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In the center of the city, in the center of life, with passion for care
Serge Rozenberg CHU St Pierre VUB-‐ULB Belgium
serge_rozenberg@stpierre-‐bru.be
CARDIO ‘015 Hormone replacement therapy :
actuelle ou obsolète ?
Conflict of interest & Disclosure
§ Conflicts of interest: § None for this presentation § Disclosures § Research funding IRIS- King Baudouin
Fondation, Vesale research Foundation, Amgen, MSD
§ Speakers bureau &/or Advisory Boards § Abbot, Pfizer, Will, Gedeon Richter, MSD,
Amgen, Mithra
Overview
• Overview of risk-‐benefit • Symptoms • Osteoporosis • CVD • DVT-‐PE • Breast cancer
Should Women use HRT?
Pendulum Swing
Yes HRT: Hormone Replacement Therapy WHI: Women’s Health IniOaOve
Age at menopause as a risk factor for cardiovascular mortality
Yvonne Van der Schouw et al 1996
Should Women use HRT?1
Pendulum Swing
NO HRT: Hormone Replacement Therapy
WHI : E+P per 10 000 woman years
• -‐ 46 fractures • + 8 breast cancer • + 9 stroke • + 12 DVT, deep, + 9 pulmonary embolism • Other events that increased with estrogen + progesOn treatment included
deaths from lung cancer, gallbladder disease, probable demenOa and urinary inconOnence
H Nelson et al Ann Intern Med. 2012;157:104-113.
Antoine, Ameye, Paesmans Rozenberg Maturitas 2014
Should Women use HRT? New data WHI, DOPS, KEEPS,
ELITE, E3N Pendulum Swing
Yes ? HRT: Hormone Replacement Therapy WHI: Women’s Health IniOaOve DOPS: Danish PrevenOon Osteoporosis Study KEEPS : Kronos Early Estrogen Prevention Study ELITE: Early versus Late Intervention Trial with Estradiol
What are the indications for MHT?
Flushes • Over half (50.3%) of postmenopausal women experienced either mild (24.6%), moderate (17.6%), or severe (8.1%) VMS.
• DiBonaventura et al Int J Womens Health. 2013 May 24;5:261-‐9.
HRT reduces symptom frequencye and severity as compared with placebo OR= 0.13, 95% CI 0.08-0.22. MacLennan et al Climacteric. 2001 Mar;4(1):58-74./Cochrane review
Menopause and Urogenital Ageing
© National Geographic. Photo: Brendan McCarthy
Recurrent urinary tract infecOon (UTI)
Discharge and odour
Decrease in blood flow
Decrease in lubricaOon
Loss of elasOcity
Pain
Atrophic vaginiOs
Sexual dissatisfaction
Atrophic Vagini.s1
1. Adapted from Castelo-Branco C, et al. Maturitas 2005; 52S: S46-52
Osteoporosis : Definition Consensus Development 1993
Normal trabecular bone
Osteoporotic trabecular bone
SequenOal Treatment of a Fragility Fracture Risk
Strontium ranelate
Bisphosphonates Denosumab
HRT SERMs TSEC
PTH
New druggs Odanacatib ?
50 65 75 Age
Risk
Palacios S. Drugs of Today 2011, 47(3): 187-195
Take Home message • Use it if you need it !
Holy Smoke !
Cumula.ve Annualized Incidence Rates for Clinical Outcomes in the WHI Estrogen-‐Alone Trial According to 10-‐Year Age Groups at Enrolment1
1. LaCroix, A. Z. et al. JAMA 2011;305:1305-‐1314
1. Ross. N Engl J Med 1999; 340:115-‐126
Atherosclerosis1
DOPs (Danish Osteoporosis Prevention Study),
• 20 yr study, • partly randomised, • tests hypothesis that HRT iniOated shortly ajer menopause reduces the risk of later osteoporoOc fractures.
• Adapted from Schierbeck et al BMJ 2012
Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial
Schierbeck et al BMJ 2012
Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal
women: randomised trial
Schierbeck et al BMJ 2012
Young & early menopause
Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial
Schierbeck et al BMJ 2012
HRT users less at risk
Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial
Schierbeck et al BMJ 2012
ELITE: Early versus Late Intervention Trial
• ELITE: Early versus Late IntervenOon RCT to determine HT effects on subclinical atherosclerosis across menopause strata.
• Double blind, 2 × 2 factorial design (n=643 free of CVD)
• 1mg E2 (vaginal progesterone gel) or placebo for up to 6 to 7 years according to Ome since menopause (<6 or ≥10 y)
• measurements of the caroOd artery. CaroOd artery inOma-‐media thickness (CIMT) every six months.
• cardiac computed tomography • Hodis HN et al Menopause. 2015 Apr;22(4):391-‐401.
CIMT outcome Menopause stratum
CIMT rate (95%CI)
CIMT rate (95%CI)
P value within stratum
P value interac.on
E2 (n=297) Placebo (n=299)
0.007
< 6 YRS 0.0044 (0.0026-‐0.0061)
0.078 (0.0060-‐0.0096)
0.079
> 10 YRS 0.0100 (0.0085-‐0.0115)
0.088 (0.0073-‐0.0103)
0.29
P VALUE P<0.001
Rate of change in common carotid artery intima- media thickness measured every 6 months Adapted from Hodis IMS Cancun 2014
Not Significant
KEEPS: RCT
• Kronos Early Estrogen PrevenOon Study. CEE or transdermal E2 on atherosclerosis.
• Healthy menopausal women aged 42 -‐ 58 years, between 6 and 36 months from last menses without prior CVD
• Coronary artery calcium (CAC) score less than 50 Agatston units and had not received estrogen or lipid-‐lowering therapy for at least 90 days.
• IntervenOon: Oral (o-‐CEE), 0.45 mg/d, or transdermal 17-‐estradiol (t-‐E2), 50 mcg/d, each with 200 mg of oral progesterone for 12 days per month, or placebo for 48 months.
• Herman Annals of Internal medicine July 2014
Arterial Imaging Outcomes and Cardiovascular Risk Factors in Recently Menopausal Women (KEEPS)
Harman, et al Ann Intern Med. 8/ 2014
Not Significant
Effects of low-dose versus placebo or conventional-dose postmenopausal hormone therapy on variables related to
cardiovascular risk: a systematic review and meta-analyses of randomized clinical trials.
• 28 trials (3360 paOents). • Low-‐dose HT vs placebo or convenOonal-‐dose HT did not effect weight, BMI, BP, CRP or HDL-‐C.
• Casanova G et al J Clin Endocrinol Metab. 2015 Mar;100(3):1028-‐37. doi: 10.1210/jc.2014-‐3301. Epub 2014 Dec 16.
Effects of low-dose versus placebo or conventional-dose postmenopausal hormone therapy on variables related to
cardiovascular risk: a systematic review and meta-analyses of randomized clinical trials.
• low-‐dose HT was associated with bever lipid profile vs placebo, and induced higher total and LDL-‐C and lower triglycerides vs convenOonal-‐dose HT.
• Casanova G et al JCEM 2015 Mar;100(3):1028-‐37.
COMMITTEE OPINION juin 2013 (Replaces No. 420, November 2008) Committee on Gynecologic Practice (ACOG)
VTE
Postmenopausal Hormone Therapy and Risk of Idiopathic Venous Thromboembolism :Results From
the E3N Cohort Study
Canonico et al Arterioscler Thromb Vasc Biol. 2010;30:340-345
Through the eyes of an amazone
Marie Mandy
No increase increase
Anderson et al Lancet Oncology 2012
Decrease
Invasive Breast Cancer in WHI studies: Absolute risk – events/10,000 women-years in the two WHI trials1,2
+9 - 6
WHI: Women’s Health IniOaOve E +P: Estrogen plus ProgesOn
E + P Placebo E only Placebo
Women aged 50-59 years
1. Adapted from Chlebowski RT, et al. JAMA 2010; 304:1684-92 2. Adapted from Anderson GL, et al. Lancet Oncology 2012: 13: 476-86
From Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort Fournier A et al 2014
From Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort Fournier A et al 2014
From Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort Fournier A et al 2014
Take Home message • Don’t use it if you don’t need it !
Take Home message
• Use the smallest needed dose and the safest regimens !
Key points • Postmenopausal hormone therapy (PMHT) is
indicated for the relief of menopausal symptoms in paOents aged <60 years with climacteric symptoms
• Low doses of PMHT should be used when possible
• PMHT can be prescribed for a short period of Ome to treat osteoporosis when non-‐oestrogen therapies are unsuitable or in women who suffer simultaneously from climacteric symptoms and osteoporosis
• Postmenopausal hormone therapy: risks and benefits. Rozenberg S, Vandromme J, Antoine C. Nat Rev Endocrinol. 2013 Feb 19.
Key points • PMHT for PrevenOon of coronary heart disease ?
• For young healthy women not an indicaOon but no certainly no contra-‐indicaOon
• Oestrogen therapy might reduce the risk of atherosclerosis in young women early ajer menopause, but risk of coronary heart disease might be worsened as a result of thrombosis in at-‐risk and elderly paOents
• PMHT may increase Breast cancer risk : • Use of a estrogen only (hysterectomized women), sequenOal progesOn
and a non-‐androgenic progesOn might be safer than use of conOnuous androgenic progesOn
• Short term (< 5 yrs entails less or no risk) • long-‐term (>5 years) EPT containing progestagens other than
progesterone or dydrogesterone may be associated with some residual risk even many years ajer treatment cessaOon
• Postmenopausal hormone therapy: risks and benefits. Rozenberg S, Vandromme J, Antoine C. Nat Rev Endocrinol. 2013 Feb 19.