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.