Fw: Requested DocAlert: Adjudicated Data From the Women's Health Initiative Estrogen-Plus-Progestin Substudy

[Guest guest]

Requested DocAlert^®ironically, I just got this email about the WHI

study tonight.

remember gracia it was not an bio-identical hormone study- just the synthetics.

nancie

Requested DocAlert: Adjudicated Data From the Women's Health Initiative

Estrogen-Plus-Progestin Substudy

Dear Clinician:

Here is the information you requested (sponsored by Wyeth

Pharmaceuticals).

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The Women's Health Initiative (WHI) trials included two parallel

randomized, double-blind, placebo-controlled clinical trials conducted to

determine whether hormone therapy with conjugated estrogens (CE) alone or in

combination with progesterone (medroxyprogesterone acetate, or MPA) would reduce

cardiovascular events in mostly healthy postmenopausal women.1

WHI Estrogen + Progestin (E+P) Substudy

The E+P substudy of WHI recruited 16,608 women with an intact uterus

between 1993 and 1998 from 40 U.S. clinical centers and randomized them to CE

0.625 mg/MPA 2.5 mg (n=8,506) or placebo (n=8,102).2 The participants ranged in

age from 50 to 79 years, with a mean age of about 63 years. Only about one third

of the participants were younger than 60 years at the time of randomization, and

approximately 20% were older than 70 years.1,2

The primary efficacy outcome was coronary heart disease (CHD) and the

primary safety outcome was invasive breast cancer.1,2 Other outcomes included

stroke, venous thromboembolism (VTE), hip and other fractures, and endometrial,

colorectal, and other cancers.1,2 The trial was scheduled to continue until 2005

after an average follow-up of approximately 8.5 years. In July 2002, the

National Institutes of Health announced that, based on the recommendation of the

Data Safety Monitoring Board, it was stopping the E+P substudy early, after a

mean follow-up of 5.2 years. The decision was based on prespecified statistical

boundaries that were crossed for the breast cancer outcome.2 Adjudicated or

finalized data for the prespecified outcomes were subsequently published with an

average of 5.6 years of patient follow-up.3-8

WHI E+P Substudy Data

a.. Annualized Risk: The graph below illustrates annualized differences

in absolute risk for various clinical outcomes using adjudicated data.3-8 The

adjudicated WHI findings demonstrated that in 1,000 women taking CE/MPA or

placebo over 1 year, CE/MPA users experienced:

a.. 0.8 additional invasive breast cancer events3

b.. 0.8 additional stroke events8

c.. 1.8 additional VTE events4

d.. 0.7 additional CHD events8

e.. 0.1 fewer endometrial cancer events6

f.. 0.6 fewer colorectal cancer events5

g.. 0.5 fewer hip fractures7

All differences between CE/MPA and placebo were statistically

significant (nominal confidence intervals significant) except for CHD and

endometrial cancer.3-8 Protection against endometrial cancer with progestin is

demonstrated by the similar number of cases between treatment

groups.6

a.. Risk by Age: The graph below illustrates the risk of CHD,8 invasive

breast cancer,3 stroke,8 VTE,4 colorectal cancer,5 and hip fracture7 by age for

women in the WHI E+P Substudy. Compared with placebo, CE/MPA was associated with

an increased risk of VTE in women aged 50 to 59 years (HR 2.27, 95% CI

1.19-4.33), as well as in women aged 60 to 69 years (HR 4.28, 95% CI 2.38-7.72)

and women aged 70 to 79 years (HR 7.45, 95% CI 4.32-14.38).4 It was also

associated with an increased risk of CHD in women aged 70 to 79 years (HR 1.26,

95% CI 1.00-1.59).8

Treatment of Menopausal Symptoms

Hormone therapy is the only FDA-approved medicine for relief of hot

flashes, night sweats, or vaginal dryness and may prevent postmenopausal

osteoporosis.9

Consider PREMPRO® (conjugated estrogens/medroxyprogesterone acetate

tablets)-0.625 mg of the conjugated estrogens found in PREMARIN® tablets plus

2.5 mg medroxyprogesterone acetate for oral administration. PREMPRO, the most

widely prescribed estrogen and progestin,10 has been proven to provide relief of

moderate to severe vasomotor and vaginal symptoms plus prevention of

postmenopausal osteoporosis-at all doses.11-13

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Important Safety Information

CARDIOVASCULAR AND OTHER RISKS

Estrogens and progestins should not be used for the prevention of

cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS,

Cardiovascular disorders and Dementia in the Prescribing Information.)

The estrogen-plus-progestin substudy of the Women's Health

Initiative (WHI) reported increased risks of myocardial infarction, stroke,

invasive breast cancer, pulmonary emboli, and deep vein thrombosis (DVT) in

postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with

conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate

(MPA 2.5 mg) per day relative to placebo. (See CLINICAL STUDIES and WARNINGS,

Cardiovascular disorders and Malignant neoplasms, Breast cancer in the

Prescribing Information.)

The estrogen-alone substudy of the WHI reported increased risks of

stroke and deep vein thrombosis in postmenopausal women (50 to 79 years of age)

during 6.8 years and 7.1 years, respectively, of treatment with oral conjugated

estrogens (CE 0.625 mg) per day relative to placebo. (See CLINICAL STUDIES and

WARNINGS, Cardiovascular disorders in the Prescribing Information.)

The Women's Health Initiative Memory Study (WHIMS), a substudy of

WHI, reported an increased risk of developing probable dementia in

postmenopausal women 65 years of age or older during four years of treatment

with CE 0.625 mg combined with MPA 2.5 mg and during 5.2 years of treatment with

CE 0.625 mg alone, relative to placebo. It is unknown whether this finding

applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS,

Dementia and PRECAUTIONS, Geriatric Use in the Prescribing Information.)

Other doses of conjugated estrogens and medroxyprogesterone acetate,

and other combinations and dosage forms of estrogens and progestins were not

studied in the WHI clinical trials, and in the absence of comparable data, these

risks should be assumed to be similar. Because of these risks, estrogens with or

without progestins should be prescribed at the lowest effective doses and for

the shortest duration consistent with treatment goals and risks for the

individual woman.

a.. PREMPRO® (conjugated estrogens/medroxyprogesterone acetate tablets)

is indicated in women who have a uterus for the treatment of moderate to severe

vasomotor symptoms associated with menopause, the treatment of moderate to

severe symptoms of vulvar and vaginal atrophy associated with menopause, and the

prevention of postmenopausal osteoporosis.

b.. When prescribing solely for the treatment of symptoms of vulvar and

vaginal atrophy, topical vaginal products should be considered. When prescribing

solely for the prevention of postmenopausal osteoporosis, therapy should only be

considered for women at significant risk of osteoporosis and for whom

non-estrogen medications are not considered to be appropriate.

c.. PREMPRO should not be used under any of the following conditions or

circumstances: undiagnosed abnormal genital bleeding; known, suspected, or a

history of breast cancer; known or suspected estrogen-dependent neoplasia;

active venous thromboembolism or a history of this condition; active or recent

arterial thromboembolism; liver dysfunction or disease; in patients with a known

hypersensitivity to its ingredients; known or suspected pregnancy.

d.. In a clinical trial, the most commonly reported (?5%) adverse events

for PREMPRO 0.45 mg/1.5 mg and PREMPRO 0.625 mg/2.5 mg that were statistically

different than placebo were mastalgia, vaginal bleeding, vaginal moniliasis, leg

cramps, dysmenorrhea, breast enlargement, and vaginitis. In a clinical trial,

there was no difference in the commonly reported (?5%) adverse events for women

taking PREMPRO 0.3 mg/1.5 mg compared to those taking placebo.

To see Prescribing Information for PREMPRO, please

<http://imageb.epocrates.com/mailbot/links?EdID=35909167 & LinkID=465> or visit:

http://www.wyeth.com/content/ShowLabeling.asp?id=133<http://imageb.epocrates.com\

/mailbot/links?EdID=35909167 & LinkID=465>.

REFERENCES

1. The Women's Health Initiative Steering Committee. Effects of conjugated

equine estrogen in postmenopausal women with hysterectomy: the Women's Health

Initiative randomized controlled trial. JAMA. 2004;291:1701-1712.

2. Writing Group for Women's Health Initiative Investigators. Risks and

benefits of estrogen plus progestin in healthy postmenopausal women: principal

results from the Women's Health Initiative randomized trial. JAMA.

2002;288:321-333.

3. Chlebowski RT, Hendrix SL, Langer RD, et al, for the WHI Investigators.

Influence of estrogen plus progestin on breast cancer and mammography in healthy

postmenopausal women: the Women's Health Initiative randomized trial. JAMA.

2003;289:3243-3253.

4. 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.

5. Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, et al, for the Women's

Health Initiative Investigators. Estrogen plus progestin and colorectal cancer

in postmenopausal women. N Engl J Med. 2004;350:991-1004.

6. GL, Judd HL, Kaunitz AM, et al, for the Women's Health

Initiative Investigators. Effects of estrogen plus progestin on gynecologic

cancers and associated diagnostic procedures. JAMA. 2003;290:1739-1748.

7. Cauley JA, Robbins J, Chen Z, et al, for the Women's Health Initiative

Investigators. Effects of estrogen plus progestin on risk of fracture and bone

mineral density: the Women's Health Initiative randomized trial. JAMA.

2003;290:1729-1738.

8. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone

therapy and risk of cardiovascular disease by age and years since menopause.

JAMA. 2007;297:1465-1477.

9. U.S. Food and Drug Administration. Menopause & hormones. Available at:

http://www.fda.gov/womens/menopause/mht-FS.html<http://imageb.epocrates.com/mail\

bot/links?EdID=35909167 & LinkID=1220>. Accessed March 19, 2007.

10. Data on file, Wyeth Pharmaceuticals Inc. IMS Health data for dispensed

TRxs, October 2007.

11. Utian WH, Shoupe D, Bachmann G, et al. Relief of vasomotor symptoms

and vaginal atrophy with lower doses of conjugated equine estrogens and

medroxyprogesterone acetate. Fertil Steril. 2001;75:1065-1079.

12. R, Gallagher JC, Kleerekoper M, et al. Effect of lower doses

of conjugated equine estrogens with and without medroxyprogesterone acetate on

bone in early postmenopausal women. JAMA. 2002;287:2668-2676.

13. R, Gallagher JC, Kleerekoper M, et al. Bone response to

treatment with lower doses of conjugated estrogens with and without

medroxyprogesterone acetate in early postmenopausal women. Osteoporos Int.

2005;16:372-379.

The above message was sponsored by Wyeth Pharmaceuticals, who is solely

responsible for its content.

© 2008, Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101 January 2008

213340-01

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