BATTLE OF THE TITANS: W.H.I. VERSUS K.E.E.P.S.

THE ONLY THING CONSTANT IN LIFE IS CHANGE----Francois de la RochefoucauldBATTLE OF THE TITANS:W.H.I. VERSUS K.E.E.P.S.T. WATSON JERNIGAN, MD MA NMCPPROFESSOR AND CHAIRMANDEPARTMENT OF OB/GYNQUILLEN COLLEGE OF MEDICINEDisclosure 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.OBJECTIVESAs a result of participating in this activity, the participant will be able toDemonstrate an understanding of the intent and focus of the Womens Health Initiative (W.H.I.)Demonstrate an appreciation for the outcomes of the W. H. I.

OBJECTIVESDemonstrate an understanding of the format of the Kronos Early Estrogen Prevention Study

Demonstrate the similarities and differences between the outcomes of the two studiesINTENT OF THE PRESENTATIONAs 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.

LESSONS LEARNED ABOUT ESTROGENUse 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)IMPACT OF CARDIOVASCULAR DISEASE (CVD) ON WOMENIn 2012, CVD will impact approximately 515,000 American womenCVD claims more female lives than all forms of female cancer COMBINED64% of women who died suddenly of CVD had NO previous symptomsWhile incidence of new breast cancers cases has leveled, the number of deaths from breast cancer has decreased

MENOPAUSEAccording to records of prescriptions, there were 129 million prescriptions for Hormonal Therapy (HT) including estrogen in the year 2000In 2001, a Womens 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

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 effectBREAST CANCER HAZARD RATIOS (HRs) 1.26 (1.00-1.59)ABSOLUTE EXCESS RISKS PER 10,000 PERSON-YEARS WAS 8 MORE INVASIVE CANCERSRESULTS 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)POST-WHI MENOPAUSEAfter the 2002 WHI study was published approximately 65% of women on HT stopped therapyIn 2003, there were just over 76 million HT prescriptions dispensedBy 2008, this number had dropped to approximately 42 million prescriptions for HT in USA (29 million were for estrogen only RXs)POST W.H.I. EFFECTTrends in hormone therapy use before and after publication of the Womens Health Initiative trial: 10 years of follow-upPublished 2009 but showed the impact of the W.H.I. on European prescribing of estrogen in Barcelona, SpainBy 2007, there was a peak reduction of 89% in percentage of overall prevalenceBarbaglia, Gabriela MD, et al, Menopause Vol. 16, No. 9, 2009; 1061-1064

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 observationBreast Cancer HRs were NOT elevated as anticipatedneither were they statistically significant for reductionBREAST CANCER: 0.77 (0.59-1.01)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)TIMING HYPOTHESISWith the results of both arms of the W.H.I., there was concerns by practicing providersThe majority of menopausal patients placed on estrogen had recently undergone menopauseThese patients tended to be younger, more active, and healthierWindow of Opportunity Hypothesis developed

YEAR 2007Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since MenopauseRossouw et al reviewed the original data of the WHI and created a secondary analysisThe study reviewed both arms of the trials (E2 + P4 and E2 alone)

Rossouw, J. E. et al JAMA 2007; 297: 1465-1477YEAR 2007In the combined trials, there were 396 cases of CVD and 327 cases of stroke in the hormone treated groupIn the combined trials, there were 379 cases of CVD and 239 cases of stroke in the placebo groupFor 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

YEAR 2007Conclusion from Rossouw et als 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.

Kronos Longevity Research InstituteK: KRONOSE: EARLYE: ESTROGENP: PREVENTIONS: STUDY

K. E. E. P. S.Randomized, double-blinded, placebo-controlled, four (4) year clinical trialParticipants: healthy women ages 42-59 (mean age of 52) within three (3) years of menopauseLab values of menopausal patients: Plasma FSH > 35 and/or Serum Estradiol level < 40 pg/dlK. E. E. P. S. Patients were excluded for:Women with evidence of CVDWomen with plasma levels of Cholesterol or triglycerides that would require medical therapysevere obesityheavy smoking habitK. 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 200mgs for 12 days per month orally

Group 3: Placebo capsule daily + Placebo capsule for 12 days per month

KEEPS RANDOMIZED TRIALSEffects on Lipids and Lipoproteins in Recently Menopausal WomenCarotid Intima Media Thickness and Coronary Artery CalciumKEEPS Cognitive Function Outcomes including Verbal Learning & Memory; Auditory Attention& Working Memory; Visual Attention & Executive Function; Speeded LanguageK. E. E. P. S. Results after 48 months of treatment:As expected with any hormonal therapy, Vasomotor Symptoms (Hot Flashes & Night Sweats) were improved64% 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 studyK. E. E. P. S.For CAD: neither 0-CEE nor T-E2 significantly affected either systolic or diastolic BPYearly ultrasound imaging studies on all participants to estimate thickening of the wall of the common carotid arteriesCarotid Ultrasound studies showed similar rates of progression of arterial wall thickness in all 3 treatment groups over 4 years of studyK. 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 groupsK.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.

WHAT DOES THIS MEAN TO YOU?HORMONES 2013Times they are a changinSymptomatic young postmenopausal patients are candidates for estrogen WITHOUT over concern for CAD progressionControversy remains on Estrogen (Progestin?) impact on Cardiovascular system of menopausal patients who have no evidence of pre-existing condition

INDIVIDUALIZATION OF THERAPYA FINAL THOUGHTRELATIVE RISKCHARACTERISTIC14 2 FAMILY MEMBERS WITH BREAST CA 2.2 1 FAMILY MEMBER WITH BREAST CA1.8 OBESITY1.6 YOUNG AGE AT MENARCHE1.3 >30 AT BIRTH OF FIRST CHILD0.7MENOPAUSE