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HRT and atherosclerosis in early menopause

The claim that the cardiovascular benefits of postmenopausal hormone therapy (HRT) are greatest when treatment is given close to the menopause has been somewhat confirmed in a placebo-controlled randomised trial which stratified subjects according to time since menopause. ¹ Results showed that oral estradiol therapy (with or without progesterone) was associated with less progression of subclinical atherosclerosis (measured as carotid artery intima-media thickness, CIMT) than placebo when therapy was initiated within six years of the menopause – though not when started 10 or more years after.

This window hypothesis emerged in one of the great U-turns of the Women’s Health Initiative (WHI), when a secondary analysis proposed that women who began HRT within the first 10 years following the menopause actually reduced their risk of coronary heart disease (a hazard ratio of 0.76). ² However, those who started 10–19 and more than 20 years after slightly increased their risk (HR 1.10 and 1.28 respectively). The data also showed that hormone users aged 50–59 had a 30% lower risk of all-cause mortality than those given placebo. Thus, with a continuing recognition of HRT’s unequivocal effect on climacteric symptoms, the concept of a window of prescribing opportunity began to take shape. Indeed, the WHI study’s first author Jacques Rossouw told the New York Times at the time that ‘we were as clear as could be that there seems to be a window of opportunity to use it in that short interval’. ³

This view was tentatively accepted by NICE in its menopause guideline published last year. In its consideration of clinical benefits and harm NICE ‘decided to recommend that menopausal women and healthcare professionals involved in their care understand that HRT doesn’t increase the cardiovascular disease risk when started in women aged under 60 years’. ⁴ This is not quite an endorsement of any protective effect, but NICE did go on to say that the evidence from observational studies (as opposed to the RCTs) suggested that:

the risk of CHD was significantly lower for women using HRT compared with no treatment across different follow-up periods (4, 10, 16 and 20 years) and different HRT durations (1, 2, 5 or 10 years) although the risk seemed to significantly increase in current users with pre-existing heart disease.

As background to the recommendations, NICE explained that, while the likelihood of cardiovascular symptoms does increase with age in women, the menopause itself does not cause cardiovascular disease, although there may be associated risk factors (smoking, poor diet, lack of exercise) that increase its risk around the time of menopause.

Evidence from the latest report comes from the Early versus Late Intervention Trial with Estradiol (ELITE) study, which stratified 643 postmenopausal women according to time since menopause (<6 years (early postmenopause) or ≥10 years (late postmenopause)). They were randomly assigned to oral 17β-estradiol (1 mg per day) plus sequential progesterone as vaginal gel.

After a median of five years, the effect of estradiol with or without progesterone on CIMT progression was found to differ significantly between the early and late postmenopause groups; the mean CIMT of women who were less than six years past menopause at the time of randomisation increased by 0.0078 mm per year in the placebo group and 0.0044 mm per year in the estradiol group; however, among those who were 10 or more years past menopause the rates of CIMT progression in the placebo and estradiol groups were similar.

An accompanying editorial in the NEJM noted that ‘these data are of keen biologic interest, because they suggest that favorable responses of receptors in the vasculature to estrogen may be lost with lack of exposure to estrogen’. ⁵ However, the editorial continued that relevance of the results remains ‘questionable’ because the trial used only surrogate markers of CHD and not clinical events:

Although the ELITE trial results support the hypothesis that postmenopausal hormone therapy may have more favorable effects on atherosclerosis when initiated soon after menopause, extrapolation of these results to clinical events would be premature, and the present guidance [caution against primary prevention] remains prudent.

A little more evidence in acupuncture and hot flushes

Who knows how many women use acupuncture for the relief of hot flushes? Answers, like a needle in a haystack, will be hard to find, as indistinct as the hazy results from underpowered efficacy studies. So no surprise that a Cochrane review reporting in 2013 found insufficient evidence to demonstrate any benefit from acupuncture in controlling menopausal symptoms. ¹ No evidence when acupuncture was compared with sham acupuncture, but maybe some benefit when compared with no treatment – although less effective than hormones.

Acupuncturists make a distinction between traditional Chinese medicine acupuncture and western acupuncture, which seems more dependent on a modern understanding of physiology. But whichever of the two are considered, evidence for a benefit is elusive. For example, a sham-controlled randomised trial just reported from Australia found Chinese medicine acupuncture non-superior to sham acupuncture in women with moderately severe menopausal hot flushes. ²

The 327 subjects, who were all over 40 and experiencing more than 7 ‘moderate’ hot flushes per day, received 10 treatments over eight weeks of either standard Chinese medicine needle acupuncture or non-insertive sham acupuncture. However, at the end of treatment, mean hot flush scores were 15.36 in the acupuncture group and 15.04 in the sham group.

According to a comment on this study in JAMA, more than 50% of women now suffering hot flushes and night sweats use some form of complementary therapy for relief. Yet despite its popularity, acupuncture is rarely given formal approval (unless by complementary therapists). For example, a 2015 North American Menopause Society review of non-hormonal therapies for hot flushes states clearly that acupuncture cannot be recommended; similarly, Guidelines from the American College of Obstetricians and Gynecologists say that conventional hormone therapy is preferred over custom-mixed bioidentical hormones, and that phytoestrogens and herbal supplements have not been shown to be helpful for treating hot flushes.^3,4

Meanwhile, another systematic review from the Cochrane database has come up with even more ‘insufficient evidence’ – this time that Chinese herbal medicines are any more or less effective than placebo or hormone therapy for the relief of vasomotor symptoms. ⁵ Effects on safety were inconclusive. Although 22 randomised trials were included, the authors found the quality of evidence ranged from ‘very low to moderate’. ‘Scientific evidence for their effectiveness and safety is needed,’ say the reviewers.

Routine mammography and screening for coronary artery disease

US cardiologists have shown animated interest in a presentation at April’s annual meeting of the American College of Cardiology (ACC) which described routine mammography as a ‘useful tool’ in the estimation of female heart disease risk. For the first time, study results have shown a convincing link between the volume of calcium in arteries of the breast – readily visible on digital mammography – and the level of calcium build-up in the coronary arteries. ¹

Coronary arterial calcification, said the ACC, is considered a very early sign of cardiovascular disease and that the presence of breast arterial calcification ‘appears to be an equivalent or stronger risk factor’ for coronary artery calcification than other well established cardiovascular risk factors such as high cholesterol, high blood pressure and diabetes.

In this study breast arterial calcification was assessed by digital mammography and noted in 42% of subjects. Overall, 70% of these women were also found to have calcification of the coronary arteries as validated by CT scan of the chest. Moreover, half of the women under 60 years with demonstrated coronary artery calcification also had breast arterial calcification – an important finding, said the ACC, as very few would be thinking about or considered for early signs of heart disease. The researchers said that if a younger woman had breast arterial calcification, there was an 83% chance she also had coronary artery calcification. Remarkably, added first author Howard Hecht from Mount Sinai St Luke’s Hospital in New York, breast arterial calcification appeared to be as strong a predictor of cardiovascular risk as standard risk scores such as the well established Framingham model.

Yet what seemed to raise interest just as much as the results were the health economics implications. ‘This information is available on every mammogram, with no additional cost or radiation exposure,’ said Hecht,

and our research suggests breast arterial calcification is as good as the standard risk factor-based estimate for predicting risk. The more breast arterial calcification a woman has, the more likely she is to have calcium in her heart’s arteries as well. If all it requires is to take a closer look at the images, how can we ignore it?

These implications, added Hecht, should now be tested further in full-scale trial.

Since presentation at the ACC meeting in April, the study has been published in the College’s imaging journal. ²