Effects on vulvar and vaginal atrophy.
Two pivotal controlled studies have demonstrated the efficacy of ESTRING (estradiol vaginal ring)
in the treatment of postmenopausal urogenital symptoms due to estrogen deficiency.
In a U.S. study where ESTRING was compared with conjugated estrogens vaginal cream, no difference
in efficacy between the treatment groups was found with respect to improvement in the physician's
global assessment of vaginal symptoms (83 percent and 82 percent of patients receiving ESTRING
and cream, respectively) and in the patient's global assessment of vaginal symptoms (83 percent
and 82 percent of patients receiving ESTRING and cream, respectively) after 12 weeks of treatment. In an Australian study, ESTRING was also compared with conjugated estrogens vaginal cream and no difference in the physician's assessment of improvement of vaginal mucosal atrophy (79 percent and 75 percent for ESTRING and cream, respectively) or in the patient's assessment of improvement in vaginal dryness (82 percent and 76 percent for ESTRING and cream, respectively) after 12 weeks of treatment.
In the U.S. study, symptoms of dysuria and urinary urgency improved in 74 percent and 65 percent,
respectively, of patients receiving ESTRING as assessed by the patient. In the Australian study,
symptoms of dysuria and urinary urgency improved in 90 percent and 71 percent, respectively, of
patients receiving ESTRING as assessed by the patient.
In both studies, ESTRING and conjugated estrogens vaginal cream had a similar ability to reduce
vaginal pH levels and to mature the vaginal mucosa (as measured cytologically using the
maturation index and/or the maturation value) after 12 weeks of treatment. In supportive studies,
ESTRING was also shown to have a similar significant treatment effect on the maturation of the
urethral mucosa.
Endometrial overstimulation, as evaluated in non-hysterectomized patients participating in the
U.S. study by the progestogen challenge test and pelvic sonogram, was reported for none of the
58 (0 percent) patients receiving ESTRING and 4 of the 35 patients (11 percent) receiving
conjugated estrogens vaginal cream.
Of the U.S. women who completed 12 weeks of treatment, 95 percent rated product comfort for
ESTRING as excellent or very good compared with 65 percent of patients receiving conjugated
estrogens vaginal cream, 95 percent of ESTRING patients judged the product to be very easy or
easy to use compared with 88 percent of cream patients, and 82 percent gave ESTRING an overall
rating of excellent or very good compared with 58 percent for the cream.
Women’s Health Initiative Studies
The Women’s Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy
postmenopausal women in two substudies to assess the risks and benefits of either the use of
daily oral conjugated estrogens (CE 0.625 mg) alone or in combination with medroxyprogesterone
acetate (MPA 2.5 mg) compared to placebo in the prevention of certain chronic diseases.
The primary endpoint was the incidence of coronary heart disease (CHD)
(nonfatal myocardial infarction [MI], silent MI and CHD death), with invasive breast cancer
as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD,
invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer
(only in the CE/MPA substudy), colorectal cancer, hip fracture, or death due to other cause.
These substudies did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
The estrogen alone substudy was stopped early because an increased risk of stroke was observed
and it was deemed that no further information would be obtained regarding the risks and benefits
of estrogen alone in predetermined primary endpoints. Results of the estrogen alone substudy,
which included 10,739 women (average age 63 years, range 50 to 79; 75.3 percent White,
15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of
6.8 years are presented in Table 2.
TABLE 2: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN ALONE SUBSTUDY OF WHI
For those outcomes included in the WHI "global index" that reached statistical significance,
the absolute excess risk per 10,000 women-years in the group treated with CE alone was 12 more
strokes, while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures.
The absolute excess risk of events included in the "global index" was a nonsignificant 2 events per
10,000 women-years. There was no difference between the groups in terms of all-cause mortality.
(See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Final centrally adjudicated results for CHD events and centrally adjudicated results for
invasive breast cancer incidence from the estrogen alone substudy, after an average follow-up
of 7.1 years, reported no overall difference from primary CHD events (nonfatal MI, silent MI
and CHD death) and invasive breast cancer incidence in women receiving CE alone compared with
placebo (see Table 2).
Centrally adjudicated results for stroke events from the estrogen alone substudy,
after an average follow-up of 7.1 years, reported no significant differences in distribution of
stroke subtypes or severity, including fatal strokes, in women receiving CE alone compared to
placebo. Estrogen alone increased the risk for ischemic stroke, and this excess risk was present
in all subgroups of women examined (see Table 2).
The estrogen plus progestin substudy was also stopped early. According to the predefined stopping
rule, after an average follow-up of 5.2 years of treatment, the increased risk of breast cancer
and cardiovascular events exceeded the specified benefits included in the “global index.”
The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years
(relative risk [RR] 1.15, 95 percent nCI 1.03-1.28).
For those outcomes included in the WHI “global index” that reached statistical significance after
5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with
CE/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers,
while the absolute risk reductions per 10,000 women-years were 7 fewer colorectal cancers and 5
fewer hip fractures. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Results of the estrogen plus progestin substudy, which included 16,608 women (average of 63 years,
range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other),
are presented in Table 3. These results reflect centrally adjudicated data after an average
follow-up of 5.6 years.
TABLE 3: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN
AVERAGE OF 5.6 YEARSa
Women’s Health Initiative Memory Study
The estrogen alone Women’s Health Initiative Memory Study (WHIMS), a substudy of the WHI, enrolled 2,947
predominantly healthy postmenopausal women 65 years of age and older (45 percent were 65 to 69 years of
age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of age and older) to evaluate
the effects of daily conjugated estrogens (CE 0.625 mg) on the incidence of probable dementia
(primary outcome) compared with placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen alone group
(37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed
with probable dementia. The relative risk of probable dementia in the estrogen alone group was 1.49
(95 percent CI, 0.83-2.66) compared to placebo. It is unknown whether these findings apply to younger
postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)
The estrogen plus progestin WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women
65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of
age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE 0.625 mg plus
medroxyprogesterone acetate (MPA 2.5 mg) on the incidence of probable dementia (primary outcome)
compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen plus progestin group
(45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed
with probable dementia. The relative risk of probable dementia in the hormone therapy group was
2.05 (95 percent CI, 1.21-3.48) compared to placebo.
When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall
relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups
became apparent in the first year of treatment. It is unknown whether these findings apply to younger
postmenopausal women. (See BOXED WARNING, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)