Research Article| Volume 27, ISSUE 3, P261-274, July 1997

Download started.


The postmenopausal estrogen/progestin interventions study: primary outcomes in adherent women

      This paper is only available as a PDF. To read, Please Download here.


      Objective: To assess the efficacy of unopposed estrogen, and three estrogen/progestin regimens on selected heart disease risk factors among adherent women and to contrast those results with efficacy among all women in the PEPI study. Design: A 3-year, multicenter, randomized, double-blinded, placebo-controlled clinical trial. Participants: A total of 847 healthy postmenopausal women aged 45 to 64 years of age with no known contraindication to hormone therapy, who attended their 36 month clinical visit. Intervention: Participants were randomized in equal numbers to one of the following treatments: (1) placebo; (2) conjugated equine estrogen (CEE) 0.625 mg daily; (3) CEE 0.625 daily plus medroxyprogesterone acetate (MPA) 10 mg, days 1–12; (4) CEE 0.625 daily plus MPA 2.5 mg daily; or (5) CEE 0.625 daily plus micronized progesterone (MP) 200 mg, days 1–12. Analysis: Analyses are based on adherent women, where adherence is defined as taking at least 80% of pills at each 6-month visit. Results: Adherence rates were high in all groups except women with a uterus assigned to unopposed CEE. The difference in HDL-C levels resulting from the CEE vs. CEE + MP was approximately three times larger than in the intent-to-treat analyses, reaching statistical significance (P<0.05). In each active treatment, LDL-C decreased 10–15%. Triglycerides increased 15–20% in each opposed CEE arm and over 25% in the CEE only arm; this difference was not statistically significant. Fibrinogen increased by 7% among placebo adherers, but decreased or remained fairly stable among the active arm adherers. Systolic blood pressure increased 3–5% in all treatment arms. Women adherent to the CEE + MPA arms had twice the increase of 2 h glucose levels as women adherent to CEE only, or CEE + MP (8–9% vs. 3–4%). Two-hour insulin levels decreased 3–12% for all arms. The patterns of change for fibrinogen, SBP, 2 h glucose and insulin were similar to those from the intent-to-treat analyses. Conclusions: In analyses limited to adherent women, all active treatments, compared to placebo, continued to have similar and favorable effects on LDL-cholesterol and fibrinogen and no significant effects on blood pressure or insulin levels. Given the overall high adherence rates in PEPI, the results are similar to the intent-to-treat analyses, as expected. Only the trend of HDL-C to have a larger increase in the CEE only arm (in the intent-to-treat analyses) gained statistical significance in analyses restricted to adherers.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Maturitas
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • The Writing Group for the PEPI Trial
        Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.
        JAMA. 1995; 273: 199-208
        • Friedman LM
        • Furberg CD
        • DeMets DL
        Fundamentals of clinical trials.
        2nd ed. PSG Publishing, Littleton, Mass1985
        • Espeland MA
        • Bush TL
        • Mebane-Sims I
        • Stefanick ML
        • Johnson S
        • Sherwin R
        • Waclawiw M
        Rationale, design, and conduct of the PEPI Trial. Postmenopausal Estrogen/Progestin Interventions.
        Control Clin Trials. 1995; 16: S3-S19
        • Miller VT
        • Byington RL
        • Espeland MA
        • Langer R
        • Marcus R
        • Shumaker S
        • Stern MP
        Baseline characteristics of the PEPI participants. Postmenopausal Estrogen/Progestin Interventions.
        Control Clin Trials. 1995; 16: 54s-65s
        • Johnson S
        • Mebane-Sims I
        • Hogan PE
        • Stoy DB
        Recruitment of postmenopausal women in the PEPI Trial. Postmenopausal Estrogen/Progestin Interventions.
        Control Clin Trials. 1995; 16: 20S-35S
        • Wood PD
        • Kessler G
        • Lippel K
        • Stefanick ML
        • Wasilauskas CH
        • Wells HB
        Physical and laboratory measurements in the PEPI Trial Postmenopausal Estrogen/Progestin Interventions.
        Control Clin Trials. 1995; 16: 36S-53S
        • Warnick GR
        Enzymatic methods for quantification of lipoprotein lipids.
        Methods Enzymol. 1986; 129: 101-123
        • Bachorik PS
        • Albers JJ
        Precipitation methods for quantification of lipoproteins.
        Methods Enzymol. 1986; 129: 78-100
      1. Hainline A Karon J Lippel K Manual of laboratory operations. Lipid research clinics program, lipid and lipoprotein analysis. 2nd ed. NIH-Department of Health and Human Services, 1982
        • Trinder P
        Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor.
        Ann Clin Biochem. 1969; 6: 24
        • Morgan CR
        • Laarow A
        Immunoassay of insulin: two antibody system. Plasma levels of normal, subdiabetic and diabetic rats.
        Diabetes. 1963; 12: 115-126
        • Clauss A
        Gerinnungs physiologische schnellmethode zur bestimmung des fibrinogens.
        Acta Haemat. 1957; 17: 237-246
        • SAS Institute
        4th ed. SAS/STAT User's Guide. vol 2. SAS Institute, Cary, NC1989 (Version 6)
        • Goldbourt U
        • Medalie JH
        High density lipoprotein cholesterol and incidence of coronary heart disease-the Israeli Ischemic Heart Disease Study.
        Amer J Epidemiol. 1979; 109: 296-308
        • Castelli WP
        Cardiovascular disease in women.
        Am J Obstet Gynecol. 1988; 158: 1553-1560
        • Bass KM
        • Newschaffer CJ
        • Klag MJ
        • Bush TL
        Plasma lipoprotein levels as predictors of cardiovascular death in women.
        Arch Intern Med. 1993; 153: 2209-2216
        • Gordon DJ
        • Probstfield JL
        • Garrison RJ
        • Neaton JD
        • Castelli WP
        • Knoke JD
        • Jacobs Jr, DR
        • Bangdiwala S
        • Tyroler HA
        High-density lipoprotein cholesterol and cardiovascular disease, four prospective American studies.
        Circulation. 1989; 79: 8-15
        • Scandinavian Simvastatin Survival Study Group
        Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
        Lancet. 1994; 344: 1383-1389
        • Bradford RH
        • Downton M
        • Chremos AN
        • Langendorfer A
        • Stinnett S
        • Nash DT
        • Mantell G
        • Shear CL
        Efficacy and tolerability of lovastatin in 3390 women with moderate hypercholesterolemia.
        Ann Int Med. 1993; 118: 850-855
        • Barrett-Connor E
        • Bush TL
        Estrogen and coronary heart disease in women.
        JAMA. 1991; 265: 1861-1867
        • Tikkanen MJ
        Mechanisms of cardiovascular protection by postmenopausal hormone replacement therapy.
        Cardiovaso Risk Factors. 1993; 3: 138-143
        • Riedel M
        • Rafflenbeul W
        • Lichtlen P
        Ovarian sex steroids and atherosclerosis.
        Clin Invest. 1993; 71: 406-412
        • Gangar KF
        • Reid BA
        • Crook D
        • Hillard TC
        • Whitehead MI
        Oestrogens and atherosclerotic vascular disease: local vascular factors.
        Bailliere's Clin Endocrinol Metab. 1993; 7: 47-59
        • Miller VT
        Dyslipoproteinemia in women. Special Considerations.
        Endocrinol Metab Clinics N Am. 1990; 19: 381-398
        • Gordis L
        Conceptual and methodologic problems in measuring patient compliance.
        in: Haynes RB Taylor DW Sackett DL Compliance in Health Care. John Hopkins Press, Baltimore1979: 23-45
        • Black DM
        • Brand RJ
        • Greenlick M
        • Hughes G
        • Smith J
        • SHEP Pilot Research Group
        Compliance to treatment for hypertension in elderly patients: The SHEP Pilot Study.
        J Gerontol. 1987; 42: 552-557
        • Pullar T
        • Kumar S
        • Tindall H
        • Feely M
        Time to stop counting the tablets?.
        Clin Pharmacol Ther. 1989; 46: 163-168
        • Brittain E
        • Wittes J
        The run-in period in clinical trials: The effect of misclassification on efficiency.
        Control Clin Trials. 1990; 11: 327-338
        • The Writing Group for the PEPI Trial
        Effects of hormone therapy on bone mineral density. Results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.
        JAMA. 1996; 276: 1389-1396
        • Sackett DL
        • Gent M
        Controversy in counting and attributing events in clinical trials.
        N Engl J Med. 1979; 301: 1410-1412
        • Armitage P
        Controversies and achievements in clinical trials.
        Control Clin Trials. 1984; 5: 67-72
        • Efron B
        • Feldman D
        Compliance as an explanatory variable in clinical trials (with discussion).
        J Am Statistic Assoc. 1991; 86: 9-26
        • Rochon J
        Supplementing the intent-to-treat analysis: accounting for covariates observed postrandomization in clinical trials.
        J Am Statistic Assoc. 1995; 90: 292-300
        • Black LJ
        • Sato M
        • Rowley ER
        • Magee DE
        • Bekele A
        • Williams DC
        • Cullinan GJ
        • Bendele R
        • Kauffman RF
        • Bensch WR
        • et al.
        Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats.
        J Clin Invest. 1994; 93: 63-69
        • Gradym D
        • Rubin SM
        • Petitti DB
        • et al.
        Hormone therapy to prevent disease and prolong life in postmenopausal women.
        Ann Intern Med. 1992; 117: 1016-1037