RESEARCH - WHI: further analysis of venous thrombosis risk with estrogen plus progestin

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WHI: further analysis of venous thrombosis risk with estrogen plus

progestin

Rheumawire

Oct 6, 2004

Chicago, IL - Closer analysis of venous thrombosis (VT) outcomes in the

Women's Health Initiative (WHI) confirms that the use of estrogen plus

progestin was associated with a more than two-fold increased risk of VT

compared with placebo. The risk was further increased with increasing

age, obesity, and the presence of the factor V Leiden mutation.

In a separate report, results of an observational study suggest that VT

risk is increased with use of conjugated equine estrogen, but not

apparently with esterified estrogen.

Both reports appear in the October 6, 2004 issue of the Journal of the

American Medical Association.[1, 2]

The main results from WHI, published in July 2002, had shown a two-fold

increase in VT risk with estrogen plus progestin.[3] In this analysis,

researchers with first author Dr Cushman (University of Vermont,

Burlington) report final WHI results, including about 0.4 years of

additional follow up reflecting the close out of the study. They also

looked more closely at risk factors that might be associated with

further increased risk to help inform women who may be considering

hormone use.

The trial included 16 608 postmenopausal women between 50 and 79 years

of age, randomized to placebo or 0.625 mg/day of conjugated equine

estrogen (CEE) plus 2.5 mg/day of medroxyprogesterone acetate.

VT occurred in 167 women in the E+P group (3.5 per 1000 person-years),

compared with 76 taking placebo (1.7 per 1000 person-years), for a

hazard ratio of 2.6 (95% CI 1.57-2.70).

Compared with women 50 to 59 years of age on placebo, the risk for VT

associated with treatment increased with increasing age.

Overweight and obesity also increased the risk for VT among women taking

estrogen plus progestin.

Finally, baseline gene variants related to thrombosis risk were measured

in the first 147 women who developed VT during the trial, and in 513

controls. The researchers found that the factor V Leiden mutation

increased VT risk compared with women in the placebo group without this

mutation by almost seven-fold (HR 6.69, 95% CI 3.09-14.49). Other

genetic factors examined did not appear to modify the association

between hormone therapy and the risk for VT.

Cushman told rheumawire that it's unlikely at this point that older

women would be considering the use of hormones so the " more clinically

relevant finding " is the increased risk with obesity and overweight. " If

you have a woman sitting in front of you, and you want to use hormone

therapy, she needs to understand that her risk is higher from an

absolute perspective than a thinner woman who's considering taking

them, " Cushman said. They calculated that the absolute risk for obese

women with no other thrombosis risk factors would be " a little more than

1%, " she said, " so you wouldn't necessarily withhold treatment, but

you'd want to make sure they understand the risk, and that they know the

symptoms [of venous thrombosis] to look for. "

The finding relating to factor V Leiden would probably not be considered

in this decision unless the patient has a family history of thrombosis,

because in general this information would not be available, she said.

They calculated that 800 women would need to be screened for factor V

Leiden to prevent one episode of VT, which is unlikely to be

cost-effective. " This is an inter-relation that we know exists, but we

don't know that it would make sense to screen for it based on the

findings. "

In a separate report in the same issue of JAMA, Dr L

(PhD, University of Washington, Seattle) and colleagues some of whom

were also coauthors on the previous paper used data from the Group

Health ative (GHC), a large health maintenance organization in

Washington State, to look at what they speculated might be differential

effects of CEE versus esterified estrogens (EE) on venous thrombosis

risk.

Clinical trial evidence indicating an increased risk of VT with hormone

therapy used CEE, et al write, and so might not be generalizable

to other estrogen compounds. EEs have received less attention, they

point out, but all these products continue to be used to treat

menopause-related vasomotor symptoms.

In October 1999, the GHC pharmacies switched the standard postmenopausal

therapy from EE to CEE for current and new users of hormone therapy, the

researchers write. " The formulary change occurred during data collection

for a case-control study of cardiovascular outcomes that included VT,

which presented us with the opportunity to examine the association of

oral EE and CEE with VT risk in perimenopausal and postmenopausal

women, " et al write.

Between January 1995 and December 2001, 586 incident cases of VT were

identified, and matched for age, hypertension status and calendar year

with 2268 controls.

Compared with women not currently using hormones, women currently using

EE had no increase in VT risk, while those taking CEE did.

When analysis was restricted to estrogen users, current users of CEE had

a higher risk of VT than those currently using EE (OR 1.78, 95% CI

1.11-2.84). Increasing daily doses of CEE was also associated with

increased risk, and concomitant progestin use again increased risk among

all estrogen users, compared with estrogen alone (OR 1.60, 95% CI

1.13-2.26).

" I think it was the assumption that most estrogens are the same and you

could exchange them without much problem, " told rheumawire. " Our

data suggest that may not be the case. "

If these results are replicated, he said, EE might be a better

alternative for those choosing short-term symptom relief during

menopause. He cautioned though that EEs have never been studied in large

trials, so their effects on other endpoints might be more favorable than

CEE, but they might not. " There's just so much that's not known about

these drugs, " he said.

Sources

Cushman M, Kuller LH, Prentice R, et al. For the

Women's Health Initiative Investigators. Estrogen plus progestin and

risk of venous thrombosis. JAMA 2004; 292:1573-1580.

NL, Heckbert SR, Lemaitre RN, et al. Esterified

estrogens and conjugated equine estrogens and the risk of venous

thrombosis. JAMA 2004; 292:1581-1587.

Rossouw JE, GL, Prentice RL, LaCroix AZ,

Kooperberg C, Stefanick ML, RD, Beresford SA, BV,

KC, Kotchen JM, Ockene J; Writing Group for the Women's Health

Initiative Investigators. Risks and benefits of estrogen plus progestin

in health postmenopausal women: Principal results from the Women's

Health Initiative randomized controlled trial. JAMA 2002 Jul 17;

288(3):321-333.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org