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THE ONLY THING CONSTANT IN LIFE IS CHANGE

THE ONLY THING CONSTANT IN LIFE IS CHANGE. ----Francois de la Rochefoucauld. BATTLE OF THE TITANS: W.H.I. VERSUS K.E.E.P.S. T. WATSON JERNIGAN, MD MA NMCP PROFESSOR AND CHAIRMAN DEPARTMENT OF OB/GYN QUILLEN COLLEGE OF MEDICINE. Disclosure Statement of Financial Interest.

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THE ONLY THING CONSTANT IN LIFE IS CHANGE

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  1. THE ONLY THING CONSTANT IN LIFE IS CHANGE ----Francois de la Rochefoucauld

  2. BATTLE OF THE TITANS:W.H.I. VERSUS K.E.E.P.S. T. WATSON JERNIGAN, MD MA NMCP PROFESSOR AND CHAIRMAN DEPARTMENT OF OB/GYN QUILLEN COLLEGE OF MEDICINE

  3. Disclosure Statement of Financial Interest DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

  4. OBJECTIVES • “As a result of participating in this activity, the participant will be able to…” • Demonstrate an understanding of the intent and focus of the Women’s Health Initiative (W.H.I.) • Demonstrate an appreciation for the outcomes of the W. H. I.

  5. OBJECTIVES • Demonstrate an understanding of the format of the Kronos Early Estrogen Prevention Study • Demonstrate the similarities and differences between the outcomes of the two studies

  6. INTENT OF THE PRESENTATION • As health care providers, all of us here are affected by the changing world outside of our care areas. Every year/month/day, there is new information to process and to implement into our day-to-day practices. This presentation attempts to add to the information about treatment of patients in early menopause especially in contrast to previous information.

  7. LESSONS LEARNED ABOUT ESTROGEN • Use of estrogens improve menopausal symptoms such as hot flashes and night sweats (1940s) • Use of estrogens can cause thromboembolic phenomenon (1950s) • Use of unopposed estrogen can lead to endometrial hyperplasia or even endometrial cancer (1970s) • Use of estrogens can reduce incidence of Coronary Heart Disease (CAD) (1990s)

  8. IMPACT OF CARDIOVASCULAR DISEASE (CVD) ON WOMEN • In 2012, CVD will impact approximately 515,000 American women • CVD claims more female lives than all forms of female cancer COMBINED • 64% of women who died suddenly of CVD had NO previous symptoms • While incidence of new breast cancers cases has leveled, the number of deaths from breast cancer has decreased

  9. MENOPAUSE • According to records of prescriptions, there were 129 million prescriptions for Hormonal Therapy (HT) including estrogen in the year 2000 • In 2001, a Women’s Health Initiative (WHI) study was undertaken to evaluate the efficacy of Estrogen and Progestin as well as Estrogen alone in preventing heart disease in postmenopausal women

  10. RESULTS OF E2+P4 TRIAL OF W.H.I. • The study was halted after 5.2 years because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect • BREAST CANCER HAZARD RATIOS (HRs) 1.26 (1.00-1.59) ABSOLUTE EXCESS RISKS PER 10,000 PERSON-YEARS WAS 8 MORE INVASIVE CANCERS

  11. RESULTS OF E2 + P4 TRIAL OF W.H.I. • The HRs for CHD, Stroke, Pulmonary Embolus (PE), and Total Cardiovascular Disease (CVD) were all elevated: CHD: 1.29 (1.02-1.63) STROKE: 1.41 (1.07-1.85) PE: 2.13 (1.39-3.25) TOTAL CVD: 1.22 (1.09-1.36)

  12. POST-WHI MENOPAUSE • After the 2002 WHI study was published approximately 65% of women on HT stopped therapy • In 2003, there were just over 76 million HT prescriptions dispensed • By 2008, this number had dropped to approximately 42 million prescriptions for HT in USA (29 million were for estrogen only RXs)

  13. POST W.H.I. EFFECT • “Trends in hormone therapy use before and after publication of the Women’s Health Initiative trial: 10 years of follow-up” • Published 2009 but showed the impact of the W.H.I. on European prescribing of estrogen in Barcelona, Spain • By 2007, there was a peak reduction of 89% in percentage of overall prevalence • Barbaglia, Gabriela MD, et al, Menopause Vol. 16, No. 9, 2009; 1061-1064

  14. RESULTS OF E2 ALONE TRIAL OF W.H.I. • In 2004, the NIH decided to end the intervention phase of the trial early after 6.8 years of observation • Breast Cancer HRs were NOT elevated as anticipated…neither were they statistically significant for reduction BREAST CANCER: 0.77 (0.59-1.01)

  15. RESULTS OF E2 ALONE TRIAL OF W.H.I. • Despite the use of estrogen for greater duration, there was NOT overall increase in harm ratios as with E2 + P4: CHD: 0.91 (0.75-1.12) PE: 1.34 (0.87-2.06) STROKE: 1.39 (1.10-1.77) TOTAL CVD: 1.12 (1.01-1.24)

  16. “TIMING HYPOTHESIS” • With the results of both arms of the W.H.I., there was concerns by practicing providers • The majority of menopausal patients placed on estrogen had recently undergone menopause • These patients tended to be younger, more active, and healthier • “Window of Opportunity” Hypothesis developed

  17. YEAR 2007 • “Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause” • Rossouw et al reviewed the original data of the WHI and created a secondary analysis • The study reviewed both arms of the trials (E2 + P4 and E2 alone) Rossouw, J. E. et al JAMA 2007; 297: 1465-1477

  18. YEAR 2007 • In the combined trials, there were 396 cases of CVD and 327 cases of stroke in the hormone treated group • In the combined trials, there were 379 cases of CVD and 239 cases of stroke in the placebo group • For women with less than 10 years since Menopause, the RR was 0.76 95% CI 0.50-1.16 Rossouw, J. E. et al JAMA 2007; 297: 1465-1477

  19. YEAR 2007 • Conclusion from Rossouw et al’s article: “Sub group analyses in the 2 WHI trials of HT suggested a non-significant reduction in the risk of CHD in women aged 50-59 years in the trial of CEE or in women with less than 10 years of menopause in the trial of CEE + MPA.”

  20. Kronos Longevity Research Institute • K: KRONOS • E: EARLY • E: ESTROGEN • P: PREVENTION • S: STUDY

  21. K. E. E. P. S. • Randomized, double-blinded, placebo-controlled, four (4) year clinical trial • Participants: healthy women ages 42-59 (mean age of 52) within three (3) years of menopause • Lab values of menopausal patients: Plasma FSH > 35 and/or Serum Estradiol level < 40 pg/dl

  22. K. E. E. P. S. • Patients were excluded for: …Women with evidence of CVD …Women with plasma levels of Cholesterol or triglycerides that would require medical therapy …severe obesity …heavy smoking habit

  23. K. E. E. P. S. • 772 participants • Randomized into three (3) groups of therapy • Group 1: CEE 0.45 mgs daily orally + Micronized Progesterone 200 mgs for 12 days per month orally Group 2: Transdermal estradiol patch 50 ugs daily + Micronized Progesterone 200 mgs for 12 days per month orally Group 3: Placebo capsule daily + Placebo capsule for 12 days per month

  24. KEEPS RANDOMIZED TRIALS • Effects on Lipids and Lipoproteins in Recently Menopausal Women • Carotid Intima Media Thickness and Coronary Artery Calcium • KEEPS Cognitive Function Outcomes including Verbal Learning & Memory; Auditory Attention& Working Memory; Visual Attention & Executive Function; Speeded Language

  25. K. E. E. P. S. • Results after 48 months of treatment: • As expected with any hormonal therapy, Vasomotor Symptoms (Hot Flashes & Night Sweats) were improved • 64% of all participants (466) completed all 4 years of the trial (WHI compliance 50%-60%) • another 16% of participants (118) discontinued the study medication but continued to be followed throughout study

  26. K. E. E. P. S. • For CAD: neither 0-CEE nor T-E2 significantly affected either systolic or diastolic BP • Yearly ultrasound imaging studies on all participants to estimate thickening of the wall of the common carotid arteries • Carotid Ultrasound studies showed similar rates of progression of arterial wall thickness in all 3 treatment groups over 4 years of study

  27. K. E. E. P. S. • Researches saw no statistically significant differences in rates of breast cancer, endometrial cancer, myocardial infarction, TIA, stroke or venous thromboembolic disease between the three groups

  28. K.E.E.P.S. • “We conclude that hormone treatment at the doses employed and in this healthy, recently menopausal population neither significantly reduced nor accelerated progression of atherosclerosis as measured by arterial imaging.”

  29. WHAT DOES THIS MEAN TO YOU?

  30. HORMONES 2013 • “Times they are a changin’” • Symptomatic young postmenopausal patients are candidates for estrogen WITHOUT over concern for CAD progression • Controversy remains on Estrogen (Progestin?) impact on Cardiovascular system of menopausal patients who have no evidence of pre-existing condition

  31. INDIVIDUALIZATION OF THERAPY

  32. A FINAL THOUGHT • RELATIVE RISKCHARACTERISTIC • 14 2 FAMILY MEMBERS WITH BREAST CA • 2.2 1 FAMILY MEMBER WITH BREAST CA • 1.8 OBESITY • 1.6 YOUNG AGE AT MENARCHE • 1.3 >30 AT BIRTH OF FIRST CHILD • 0.7 MENOPAUSE <49 YEARS OF AGE • 1.3 HORMONE THERAPY (E+P)<5 YEARS Archer, David. “Postmenopausal HRT: What is fact, what is fiction” OBG MANAGEMENT; June 2006: 76-85.

  33. “THE ONLY CONSTANT IS CHANGE, CONTINUING CHANGE, INEVITABLE CHANGE—THAT IS THE DOMINANT FACTOR IN SOCIETY TODAY. NO SENSIBLE DECISION CAN BE MADE ANY LONGER WITHOUT TAKING INTO ACCOUNT NOT ONLY THE WORLD AS IT IS, BUT THE WORLD AS IT WILL BE.”--ISSAC ASIMOV

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