A new study in the general US population has found that the sharp drop in use of
hormone-replacement therapy (HRT) in the three years from 2002 onward was
associated with significantly fewer MIs among women, but that the stroke rate
was unaffected [1]. Dr Kanaka D Shetty (RAND Corp, Santa Monica, CA) and
colleagues report their findings in the May 2009 issue of Medical Care.

They explain that the use of HRT was curtailed dramatically in 2002 following
the results of the WHI trial, which found that HRT increased the risk of
coronary heart disease in healthy postmenopausal women. This was in contrast to
the prior perceived benefit of HRT on cardiovascular risk--Shetty et al thus
exploited this "natural experiment" to see whether the cardiovascular harms (or
benefits) of HRT seen in randomized controlled trials such as WHI extended to
the general population of women.

"We found that the decline in US HRT use after 2002 appeared to cause a decline
in the AMI rate (while controlling for other factors); we did not observe
statistically significant changes in the stroke rate," Shetty told heartwire .
She and her colleagues say their findings mirror those of a previous study,
which used this same natural experiment in a different context, to conclude that
the reduction in HRT use led to a substantial drop in incidence of breast
cancer.

Dr Rita Redberg (University of California, San Francisco), who was not involved
in this research, told heartwire : "This is a very interesting study; they did a
very careful look at some large databases and found a fairly dramatic drop in MI
rates and a temporal association." However, she countered that, as this was an
observational study, "you can't assume this was due to the decline in HRT use,
you can never show causation, but it's a striking observation."

Observational Data Useful, But Individual Responses Still Important

Shetty et al examined the relationship between HRT use and cardiovascular
outcomes (deaths and nonfatal hospitalizations) in the entire US population of
women aged 40 to 79 years using death records and hospital-discharge data
obtained from Healthcare Cost and Utilization Project's Nationwide Inpatient
Sample and nationally representative surveys of medication usage and behavioral
risk factors.

Decreases in HRT use were not associated with significant changes in
hospitalization or death due to acute stroke, but they were associated with 25
fewer MIs per 10 000 person years (p=0.021).

This means that for every 10 000 additional HRT users in a single year there
would be 25 more cases of AMI, say the researchers. And although direct
comparisons are not possible--because they are measuring treatment effects for
different populations--these figures are of the same magnitude as the WHI data,
which found seven more coronary heart disease events per 10 000 on HRT for a
year, they say.

They note, however, "unlike the WHI trial, we find no significant change in the
number of strokes as consequence of the decline in HRT use." Redberg says she is
not particularly perturbed by this finding: "MIs and stroke do share the same
risk factors, so you would think they would both go down, but we accept
differences in risk of MI and stroke with other medications, such as aspirin,"
she notes.

Shetty told heartwire their findings "indicate that randomized clinical trial
[RCT] results--like the WHI study--may not fully predict effects in typical
users. The selection criteria for RCTs make the experimental results cleaner,
but the generalizability poorer. Clinicians should be cautious about
automatically applying RCT results to clinical questions."

And although the new data represent the mean effect across all subpopulations,
results may differ in individual HRT users: "For this reason, we are undertaking
a study of the effects of HRT on individual persons in the overall population,"
she said.

Effect Not Likely to Be Caused by Awareness Campaigns

The researchers note a number of limitations to their study, including the fact
that they could not specifically examine the so-called "timing hypothesis"--the
suggestion that HRT use in early menopause is protective against heart disease,
because they had no information on how soon after menopause women began using
HRT. Also, they could not look at different types of HRT, only overall HRT use.

To heartwire , Shetty countered claims in some news reports [2] that it was
premature to attribute her findings to the decline in HRT use and that they
could be explained by AHA and National Heart, Lung, and Blood Institute
women-and-heart-disease awareness campaigns, which began around the same time.

"We didn't specifically control for that campaign. However, we did control for
trends in treatment and smoking, which answers this point to some extent. If
this campaign was that successful, it should be reflected in increased treatment
of risk factors as well as decreased smoking. [But] we can't control for other,
more subtle, findings like general awareness.

"Although the campaign could have caused this effect, it's not likely. In
addition, I think our conclusions were pretty cautious regarding causation," she
says.

HRT Use Short-Term for Menopausal Symptoms Is Reasonable

As to recommendations for HRT use, Shetty says: "The short-term benefit of HRT,
in terms of [menopause] symptom relief, may outweigh negative cardiovascular
effects. This concords reasonably well with current guidelines but deserves
further study. We did not have sufficient statistical power to answer this
question. Given the fact that HRT remains widely used for symptom relief, this
remains an important research area."

Redberg agrees that the existing guidance for use of HRT is reasonable: "I try
to recommend nonpharmacological approaches to women, but if they are still
suffering symptoms, I tell them I don't think they are at increased
cardiovascular risk by taking HRT for six months."