Slide 1: Menopausal Hormone Therapy. Women’s Health Initiate (WHI) 2002

Slide 2: Why? The Nurse’s Health Study – a series of prospective cohort studies in the 1970s-1980s, found hormone therapy (HT) to be associated with decreased CV risk. WHI sought to follow-up evaluating the risks and benefits of HT in postmenopausal women, this time in a randomized and controlled fashion.

Primary outcome: rate of CV disease. Primary adverse event: rate of invasive breast cancer.

Slide 3: How? Study population: 16,608 post menopausal women (ages 50-79) randomized to estrogen plus progestin or placebo. Follow up timeline. 6 weeks phone call. 6 months clinical visit. 12 months clinical visit. 18 month clinical visit. 24 months clinical visit. 3 and 6 years EKG. Annual mammograms. 40 study centers. 63.3 mean age. 5.2 years mean follow-up. 40% former smokers, 10% current smokers in both groups.

Slide 4: What happened? Compared to placebo, estrogen plus progesterone group have global index for risk, absolute risk (AR) increase +0.19%. Total CV events AR increase +0.25%, color cancer AR reduction -0.06%, total fractures AR reduction -0.44%, stroke AR increase +0.08%, invasive breast cancer AR increase 0.08%, venous thromboembolism AR increase +0.17%.

Only nominal statistical significance p<0.05 Global index = risk summary of CV disease, stroke, cancer, and other adverse events Slide 5: What did critics say? Authors say "over 1 year, 10,000 women taking estrogen plus progestin compared with placebo might experience 7 more CHD events, 8 more strokes, 8 more PEs, 8 more invasive breast cancers, 6 fewer colorectal cancers, and 5 fewer hip fractures. WHI studies only effect of continuous HT, what about cyclic HT. Mean age of EHI study population is age 63. Can results be generalized to younger, recently menopausal women in their 50s? The difference in CV events and strokes are statistically nonsignificant after adjustments to correct for multiple analyses over time. What is statistically significant may not be clinically significant. For example, how does one view the +0.08% increased risk in breast cancer? Slide 6: Further studies. 2009. DOPS-RCT N=1,006. Early menopausal HT reduced risk of mortality, HF, and MI without increased risk of cancer, VTE, or stroke. 2014. KEEPS-RCT, N=727. Early menopausal HT reduced vasomotor symptoms, improved sexual function, and maintained bone density with a neutral impact on carotid intima-media thickness (CIMT). 2016. ELITE-RCT, N=643. Early HT initiation within 6 years of menopause was associated with less progression of CIMT as compared to late HT initiation greater than 10 years after menopause. 2022. Per current guidelines from USPSTF and ACOG. HT is a safe and effective option for otherwise healthy women experiencing moderate to severe menopausal vasomotor symptoms.

References

  • Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the 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 controlled trial. JAMA. 2002 Jul 17;288(3):321-33. PMID 12117397.
  • Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Chlebowski RT, Howard BV, Thomson CA, Margolis KL, Lewis CE, Stefanick ML, Jackson RD, Johnson KC, Martin LW, Shumaker SA, Espeland MA, Wactawski-Wende J; WHI Investigators. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women’s Health Initiative Randomized Trials. JAMA. 2017 Sep 12;318(10):927-938. PMID 28898378.
  • Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, Thomson CA, LaCroix AZ, Wactawski-Wende J, Jackson RD, Limacher M, Margolis KL, Wassertheil-Smoller S, Beresford SA, Cauley JA, Eaton CB, Gass M, Hsia J, Johnson KC, Kooperberg C, Kuller LH, Lewis CE, Liu S, Martin LW, Ockene JK, O’Sullivan MJ, Powell LH, Simon MS, Van Horn L, Vitolins MZ, Wallace RB. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013 Oct 2;310(13):1353-68. PMID 24084921.
  • Goldman JA. The Women’s Health Initiative 2004 – Review and Critique. MedGenMed. 2004;6(3):65. Published 2004 Aug 9. PMID PMC1435607.
  • Klaiber EL, Vogel W, Rako S. A critique of the Women’s Health Initiative hormone therapy study. Fertil Steril. 2005 Dec;84(6):1589-601. PMID 16359951.
  • Clark JH. A critique of Women’s Health Initiative Studies (2002-2006). Nucl Recept Signal. 2006;4:e023. Published 2006 Oct 30. PMID PMC1630688.
  • Utian WH. A decade post WHI, menopausal hormone therapy comes full circle–need for independent commission. Climacteric. 2012 Aug;15(4):320-5. PMID 22762439 .
  • Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, Køber L, Jensen JE. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ. 2012 Oct 9;345:e6409. PMID 23048011.
  • Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP; ELITE Research Group. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016 Mar 31;374(13):1221-31. PMID 27028912.
  • Lobo RA. Where are we 10 years after the Women’s Health Initiative? J Clin Endocrinol Metab. 2013 May;98(5):1771-80. PMID 23493433.

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