduced in the adherent group. The authors concluded that women 50 to 59 years old receiving estrogen had a lower prevalence of subclinical coronary artery disease.

Commentary

This report on coronary-artery calcium levels in the estrogen-only arm of the WHI confirms previous observational studies.2, 3 The argument that hormone therapy benefits the heart in younger postmenopausal women is further strengthened, an argument that is consistently supported by more than 20 years of basic and animal research, plus many observational studies. It is increasingly clear that once the blood vessels are involved with atherosclerosis, the ability to respond favorably to estrogen is progressively lost, until a state is reached when exposure to estrogen is associated with thrombosis originating in unstable atheromatous plaques. Kudos to Tom Clarkson for leading the way in clarifying this bivalent response with his hormone trials in monkeys.4

This evidence is unequivocal and very robust. Now it is time to resurrect the contention that estrogen therapy can provide primary prevention of coronary heart disease, at least when administered to younger postmenopausal women. This possible benefit of estrogen was diminished with the popularity and promotion of statin treatment. However, estrogen may have a very important advantage over statins. Studies have failed to document a slowing of coronary artery calcium progression with statin treatment.5, 6 This is a striking difference, although the statin studies were limited by a treatment duration of only one year. The possibility that estrogen has a greater impact on calcification in atheromas deserves further study; is it possible that estrogen therapy would be even more efficacious in preventing coronary disease?

For now, patients deserve to know that women under the age of 60 receiving estrogen therapy have less atherosclerosis, fewer cardiac events, a reduction in new diabetes, fewer fractures, and even fewer strokes.7-9 The risk of venous thrombosis is lower and clinical events are rare in women under age 60.10

An important question remains: is there a meaningful clinical difference comparing estrogen-only therapy to treatment with estrogen-progestin combinations? I want to emphasize once again that it is not appropriate to compare the two cancelled arms of the WHI and make conclusions regarding the addition of progestin exposure. To do so requires that the participants in the two arms are identical, or near-identical, and they are not even close.11 Some indication may arise in the on-going primary prevention trials using measurement of carotid intima media thickness as a marker. Keep in mind that in Clarkson's monkey model that thus far has yielded information that agrees with human data, the effects on atherosclerosis of estrogen alone and estrogen combined with progestin were similar.12

Finally, the story is becoming clear, and it is time to repair the damages done by the WHI.

References

  1. Manson JE, et al. Estrogen therapy and coronary-artery calcification. New Engl J Med. 2007;356:2591-2602.
  2. Akhrass F, et al. Hormone replacement therapy is associated with less coronary atherosclerosis in postmenopausal women. J Clin Endocrinol Metab. 2003;88:5611-5614.
  3. Budoff MJ, et al. Effects of hormone replacement on progression of coronary calcium as measured by electron beam tomography. J Womens Health. (Larchmt) 2005;14:410-417.
  4. Clarkson TB. Estrogen effects on arteries vary with stage of reproductive life and extent of subclinical atherosclerosis progression. Menopause. 2007;14:373-384.
  5. Raggi P, et al. Aggressive versus moderate lipid-lowering therapy in hypercholesterolemic postmenopausal women: Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES). Circulation. 2005;112:563-571.
  6. Schermund A, et al. Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months: a multicenter, randomized, double-blind trial. Circulation. 2006;113:427-437.
  7. Anderson GL, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's health Initiative randomized controlled trial. JAMA. 2004;291:1701-1712.
  8. Bonds DE, et al. The effect on conjugated equine oestrogen on diabetes incidence: the Women's Health Initiative randomised trial. Diabetologia. 2006;49:459-468.
  9. Rossouw JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465-1477.
  10. Curb JD, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med. 2006;166:772-780.
  11. Stefanick ML, et al. The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann Epidemiol. 2003;13:S78-S86.
  12. Clarkson TB, et al. A comparison of tibolone and conjugated equine estrogens effects on coronary artery atherosclerosis and bone density of postmenopausal monkeys. J Clin Endocrinol Metab. 2001;86:5396-5404.