Natural Hormones Replacement An Evidence and Practice Based Approach

Transcription

1 Natural Hormones Replacement An Evidence and Practice Based Approach Andres Ruiz, PharmD, MSc, FACA President/Partner Stonegate Pharmacy PRESENTED BY THE AMERICAN COLLEGE OF APOTHECARIES 2830 SUMMER OAKS DRIVE BARTLETT, TN COPYRIGHT ACA This document is the property of the American College of Apothecaries. These materials may not be copied, photocopied, reproduced, translated, or distributed in any form or by any means without the prior written consent of the American College of Apothecaries.

2 Disclosures Andres Ruiz declare(s) no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria. The American College of Apothecaries is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

3 Learning Objectives At the conclusion of this program, the participating pharmacist or technician will be able to: Identify the cardiovascular and breast cancer adverse effects associated with hormone replacement therapy Discuss the safety of Testosterone Replacement Therapy with regard to cardiovascular and prostate health

4 WOMEN

5 Safety of Hormone Replacement Therapy

6 Rise of the Safety Concerns with Cardiovascular Health and Hormone Replacement Subsequent cardiac events in postmenopausal women with established CHD HERS II Persistant risk reduction with overall reduced risk of CHD events with additional follow-up. CHD events and breast cancer in healthy women 2006-WHI CE monotherapy CHD events and breast cancer in healthy women CHD and stroke across categories of age and years since menopause 1998-HERS 2002-Womens Health Iniative (WHI) CE + MPA 2007-WHI combined analysis

7 HERS: CE + MPA Trial Randomized, double-blind, placebo-controlled trial (Jan Sept 1994) Primary outcome: CHT on subsequent cardiac events in postmenopausal women with established CHD n= 2,763; < 80 years and postmenopausal **Mean age= 66.7 years CE (0.625mg)+ MPA(2.5mg) = 1,380 Placebo= 1,383

8 HERS: CE + MPA Trial 1 Outcomes and thrombolic events: CE + MPA vs Placebo (cases/10,000 pt years) 331 vs. 336 CHD events (P = 0.91) 126 vs. 102 CHD deaths (P = 0.23) 205 vs. 228 nonfatal MIs (P = 0.46) 60 vs. 21 thromboembolic events (P = 0.002) CHD events by year: CE + MPA vs Placebo [cases/10,000 pt years (95% CI)] Year 1: 425 vs. 280 events ( ) Year 2: 370 vs. 371 ( ) Year 3: 288 vs. 331 ( ) Year 4-5: ( )

9 HERS: CE + MPA Trial Author s comments Noted early increase in CHD-immediate prothrombotic, proischemic, or proarrhythmic effects Effects gradually outweight by lipid lowering effects Older population with many risk factors Possibly okay to continue CHT based on trend

10 HERS: Follow-Up 93% surviving consented to unblinded follow-up (2.7 yrs) End points CE + MPA vs Placebo (cases/10,000 pt years [ )] 418 vs. 421 CHD events ( ) 206 vs. 207 CHD deaths ( ) 231 vs. 235 nonfatal MIs ( ) Take home points Lower CHD event rates DID NOT persist CHD events increased during additional years

11 WHI: CE + MPA Trial Randomized, double-blind, placebo-controlled trial ( ) Primary outcome: CE + MPA on CHD in healthy postmenopausal women n= 16,608; years old **Mean age= 63.3 years CE (0.625mg)+ MPA(2.5mg) = 8,506 Placebo= 8,102

12 WHI: CE + MPA Trial 1 outcomes and thrombolic events: CE + MPA vs Placebo [cases/10,000 pt years (95% CI)] 37 vs. 30 CHD events ( ) 7 vs. 6 CHD deaths ( ) 30 vs. 23 nonfatal MIs ( ) 34 vs. 16 thromboembolic events ( ) 157 vs. 132 total cardiovascular disease ( ) Pre-existing CHD and CHD outcomes (400 patients) 19 vs 16 CHD events (CI )

13 WHI: CE + MPA Trial Author s comments Additional follow-up would unlikely yield favorable results CE + MPA does not confer benefit for preventing CHD among women with CHD It remains possible that transdermal E2 with P4, which more closely mimics the normal physiology and metabolism of endogenous sex hormones, may provide a different risk-benefit profile

14 WHI: CE Trial Randomized, double-blind, placebo-controlled trial ( ) Primary outcome: CE + MPA on CHD in healthy postmenopausal women n= 10,739; years old **Mean age= 63.6 years CE (0.625mg) = 5,310 Placebo= 5,429

15 WHI: CE Trial Primary outcomes: CE vs. Placebo [cases/10,000 pt years (95% CI)] 53 vs. 56 CHD events (P = 0.63) 16 vs. 63 CHD deaths (P = 0.96) 40 vs. 43 nonfatal MIs, including silent MIs (P = 0.43) 38 vs. 42 nonfatal MIs, excludng silent MIs (P = 0.41)

16 Events per 10,000 pt years Events per 10,000 pt years WHI:CE Trial CE and CHD Events by Age Group CE and CHD Events by Years Since Hysterectomy <10 10 to 19 >20 P for trend= 0.07 CE Placebo P for trend= 0.06 CE Placebo

17 WHI: CE Trial Take home points CE provide no overall coronary protection Possibly lower CHD risk with CE in women 50 to 59 years of age No possible correlation between time since menopause and coronary risk

18 Events per 10,000 pt years Events per 10,000 pt years WHI: Combined Trial WHI combined trials secondary analysis to increase sample size CHT and CHD Events by Age Group CHT and CHD Events by Years Since Menopause * CI * CI <10 10 to 19 >20 P for trend 0.16 CHT Placebo *P=0.03 compared to P for trend= 0.02 CHT Placebo *P=0.03 compared to <10

19 WHI: Combined Trial Take home points Non-significant reduction CHD in women y/o and women with < 10 years since menopause Years since menopause influence hormone effects on CHD risk most Results are consistent with findings from observational studies

20 Synthesis Despite initial hopes of cardioprotection with CHT additional follow-up and the WHI showed no benefit compared to placebo CE has not been shown to provide cardioprotection The further past menopause women initiate CHT, their risk for CHD events significantly increases, yet an age association is yet to be identified

21 Conventional Hormone Therapy: Breast Cancer 2002-WHI CE + MPA CHD events and breast cancer in healthy women 2006-WHI CE mono-therapy CHD events and breast cancer in healthy women 2008-WHI 3 year follow-up analysis CHD and breast cancer cancer 3 years post invtervention

22 WHI: CE + MPA Trial WHI CE + MPA trial with primary adverse outcome (invasive breast cancer incidence) Overall: 1.26 fold increase (38 vs. 30 cases/10,000 person-years; 95% CI, ) Never users: non-significant increase (35 vs. 33 cases/10,000 person-years; 95% CI, ) <5 years: 2 fold increase (40 vs. 20 cases/10,000 person-years; 95% CI, ) 5-10 years: near 5 fold increase (50 vs. 11 cases/10,000 person-years; 95% CI, ) 10 years: non-significant 1.12 fold increase (35 vs. 33 cases/10,000 person-years; 95% CI, )

23 WHI: CE + MPA Trial Treatment Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 CE + MPA Placebo Author s comments The risk for breast cancer emerges several years after treatment Results are consistent with epidemiological data The trial cannot distinguish the effects of estrogen from progestin Hazard Ratio

24 WHI: CE Trial WHI primary adverse outcome (invasive breast cancer incidence) Reduction in invasive breast cancer (34 vs. 42 cases/10,000 person-years; 95% CI, ) Reduction in total breast cancer (34 vs 42 cases/10,000 person-years; 95% CI, ) Adherence adjustments: significant reduction (HR, 0.67; 95% CI, ) Fewer localized disease (18 vs. 25 cases/10,000 person-years; 95% CI, )

25 WHI: CE Trial WHI primary adverse outcome (invasive breast cancer incidence) Continued Fewer ductal carcinomas (16 vs. 23 cases/10,000 patient years; 95% CI, ) but not lobular disease (5 vs. 3 cases/10,000 patient years; 95% CI, ) Larger invasive breast cancers (1.8cm (SD, 1.2) vs. 1.5cm (SD, 0.9); P = 0.03) and a higher portion were node positive (35.5% vs. 23.3%, P =0.7) CE (cases per 10,000 personyears) Placebo (cases per 10,000 person-years) 95% CI No prior HT use No prior estrogen use No prior CE + MPA use No benign breast disease No 1 relative with breast cancer

26 WHI: CE Trial Author s comments CE does not increase breast cancer incidence and may decrease the risk of early stage disease and ductal carcinomas CE might decrease breast cancer incidence in certain subgroups Early observational reporting increased risk were uncontrolled for mammography screening and may have had selection bias Subsequent or continued estrogen use would not reduce risk in women further in those with prior hormone

27 WHI: CE + MPA Follow-Up WHI CE + MPA 2.4 years additional follow-up Breast cancer incidence: 42 vs 33 per 10,000 pt years; CI No difference in breast cancer incidence (P=0.97)

28 WHI: CE + MPA Follow-Up Take home points Increased risk of breast cancer appeared to persist despite D/C of CHT In 2003, US experienced a 6.7% decline in breast cancer incidence Data from current study is insufficient to support or rebuke the temporal decline in breast cancer incidence

29 Synthesis Breast cancer risk significantly increases with continued use of CE + MPA and persists post discontinuation CE has not been shown to increase the risk of breast cancer and may prove to decrease the risk of breast cancer in particular populations

30 BHRT Safety Cardiovascular Health Breast Cancer BHRT as a Safer Alternative

31 Bioidentical Hormone Replacement Therapy: Cardiovascular Health 1995-PEPI and 1998-Gerhard M P4 does not i/w ERT cardioprotective and vascular effects 2001-EPAT and PHOREA E2 slows subclinical atherosclerosis; progestin blunts effects 2007-ESTHER Topical E2+P4 does not increase VTE risk

32 PEPI Trial Outcome Placebo CE CE+MPA (cyc) CE+MPA (con) CE + P4 (cyc) P Value HDL (mg/dl, CI) -1.2 (-2.2,0.2) 5.6 (4.5,6.7) 1.6 (0.5, 2.7) 1.2 ( ) 4.1 (3.1, 5.1) <0.001 LDL (mg/dl, CI) -4.1 (-6.5,-1.8) (16.8,- 12.1) (-20.1,-15.4) (-18.8,- 14.2) (-17,-12.5) <0.001 TG (mg/dl, CI) -3.2 (-7.2,0.7) 13.7 (9.3,18) 12.7 (8.5,16.8) 11.4 (7,15.9) 13.4 (9.1,17.7) <0.001 Fibrinogen (g/l) 0.1 (0.04,0.16) (-0.08, 0.04) Fasting Glucose (mg/dl, CI) 0.06 (0,0.12) 0.01 (-0.04,0.07) 0.01 (-0.04,0.07) < (-1.6,0.6) -2.8(-4.0,-1.7) -2.7 (-3.8,-1.7) -2.1 (-2.9,-1.2) -2.5 (-3.6,-1.4) 0.3 2h Glucose (mg/dl, CI) -0.1 (-4.0, 3.9) 2.0 (-2.3,6.4) 7.5 (4.0,11.1) 6.9 (3.3, 10.5) 3.0 (-0.6, 6.7) 0.01 JAMA. 1995;273:

33 Brachail Artery Diamerter % Brachail Artery Diamerter % Gerhard et al. E2 decreased TC by 6.7±1.8% (P<0.001) and LDL by 10.9±2.7% (P<0.001) E2 + P4 decreased TC by 5.8±1.7% (P<0.001) and LDL by 8.4±2.4% (P<0.001) Flow-mediated Endothelium Dependent Vasodilation Flow-mediated Endothelium Independent Vasodilation 12.00% 10.00% 8.00% 6.00% 4.00% 4.70% * 11.10% * 9.60% 13.00% 12.50% 12.00% 11.50% 12.70% 12.10% 11.30% 2.00% 11.00% 0.00% Placebo Estradiol Estradiol + Progesterone 10.50% Placebo Estradiol Estradiol + Progesterone *P<0.001 compared to placebo P= NS compared to E2

34 EPAT Study Outcome Placebo (n=102) All Participants No Lipid Lowering Therapy Lipid Lowering Therapy E2 (n=97) P value Placebo (n=35) E2 (n=42) P Value Placebo (n=67) E2 (n=55) P Value HDL (mg/dl) < <0.001 LDL (mg/dl) TC (mg/dl) TG (mg/dl) Fasting Insulin (pmol/l) Fasting Glucose (mg/dl) > Hemoglobin A1c > Ann Intern Med. 2001; 135:

35 PHOREA Study Results Mean maximum CIMT in the carotid arteries increased in all groups, by 0.03 mm LDL decreased 16.3 mg/dl (Group1) and 15.9 mg/dl (Group2) (P <0.001 both groups) HDL increased by 0.83 mg/dl (Group1; P > 0.2) and 3.3 mg/dl (Group2; P = 0.028) E2 was the only predictor of endothelium-dependent vasodilation (p<0.001) Take home points E2 plus progestin does not slow the progression of subclinical atherosclerosis A lower dose of progestin does not result in a more beneficial effect on CIMT Similar blunted lipid improvements noted in the PEPI trial Arterioscler Thromb Vasc Biol. 2001; 21: 262-8

36 ESTHER Study Route of Estrogen and Progesterone VTE Cases (n=259) Controls (n=603) Crude OR (95% CI) Adjustment 1 OR (95% CI) Adjsutment 2 OR (95% CI) Nonuse Oral ERT Use ( ) 4 ( ) 4.2 ( ) Transdermal ERT Use ( ) 0.8 ( ) 0.9 ( ) No progestogen P ( ) 1 ( ) 0.7 ( ) Pregnane derivatives (0.4) 0.9 ( ) 0.9 ( ) Norpregnane derivatives ( ) 4 ( ) 3.9 (1.5-10) Circulation. 2007; 115: 840-5

37 Synthesis Practitioners are left to rely on CHD risk factors as the main outcome E2 and P4 improves lipids, carbohydrate metabolism and decreased fibrinogen levels Unlike oral CHT or BHRT, transdermal E2 + P4 has a favorable VTE risk profile E2 has been shown to decrease CIMT and slow subclinical atherosclerosis P4 does NOT interfere with the vasodilatory effects or favorable lipid effects of E2 BHRT may prove to be cardioprotective

38 Bioidentical Hormone Replacement Therapy: Breast Cancer 1995-Chang JK P4 prevent breast epithelial hyperplasia P4 counteracts epithelial proliferation 1998-Foidart JM P4 prevent breast epithelial hyperplasia P4 counteracts epithelial proliferation 2008-E3N Cohort E1: BCA risk (33 cases; ) E2+P4 BCA risk (32 cases; )

39 Chang KJ et al. Outcome Placebo P4 E2 E2 + P4 Mitosis per 1,000 cells 0.51 ± ± ± ± 0.42 PCNA (labeling index %) 7.8 ± ± ± ± 4.4 P < 0.05 versus placebo P < 0.05 versus P4 group P < 0.05 versus E2 group A significant correlation between mitotic index and PCNA labeling index (P <0.05) Author s comments P4 significantly reduces the proliferative effects of E2 Data supports P4 during the luteal phase favorably effects breast epithelium P4 has a therapeutic effect to prevent breast epithelial hyperplasia when used >10 days per month at substitutive doses

40 Foidart JM et al. Outcome Placebo P4 E2 E2 + P4 Mitotic index per 1,000 cells 0.15 ± ± ± ± 0.15 (SD) PCNA labeling index (%) (SD) 0.1 ± ± ± ± 1.1 P < 0.05 versus placebo P < 0.05 versus P4 group P < 0.05 versus E2 group Author s comments Results are similar to that of Chang and colleagues Percutaneous P4 can possibly counter act sustained epithelial cell proliferation associated with isolated estrogen exposure

41 E3N Cohort Study Cases/10,000 person-years Relative risk (95% CI) Estrogen alone ( ) Estrogen combined with: Progesterone ( ) Dydrogesterone ( ) Other progestagens ( ) Weak estrogens* ( ) Norethisterone acetate ( ) MPA ( ) Others/unknown HRT ( ) All HRT ( ) *Weak Estrogens= Orally or vaginally administered promestriene or estriol Intramusculary administered estrogen or progestogen; androgen; nasally administered estrogen; transdermally administered progestogen; or tibolone

42 Synthesis Observational data has shown E2 + P4 may not increase the risk for breast cancer but E2 alone was correlated with increased risk E2 + P4 breast epithelial RCTs has shown E2 does increase cellular proliferation while P4 is associated with decreased cellular proliferation

43 Synthesis Practitioners are left to rely on CHD surrogate markers E2: improves cardiovascular surrogate markers P4: does NOT interfere with cardiovascular effects BHRT may prove to be cardioprotective P4 and E2+P4 decreases cellular proliferation E2 + P4: may not increase the risk for breast cancer

44 MEN

45 Safety of TRT Cardiovascular Risk Prostate Cancer (PCA)

46 TRT: CHD Risk Fernandez- Balsells Testosterone therapy had no significant effects on all-cause mortality, cardiovascular events, or cardiovascular risk factors Vigen TRT with significant medical comorbidities was associated with increased risk of mortality, MI, or ischemic stroke Shores TRT was associated with decreased mortality compared with no testosterone treatment Higher mortality was correlated with lower baseline T levels and a shorter duration of TRT(P< for both)

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48 TRT: Prostate Cancer Huggins In 3 patients with prostatic cancer, TRT caused a sharp rise of serum acid phosphatase In 1 case of TRT cessation there was a decrease of the acid phosphatase Isbarn The theory that testosterone invariably enhances PCa growth has not been substantiated Stimulating effect of T on the prostate is maximally reached at low T levels Serum T levels do not necessarily reflect the intraprostatic T levels

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51 Synthesis TRT has no significant effects on all-cause mortality, CHD events, or CHD risk factors TRT is associated with decreased mortality compared with no TRT TRT may prove to be cardioprotective Stimulating effect of T on the prostate is maximally reached at low T levels T and TRT does not enhance PCA

52 Need More Information? Andres Ruiz, PharmD, MSc, FACA President/Partner Stonegate Pharmacy