HORMONOTHERAPIE HORMONOTHERAPIE POSTMENOPAUSIQUE POSTMENOPAUSIQUE

GRANDES ETUDES GRANDES ETUDES EPIDEMIOLOGIQUESEPIDEMIOLOGIQUES::

ASPECTS CARDIO-VASCULAIRESASPECTS CARDIO-VASCULAIRES

Ulysse GASPARDUlysse GASPARDService de Gynécologie-ObstétriqueService de Gynécologie-ObstétriqueCHU – SAR TILMANCHU – SAR TILMANUniversité de Liège - BelgiqueUniversité de Liège - Belgique

WOMEN’S HEALTH INITIATIVEWOMEN’S HEALTH INITIATIVE

16,608 « healthy » postmenopausal women (E+P)16,608 « healthy » postmenopausal women (E+P) 10,739 « healthy » surgically women (E)10,739 « healthy » surgically women (E) Age 50 – 79 yearsAge 50 – 79 years CEE 0.625mg (E)/ + MPA 2.5mg (E+P)CEE 0.625mg (E)/ + MPA 2.5mg (E+P) Duration 5.2 years (E+P) / 6.8 years (E) (planned Duration 5.2 years (E+P) / 6.8 years (E) (planned

8.5 years)8.5 years) Primary benefit : CHD eventsPrimary benefit : CHD events Primary adverse event : breast cancerPrimary adverse event : breast cancer

Writing Group for the Women’s Health Initiative Investigators, JAMA 2002;288:321-33Writing Group for the Women’s Health Initiative Investigators, JAMA 2002;288:321-33The Women’s Health Initiative Steering Committee. JAMA 2004;291:1701-12The Women’s Health Initiative Steering Committee. JAMA 2004;291:1701-12

AIM AND RESULTS OF THE WHI STUDIESAIM AND RESULTS OF THE WHI STUDIES

WHI is a study on prevention of cardiovascular disease in WHI is a study on prevention of cardiovascular disease in elderly women by hormonal treatment and elderly women by hormonal treatment and NOTNOT on HRT in on HRT in menopausal women.menopausal women.

(Marcia Stefanick, Principal Investigator, Florence 24/04/2004)(Marcia Stefanick, Principal Investigator, Florence 24/04/2004)

Giving one [high dose] specific HRT regimen to [older] Giving one [high dose] specific HRT regimen to [older] women who do women who do NOTNOT require HRT results in neither harm require HRT results in neither harm nor benefit for 99% of them.nor benefit for 99% of them.

(John Stevenson, Amsterdam 03/10/2004)(John Stevenson, Amsterdam 03/10/2004)

WHI did not study the appropriate population in the WHI did not study the appropriate population in the appropriate time period to establish that HT does not exert appropriate time period to establish that HT does not exert a primary preventive effect on the risk of CHD.a primary preventive effect on the risk of CHD.

(Leon Speroff, Maturitas, 2004:48:3-4)(Leon Speroff, Maturitas, 2004:48:3-4)

I. HRT AND RISK OF VTE : OBSERVATIONAL I. HRT AND RISK OF VTE : OBSERVATIONAL STUDIESSTUDIES

Meta-analysis of new observational epidemiological studies (after Meta-analysis of new observational epidemiological studies (after 1996) from Daly, Grodstein, Jick, Perez Gutthann and Varas groups1996) from Daly, Grodstein, Jick, Perez Gutthann and Varas groups

RR according to type of current HRT regimen :RR according to type of current HRT regimen :

Overall RR for the Overall RR for the FIRST yearFIRST year of treatment and thereafter : of treatment and thereafter :

1 yr of HRT1 yr of HRT 4.2 (2.3 - 7.6)4.2 (2.3 - 7.6) > 1 yr > 1 yr 2.2 (1.3 - 3.8) 2.2 (1.3 - 3.8)

Dose response relationshipDose response relationship : doubling of risk in CEE users < 0.6 vs : doubling of risk in CEE users < 0.6 vs

> 0.6 (Daly and Jick)> 0.6 (Daly and Jick)

Castellsague J et al, Drug Safety 1998;18:117Castellsague J et al, Drug Safety 1998;18:117

Any unopposed opposed oral transdermalRR 2.6(1.6-4.2) 2.5(1.3-4.8) 3.1(1.6-5.8) 2.8(1.6-4.8) 2.1(1.0-4.7)

HRT AND RISK OF VTE : RANDOMIZED HRT AND RISK OF VTE : RANDOMIZED THERAPEUTIC TRIALS (RCTs)THERAPEUTIC TRIALS (RCTs)

WHI studyWHI study HR = 2.11 (1.58 - 2.82)HR = 2.11 (1.58 - 2.82) - (3.29if compliance adj.) - (3.29if compliance adj.)

(E+P) (E+P) (idem PE or DVT; adj or not) (idem PE or DVT; adj or not)

5.2 yrs FU - 2xmore 15.2 yrs FU - 2xmore 1stst year of use ("healthy survivors“ ?) year of use ("healthy survivors“ ?)

HERS studyHERS study HR = 2.7 (1.4 - 5.0)HR = 2.7 (1.4 - 5.0) p = 0.003 p = 0.003

4.1 yrs FU - 2x more 2 first years of use,4.1 yrs FU - 2x more 2 first years of use,

mainly for PE rather than DVTmainly for PE rather than DVT

Risk was decreased with Aspirin or Statins ! HR 0.5 Risk was decreased with Aspirin or Statins ! HR 0.5

(0.2 – 0.9)(0.2 – 0.9)

Tamoxifen and Raloxifene RCTs : Tamoxifen and Raloxifene RCTs : RR RR 2.3 2.3(Fisher 1998; Cummings 1999)(Fisher 1998; Cummings 1999)

BERAL's meta-analysis of RCTs : BERAL's meta-analysis of RCTs : RR 2.2 (1.5 - 3.2)RR 2.2 (1.5 - 3.2)

Beral V et al, Lancet 2002;360:942Beral V et al, Lancet 2002;360:942

Venous Thromboembolic disease outcomes in Venous Thromboembolic disease outcomes in WHI-E-only armWHI-E-only arm

VariableVariable E-only groupE-only group

n=5310n=5310

Placebo groupPlacebo group

n=5429n=5429

AdjustedAdjusted

hazard ratiohazard ratio

Adjusted Adjusted 95% CI95% CI

n (annualized %) n (annualized %)

VTE (all)VTE (all)

Deep vein ThrombDeep vein Thromb

Pulm. EmbolismPulm. Embolism BY AGEBY AGE

50-5950-59

60-6960-69

70-7970-79

101 (0.28)101 (0.28)

77 (0.21)77 (0.21)

48 (0.13)48 (0.13)

18 (0.15)18 (0.15)

49 (0.31)49 (0.31)

34 (0.40)34 (0.40)

78 (0.21)78 (0.21)

54 (0.15)54 (0.15)

37 (0.10)37 (0.10)

15 (0.13)15 (0.13)

39 (0.23)39 (0.23)

24 (0.28)24 (0.28)

1.331.33

1.471.47

1.341.34

1.221.22

1.311.31

1.441.44

0.86-2.080.86-2.08

0.87-2.47(*)0.87-2.47(*)

0.70-2.550.70-2.55

0.62-2.420.62-2.42

0.86-2.000.86-2.00

0.86-2.44(**)0.86-2.44(**)

(*) DVT significant only for nominal CI 95% p 0.03(*) DVT significant only for nominal CI 95% p 0.03

(**) P value for interaction NS (0.39)(**) P value for interaction NS (0.39)

WHI Steering Committee JAMA 2004;291:1701WHI Steering Committee JAMA 2004;291:1701

RISK OF VTE DURING USE OF RISK OF VTE DURING USE OF TRANSDERMAL HRTTRANSDERMAL HRT

Oral E (+P) Oral E (+P) in AT, PC, PS in AT, PC, PS in APCR (APTT and ETP based), in APCR (APTT and ETP based), F VIII, IX, XI F VIII, IX, XI

tPA, PAItPA, PAI11

FPA and FFPA and F1+21+2

Dose-related effectsDose-related effectsSidelmann JJ et al, BJOG 2003;110:541Sidelmann JJ et al, BJOG 2003;110:541Oger E et al, ATVB 2003;23:1671Oger E et al, ATVB 2003;23:1671

Transdermal E (+P) Transdermal E (+P) no changeno change Scarabin PY et al, ATVB 1997;17:3071Scarabin PY et al, ATVB 1997;17:3071

Scarabin PY et al, Lancet 2003;362:428Scarabin PY et al, Lancet 2003;362:428

DIFFERENTIAL ASSOCIATION OF ORAL AND DIFFERENTIAL ASSOCIATION OF ORAL AND TRANSDERMAL E-RT WITH VTE (ESTHER STUDY)TRANSDERMAL E-RT WITH VTE (ESTHER STUDY)

Oral ERT : Oral ERT : blood coagulation and blood coagulation and risk of VTE risk of VTE Transdermal ERT : little effect on coag; ? VTETransdermal ERT : little effect on coag; ? VTE

Multicentre, hospital-based, case control study of PMW : Multicentre, hospital-based, case control study of PMW : 155 documented idiopathic VTE (92 PE + 63 DVT) 155 documented idiopathic VTE (92 PE + 63 DVT) vsvs 381 381 controls matched for centre, age, time of recruitmentcontrols matched for centre, age, time of recruitment

Adj O.R. Adj O.R. oral-ERToral-ERT vs no use vs no use 3.5 (1.8 - 6.8) 3.5 (1.8 - 6.8)

TTS-ERTTTS-ERT vs no usevs no use 0.9 (0.5 - 1.6)0.9 (0.5 - 1.6) oral-ERT vs TTS-ERT estimated riskoral-ERT vs TTS-ERT estimated risk 4.0 (1.9 - 8.3)4.0 (1.9 - 8.3)

Transdermal Transdermal safer than oralsafer than oral estrogen for VTE risk estrogen for VTE risk

Scarabin P.Y. et al, Lancet 2003;362:428Scarabin P.Y. et al, Lancet 2003;362:428

II. STROKE AND HRT USEII. STROKE AND HRT USE NURSE'S HEALTH STUDY AND STROKE NURSE'S HEALTH STUDY AND STROKE

Observational cohort study of 70.533 PMW followed up Observational cohort study of 70.533 PMW followed up from 1976 to 1996; 767 strokes identifiedfrom 1976 to 1996; 767 strokes identified

Risk of stroke in HRT users vs non users :Risk of stroke in HRT users vs non users :

CEE CEE 0.625mg/d 0.625mg/d RRRR 1.35 (1.08-1.68)1.35 (1.08-1.68)

CEE CEE 1.25mg/d 1.25mg/d RRRR 1.63 (1.18-2.26)1.63 (1.18-2.26)

CEE + progestinCEE + progestin RRRR 1.45 (1.10-1.92)1.45 (1.10-1.92)

No increase in risk if CEE 0.3mg/dNo increase in risk if CEE 0.3mg/d

Grodstein F et al, Ann Intern Med 2000;133:933Grodstein F et al, Ann Intern Med 2000;133:933

- n = 8506 CEE + MPA + 8102 placebo 50 - 79y.o.; - n = 8506 CEE + MPA + 8102 placebo 50 - 79y.o.; F.U. 5.6yrsF.U. 5.6yrs

a) a) Overall strokesOverall strokes n = 151 (1.8%) treated and 107 (1.3%) placebo = +31% n = 151 (1.8%) treated and 107 (1.3%) placebo = +31%

Overall HR 1.31 (1.08-2.08) :Overall HR 1.31 (1.08-2.08) : ischemic (80%) 1.44 (1.09 - 1.90)ischemic (80%) 1.44 (1.09 - 1.90) hemorrhagic (15%) 0.82 (0.43 - 1.56)hemorrhagic (15%) 0.82 (0.43 - 1.56)

Risk of ischemic stroke only is increased in all age subgroupsRisk of ischemic stroke only is increased in all age subgroups . . Risk factors are not modified by EE + MPARisk factors are not modified by EE + MPA

b) b) Case-control studyCase-control study : 140 strokes (cases) vs 513 controls; assessment : 140 strokes (cases) vs 513 controls; assessment of biomarkers of inflammation, thrombosis, lipids : increased risk of of biomarkers of inflammation, thrombosis, lipids : increased risk of stroke NOT modified by E+P intakestroke NOT modified by E+P intake

Significant increase in thrombotic stroke if CEE+MPA; reinforce initial Significant increase in thrombotic stroke if CEE+MPA; reinforce initial results of WHI (JAMA 2002).results of WHI (JAMA 2002).

WHI (E+P):WHI (E+P): UPDATE ON STROKE IN PM WOMEN UPDATE ON STROKE IN PM WOMEN

Wassertheil-Smoller S - JAMA 2003;289:2673Wassertheil-Smoller S - JAMA 2003;289:2673

STROKE OUTCOMES IN WHI E-ONLY ARMSTROKE OUTCOMES IN WHI E-ONLY ARM

OutcomesOutcomes E-only groupE-only group

n=5310n=5310

Placebo groupPlacebo group

n=5429n=5429

Adjusted Adjusted hazard hazard

ratioratio

AdjustedAdjusted

95% CI95% CI

n (annualized %)n (annualized %)

Stroke allStroke all

FatalFatal

Non fatalNon fatal

158 (0.44)158 (0.44)

15 (0.04)15 (0.04)

114 (0.32)114 (0.32)

118 (0.32)118 (0.32)

14 (0.0414 (0.04

85 (0.23)85 (0.23)

1.391.39

1.131.13

1.391.39

0.97-1.990.97-1.99 (*) (*)

0.38-3.360.38-3.36

0.91-2.120.91-2.12

(*) (*) Excess risk of stroke only significant for nominal CI 95% (44 strokes in users Excess risk of stroke only significant for nominal CI 95% (44 strokes in users vs 32 placebo per 10.000 WY; Z = - 2.72. vs 32 placebo per 10.000 WY; Z = - 2.72.

Monitoring boundary was set at Z = - 2.69Monitoring boundary was set at Z = - 2.69

WHI Steering Committee, JAMA WHI Steering Committee, JAMA 2004;291:17012004;291:1701

WHI : STROKE RISKWHI : STROKE RISK

0

0,5

1

1,5

2

<5

0

0,5

1

1,5

2

50-59 60-69 70-79

HRHR HRHR

Stroke (E+P)Stroke (E+P) Stroke (E)Stroke (E)

5-10 10-155-10 10-15

Years postmenopauseYears postmenopause Age (years)Age (years)

Wassertheil-Smoller et al. JAMA 2003;289:2673-84Wassertheil-Smoller et al. JAMA 2003;289:2673-84

The Women’s Health Initiative Steering Committee. JAMA 2004;291:1701-12The Women’s Health Initiative Steering Committee. JAMA 2004;291:1701-12

(Courtesy J.C. Stevenson, Nov 2004)(Courtesy J.C. Stevenson, Nov 2004)

WOMEN'S ESTROGEN FOR STROKE WOMEN'S ESTROGEN FOR STROKE TRIAL (WEST STUDY)TRIAL (WEST STUDY)

664 PMW (mean age 71 years) with TIA or stroke664 PMW (mean age 71 years) with TIA or stroke

RCT E2 1mg/d vs placebo x 2-8 yearsRCT E2 1mg/d vs placebo x 2-8 years

Overall Overall RR E2 1.1 (0.8-1.4)RR E2 1.1 (0.8-1.4) for death or new stroke for death or new stroke

E2 does not reduce mortality or recurrence of strokeE2 does not reduce mortality or recurrence of stroke in in PMW with cerebrovascular disease. E2 not indicated for PMW with cerebrovascular disease. E2 not indicated for secondary prevention of cerebrovascular diseasesecondary prevention of cerebrovascular disease

Viscoli CM et al, NEJM 2001;345:1243Viscoli CM et al, NEJM 2001;345:1243

III. CHD/MI AND HRT USEIII. CHD/MI AND HRT USE MI incidenceMI incidence 50-54yrs50-54yrs 50/100.000WY50/100.000WY

60-64yrs 60-64yrs 200/100,000WY200/100,000WY Ratio M/FRatio M/F 55-65yrs55-65yrs 3.3 : 1.03.3 : 1.0

Possible reasons for Possible reasons for risk with age = risk with age = atherosclerosis + atherosclerosis + classical risk factors + classical risk factors + markers of inflammation, impaired markers of inflammation, impaired thrombotic and rheological variables thrombotic and rheological variables

Smoking impactSmoking impact calculated in PM women (studies from calculated in PM women (studies from Grodstein, Sidney, Rosenberg and Psaty)Grodstein, Sidney, Rosenberg and Psaty)overall RR 3.3 (2.9-3.7)overall RR 3.3 (2.9-3.7)

Hypertension impactHypertension impact overall RR 2.6 (2.3-2.9) overall RR 2.6 (2.3-2.9)

Lowe GDO, Maturitas 2004; Farley T et al, Maturitas 2004Lowe GDO, Maturitas 2004; Farley T et al, Maturitas 2004

NURSES’HEALTH STUDY :NURSES’HEALTH STUDY :RISK OF CHDRISK OF CHD

Observational cohort Observational cohort study of 70533 postmenopausal 70533 postmenopausal womenwomen

Follow-up : 1976 to 1996Follow-up : 1976 to 1996 1258 non fatal MI or CHD death1258 non fatal MI or CHD death

RR in current users of HRT RR in current users of HRT 0.61 (0.52-0.71)0.61 (0.52-0.71) Evidence of primary prevention of CHD (MI) by E + PEvidence of primary prevention of CHD (MI) by E + P

or E alone vs former or never use (*)or E alone vs former or never use (*) Recent Danish Nurses Obs Study : no beneficial effect of Recent Danish Nurses Obs Study : no beneficial effect of

HTHT

(*) Similar results for secondary prevention in that study(*) Similar results for secondary prevention in that study

Grodstein F et al, Ann Intern Med 2000;133:933Grodstein F et al, Ann Intern Med 2000;133:933

Lokkegaard E et al, BMJ 2003;326:426Lokkegaard E et al, BMJ 2003;326:426

CHD OUTCOMES IN WHI (E + P)CHD OUTCOMES IN WHI (E + P)

- Primary efficacy outcome of the trial = non fatal MI or death due to CHD - Primary efficacy outcome of the trial = non fatal MI or death due to CHD at 5.6yrsat 5.6yrs

OutcomesOutcomes E+P GroupE+P Group

n=8506n=8506

Placebo Placebo groupgroup

n=8102n=8102

Adjusted Adjusted Hazard RatioHazard Ratio

Adjusted CIAdjusted CI

95% (*)95% (*)

n (annualized %)n (annualized %)

All CHDAll CHD

Fatal CHDFatal CHD

188 (0.39)188 (0.39)

39 (0.08)39 (0.08)

147 (0.33)147 (0.33)

34 (0.08)34 (0.08)

1.241.24

1.101.10

0.97-1.600.97-1.60(NS)(NS)

0.65-1.890.65-1.89(NS)(NS)

(*) Adjusted for age, coronary events/therapy and for sequential monitoring(*) Adjusted for age, coronary events/therapy and for sequential monitoring

Manson JE et al NEJM 2003;349:523Manson JE et al NEJM 2003;349:523

WOMEN’S HEALTH INITIATIVEWOMEN’S HEALTH INITIATIVE

• increased CHD events in early yearsincreased CHD events in early years

• ? increased thrombogenesis / ? increased thrombogenesis / adverse remodellingadverse remodelling

• age skewed to older womenage skewed to older women

• ? oestrogen dose too high? oestrogen dose too high

• ? effect of MPA (E-alone arm ? effect of MPA (E-alone arm had early “harm”)had early “harm”)

• ? healthy survivor effect? healthy survivor effect0

0,4

0,8

1,2

1,6

2

0 1 2 3 4 5 6

years

RH

Manson et al. N Engl J Med 2003; 349: 523-34

CHD events

trend p=0.02

(Courtesy J.C. Stevenson, Nov 2004)(Courtesy J.C. Stevenson, Nov 2004)

CHD OUTCOMES IN WHI E-ONLY ARMCHD OUTCOMES IN WHI E-ONLY ARM

- Primary efficacy outcome=non fatal MI or death due to CHD at 6.8 years- Primary efficacy outcome=non fatal MI or death due to CHD at 6.8 years

OutcomesOutcomes E-only groupE-only group

n=5310n=5310

Placebo groupPlacebo group

n=5429n=5429

Adjusted Adjusted hazard ratiohazard ratio

AdjustedAdjusted

95% CI95% CI

n (annualized %)n (annualized %)

All CHDAll CHD

Fatal CHDFatal CHD

177 (0.49)177 (0.49)

54 (0.15)54 (0.15)

199 (0.54)199 (0.54)

59 (0.16)59 (0.16)

0.910.91

0.940.94

0.72-1.150.72-1.15

0.54-1.630.54-1.63

HR changes with time of study :HR changes with time of study :Year 1 1.16 Trend with time :Year 1 1.16 Trend with time :

Year 2 1.20 significant reductionYear 2 1.20 significant reduction

Year 3 0.89 of risk (P = 0.02)Year 3 0.89 of risk (P = 0.02)

Year 4 0.79Year 4 0.79

Year 5 1.28Year 5 1.28

Year 6 1.24Year 6 1.24

Year 7 0.42Year 7 0.42

WHI Steering Committee, JAMA 2004;291:1701-WHI Steering Committee, JAMA 2004;291:1701-17121712

WHI: CHD RISKWHI: CHD RISK

0

0,5

1

1,5

2

<10 >2010-19

years postmenopause age (years)

CHD events (E)HR

CHD events (E+P)HR

The Women’s Health Initiative Steering Committee. JAMA 2004; 291: 1701-12 Writing Group for the Women’s Health Initiative Investigators. JAMA 2002; 288: 321-33

0

0,5

1

1,5

2

50-59 60-69 70-79

(Courtesy J.C. Stevenson, Nov 2004)(Courtesy J.C. Stevenson, Nov 2004)

HERS (I) TRIALHERS (I) TRIAL

• 2763 women (1380 E+P vs 1383 2763 women (1380 E+P vs 1383 placebo)placebo)

• mean age 66.7 yearsmean age 66.7 years

• >6 months from cardiac event>6 months from cardiac event

• conjugated equine oestrogens 0.625 conjugated equine oestrogens 0.625 mg + MPA 2.5 mgmg + MPA 2.5 mg

• event rate 3.3% (estimated 5%)event rate 3.3% (estimated 5%)

• mean follow-up 4.1 years (estimated mean follow-up 4.1 years (estimated 4.75 years)4.75 years)

• no overall benefit seenno overall benefit seen

RH = 0.99 (0.82 – 1.14)RH = 0.99 (0.82 – 1.14)

0

0,4

0,8

1,2

1,6

0 1 2 3 4

years

RH

Hulley et al. J Am Med Assoc 1998; 260: 605-13

CHD events

trend p=0.009

(Courtesy J.C. Stevenson, Nov 2004)(Courtesy J.C. Stevenson, Nov 2004)

ARE HRT’s EFFECTS ON CHD AGE-DEPENDENT ?ARE HRT’s EFFECTS ON CHD AGE-DEPENDENT ? Nijmegen studyNijmegen study : later age at menopause = : later age at menopause = CV mortality CV mortality

(De Kleijn MJJ et al, Am J Epidemiol 2002;155:339)(De Kleijn MJJ et al, Am J Epidemiol 2002;155:339)

Brachial artery flow-mediated dilationBrachial artery flow-mediated dilation : :

in healthy and young HRT users w/o CHDin healthy and young HRT users w/o CHD

ΘΘ in older women and HRT users with CHDin older women and HRT users with CHD(Herrington D et al, ATVB 2001;21:1955)(Herrington D et al, ATVB 2001;21:1955)

Clarkson non-human primatesClarkson non-human primates : :

Age, stage of atherosclerosis, Age, stage of atherosclerosis, artery wall E artery wall ERR,,

plaque inflammation suppress efficacy of HRT for plaque inflammation suppress efficacy of HRT for

decreasing plaque area.decreasing plaque area.

Clarkson’s model : Window of opportunity for HRT benefit = Clarkson’s model : Window of opportunity for HRT benefit = 6 years postmenopause6 years postmenopause

(Clarkson, Gynaec Forum 2004;9:11)(Clarkson, Gynaec Forum 2004;9:11)

E E MMPs. Statins MMPs. Statins MMPs MMPs

- WHI (E+P):Statins +HRT : HR for CHD = 0,99;HRT and no statins - WHI (E+P):Statins +HRT : HR for CHD = 0,99;HRT and no statins HR=1.27 HR=1.27 (Manson JE et al, NEJM 2003;349:523)(Manson JE et al, NEJM 2003;349:523)

Relation of Age Distribution in WHI* to Stage of Relation of Age Distribution in WHI* to Stage of Progression of Coronary Artery AtherosclerosisProgression of Coronary Artery Atherosclerosis

Clarkson, 2002.

<35-45 yrs<35-45 yrs 45-55 yrs45-55 yrs 55-65 yrs55-65 yrs >65 yrs>65 yrs

Adventitia

Media

InternalElastic Lamina

FattyStreak/Plaque

FibrousCap

PlaqueNecrotic Core

FibrousCap Fibrous

Cap

MMP-9

Necrotic Core

PlaquePlaque

70%

0%

yrs

10%

50-54

20%

55-59

45%

60-69

25%

70-79

Timing of HT and Prevention of AtherothrombosisTiming of HT and Prevention of Atherothrombosis

Clarkson, 2002.

Hypothetical Pathogenic Sequence

No HRT

Adventitia

Media

Internal ElasticLamina

Fatty Streak/Plaque

HRT

FibrousCap

FibrousCap

FibrousCap

Mural Thrombus

35–45 yrs 45–55 yrs 55–65 yrs > 65 yrs

HRT

HRT Late

HRT Early &Continued

Plaque Necrotic Core Necrotic Core

MMP-9

Hormone Therapy and Plaque ReductionHormone Therapy and Plaque Reduction

0.40

0.30

0.20

0.10

0

Surgical Menopausal Monkeys Rx with Conjugated Estrogen With and Without MPA.

A. Early Intervention B. Late Intervention

Co

ron

ary

Art

ery

Pla

qu

e S

ize

(mm

2)

Placebo CEE Baseline Placebo CEE CEE+ MPA

70%

P<0.05

P=N.S.

Clarkson 2002. INT. J. FERTIL. 47:61

DIFFERENCES BETWEEN OBSERVATIONAL DIFFERENCES BETWEEN OBSERVATIONAL AND CLINICAL TRIAL PARTICIPANTSAND CLINICAL TRIAL PARTICIPANTS

Observational Clinical trials

Menopause symptomsMenopause symptoms

Age started HRTAge started HRT

Time since menopauseTime since menopause

Stage of atherosclerosisStage of atherosclerosis

Most users : symptomsMost users : symptoms

45-55 years45-55 years

0 – 1 year0 – 1 year

Fatty streaks, Fatty streaks, plaquesplaques

Few with symptomsFew with symptoms

63 (WHI)63 (WHI)

67 (HERS)67 (HERS)

> 70 (WEST)> 70 (WEST)

14 (WHI)14 (WHI)

18 (HERS) 18 (HERS)

> 20 (WEST)> 20 (WEST)

Advanced, unstable Advanced, unstable plaquesplaques

Adapted from Clarkson TB et al, Gynaec Forum 2004;9:11Adapted from Clarkson TB et al, Gynaec Forum 2004;9:11

Some problems with interpretation of RCTs in Some problems with interpretation of RCTs in perimenopausal womenperimenopausal women

WHI was ten-fold underpoweredten-fold underpowered to show cardioprotection of women starting HRT during menopausal transition

(Naftolin, Fertil Steril, 2004)

Importance of timingtiming of intervention : peri or postmenopausal : the 6-year window

(Clarkson data !)

E-only arm of WHI : RR of CHD = 0.91 vs 1.24 (E+P arm) Past E use in E-only arm was 35% (young age) vs 15%

use in E+P arm 50-59 yrs50-59 yrs HR HR 0.560.56 CEE alone vs placeboCEE alone vs placebo

60-69 yrs 0.92

70-79 yrs 0.94

Anderson G, 2003Anderson G, 2003

CONCLUSIONS : HT AND CVD (I)CONCLUSIONS : HT AND CVD (I)

1. Confirmation of increased risk of venousincreased risk of venous thromboembolism and thrombotic strokethromboembolism and thrombotic stroke in postmenopausal women particularly if risk factors; accidents begin early (1-2 y) E dose and route strongly implied in VTE; potentially in stroke

2.2. CHD : no primary prevention in older womenCHD : no primary prevention in older women by E+P and potentially E-alone; cardio-prevention if < 10 yearscardio-prevention if < 10 years postmenop not ruled out. No secondary preventionNo secondary prevention demonstrated. E-dose implied ??

Stevenson JC, Pract CV risk man 2003;1:7Stevenson JC, Pract CV risk man 2003;1:7

Herrington DM et al, Atherosclerosis 2003;166:203Herrington DM et al, Atherosclerosis 2003;166:203

CONCLUSIONS : HT AND CVD (II)CONCLUSIONS : HT AND CVD (II)

3.3. For risk of CHD we need to study a youngFor risk of CHD we need to study a young postmenopausal healthy populationpostmenopausal healthy population in order to establish that MT does or does not exert a primary preventive effect on CHD (Speroff L, Maturitas 2004;48:3-4)

4. The comparative study of Scarabin et al (Lancet 2003;362:428) on E2 oral vs transdermalE2 oral vs transdermal has to be expanded/initiated not only in case of VTE but also for stroke and CHD

5. The estrogenestrogen dose and route, and the progestinprogestin type dose and regimen should be carefully selectedcarefully selected (or different regimens compared) in these new randomized trials

MOTOR CARSMOTOR CARS

Lamborghini

Both are motor cars…….…….but performance differs!

Compare with HRT!

(Courtesy J.C. Stevenson, Nov. 2004)(Courtesy J.C. Stevenson, Nov. 2004)

ESTIMATING THE RISK-BENEFIT BALANCE ESTIMATING THE RISK-BENEFIT BALANCE FROM WHI STUDIESFROM WHI STUDIES

Global index of health benefit vs risk created by Data Safety and Monitoring Board Adverse outcome of HRT (E+P) demonstrated :

HR 1.15(1.03-1.28)=excess risk in 19 women/10,000WY (< 0.2%)

Adverse outcome not found in WHI E-only arm :

HR 1.01(0.91-1.12)=benefit in 2 women/10,000WY (< 0.05%)

This global index does not encompass ALL clinical outcomes recorded in the WHI studies !

- This global index was not previously validated

- Not really considered as playing a role in understanding how hormones should be used

Stevenson JC, 2004; Anderson G, 2003Stevenson JC, 2004; Anderson G, 2003

Global index of ALL clinical outcomes of WHI Global index of ALL clinical outcomes of WHI studiesstudies

Comparison of all events (excess or reduction) per 10,000 Comparison of all events (excess or reduction) per 10,000 WY in WHI studiesWY in WHI studies

WHI E+P StudyWHI E+P Study WHI E-only StudyWHI E-only Study

RISKSRISKS

All CVD 25All CVD 25

All cancers 3All cancers 3

BENEFITSBENEFITS

All fractures 44All fractures 44

Deaths 1Deaths 1

RISKSRISKS

All CVD 24All CVD 24

Deaths 3Deaths 3

BENEFITSBENEFITS

All fractures 56All fractures 56

All cancers 7All cancers 7

Overall Balance : + 17Overall Balance : + 17

= overall benefit in 8 women per = overall benefit in 8 women per 10,000 WY10,000 WY

Overall Balance : + 36Overall Balance : + 36

= overall benefit in 22 women per = overall benefit in 22 women per 10,000 WY10,000 WY

Stevenson J.C., 2004Stevenson J.C., 2004

HT AND VTE IN POSTMENOPAUSALHT AND VTE IN POSTMENOPAUSAL WOMEN : SUMMARY 1WOMEN : SUMMARY 1

RR = 2-3RR = 2-3 (OBS and RCT studies agree) RR not dependent of age or time since menopause 1st year of HT (E or E+P) = 2 x more VTE E-dose related; E-route probably related RR if HT + risk factor (eg FV Leiden)

HT or ET : increased risk of VTE in PMW HT or ET : increased risk of VTE in PMW

No primary or secondary preventionNo primary or secondary prevention

? Explanation : Prothrombotic effect of E ? (dose/route)

HRT AND STROKE IN POSTMENOPAUSAL HRT AND STROKE IN POSTMENOPAUSAL WOMEN : SUMMARY 2WOMEN : SUMMARY 2

RR =1.31-1.45RR =1.31-1.45 (OBS and RCT studies agree) (OBS and RCT studies agree) RR : RR : not dependent of age or time since menopausenot dependent of age or time since menopause

Incidence increases from 2nd year of HT onwardsIncidence increases from 2nd year of HT onwards E-dose related; thrombotic stroke onlyE-dose related; thrombotic stroke only 2nd Prevention (WEST study) RR = 1.12nd Prevention (WEST study) RR = 1.1

HT or ET : increased risk of thrombotic stroke in PMWHT or ET : increased risk of thrombotic stroke in PMW

No primary or secondary preventionNo primary or secondary prevention

? Explanation : Prothrombotic effect of E ? (dose)

HT AND CHD IN POSTMENOPAUSAL HT AND CHD IN POSTMENOPAUSAL WOMEN : SUMMARY 3WOMEN : SUMMARY 3

OBS and RCT studies disagree (healthy user bias in OBS a.o.)OBS and RCT studies disagree (healthy user bias in OBS a.o.) OBS studies (eg NHS) : OBS studies (eg NHS) : RR = 0.61RR = 0.61 (I and II Prevention) (I and II Prevention) RCT studies - Older women + one high dose regimen of RCT studies - Older women + one high dose regimen of CEE + MPACEE + MPA

- RR dependent of age and time since menopause- RR dependent of age and time since menopause E+P E+P RR = 1.24 RR = 1.24 : only significant 1st year (1.8) : only significant 1st year (1.8)

RR = 0.89RR = 0.89 if < 10 years postmenop if < 10 years postmenop RR = 1.71 if > 20 years postmenopRR = 1.71 if > 20 years postmenop

E-only RR = 0.91E-only RR = 0.91 RR = 0.56RR = 0.56 if PMW = 50-59 years of age if PMW = 50-59 years of age

Secondary PreventionSecondary Prevention (HERS I + II) (HERS I + II) RR = 0.99RR = 0.99 RR 1st year = 1.5RR 1st year = 1.5

HT or ET : slightly increased risk of CHD in older womenHT or ET : slightly increased risk of CHD in older women. . Probability of LOWER risk in early postmenopProbability of LOWER risk in early postmenop (primary(primary prevention)prevention).. No secondary preventionNo secondary prevention..

?? Explanation : Prothrombotic and Proinflammatory effects of E, Explanation : Prothrombotic and Proinflammatory effects of E, in in older women (unstable plaques) ?older women (unstable plaques) ?

Effect of ET on coronary atherosclerosis in monkeys : timing of initiationEffect of ET on coronary atherosclerosis in monkeys : timing of initiation

Thomas B. Clarkson,Gynaecology Forum;Vol.9,n°3, 2004Thomas B. Clarkson,Gynaecology Forum;Vol.9,n°3, 2004

JoAnn E. Manson, N Engl J Med 2003;349:523-34JoAnn E. Manson, N Engl J Med 2003;349:523-34

HERS II TRIALHERS II TRIAL HERS – I : HERS – I :

Higher risk of CHD events during the first year in E+P usersHigher risk of CHD events during the first year in E+P users

Decreased risk during years 3 to 5 (significant trend)Decreased risk during years 3 to 5 (significant trend)

HERS – II :HERS – II :

Unblinded follow up for 2.7 additional years (93% of those surviving)Unblinded follow up for 2.7 additional years (93% of those surviving) HERS-I HERS-I overall RHoverall RH 0.99 0.99 (0.81-1.22)(0.81-1.22)

HERS-IIHERS-II overall RHoverall RH 1.001.00 (0.77-1.29)(0.77-1.29)

HERS-I + IIHERS-I + II overall RHoverall RH 0.990.99 (0.84-1.17)(0.84-1.17)

(similar results after adjustment for confounders and use of statins)(similar results after adjustment for confounders and use of statins) CONCLUSION : CONCLUSION :

HERS-I : early harm = prothrombotic effect of E+P ?HERS-I : early harm = prothrombotic effect of E+P ?

late benefit : improvement due to HRT or healthy survivor late benefit : improvement due to HRT or healthy survivor effect ?effect ?

HERS-II : benefit did not persist at 6.8yearsHERS-II : benefit did not persist at 6.8years

E+P did not reduce risk of recurrent CHD in PM women with CHDE+P did not reduce risk of recurrent CHD in PM women with CHD

Grady D et al, JAMA 2002;288:49Grady D et al, JAMA 2002;288:49

Association Française pour l'Etude de la MénopauseAssociation Française pour l'Etude de la Ménopause

1979-2004 XXVes Journées