1 / 39

HORMONOTHERAPIE POSTMENOPAUSIQUE GRANDES ETUDES EPIDEMIOLOGIQUES : ASPECTS CARDIO-VASCULAIRES

HORMONOTHERAPIE POSTMENOPAUSIQUE GRANDES ETUDES EPIDEMIOLOGIQUES : ASPECTS CARDIO-VASCULAIRES. Ulysse GASPARD Service de Gynécologie-Obstétrique CHU – SAR TILMAN Université de Liège - Belgique. WOMEN’S HEALTH INITIATIVE. 16,608 « healthy » postmenopausal women (E+P)

terah
Télécharger la présentation

HORMONOTHERAPIE POSTMENOPAUSIQUE GRANDES ETUDES EPIDEMIOLOGIQUES : ASPECTS CARDIO-VASCULAIRES

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. HORMONOTHERAPIE POSTMENOPAUSIQUE GRANDES ETUDES EPIDEMIOLOGIQUES:ASPECTS CARDIO-VASCULAIRES Ulysse GASPARD Service de Gynécologie-Obstétrique CHU – SAR TILMAN Université de Liège - Belgique

  2. WOMEN’S HEALTH INITIATIVE • 16,608 « healthy » postmenopausal women (E+P) • 10,739 « healthy » surgically women (E) • Age 50 – 79 years • CEE 0.625mg (E)/ + MPA 2.5mg (E+P) • Duration 5.2 years (E+P) / 6.8 years (E) (planned 8.5 years) • Primary benefit : CHD events • Primary adverse event : breast cancer Writing Group for the Women’s Health Initiative Investigators, JAMA 2002;288:321-33 The Women’s Health Initiative Steering Committee. JAMA 2004;291:1701-12

  3. AIM AND RESULTS OF THE WHI STUDIES • WHI is a study on prevention of cardiovascular disease in elderly women by hormonal treatment and NOT on HRT in menopausal women. (Marcia Stefanick, Principal Investigator, Florence 24/04/2004) • Giving one [high dose] specific HRT regimen to [older] women who do NOT require HRT results in neither harm nor benefit for 99% of them. (John Stevenson, Amsterdam 03/10/2004) • WHI did not study the appropriate population in the appropriate time period to establish that HT does not exert a primary preventive effect on the risk of CHD. (Leon Speroff, Maturitas, 2004:48:3-4)

  4. I. HRT AND RISK OF VTE : OBSERVATIONAL STUDIES • Meta-analysis of new observational epidemiological studies (after 1996) from Daly, Grodstein, Jick, Perez Gutthann and Varas groups • RR according to type of current HRT regimen : • Overall RR for the FIRST year of treatment and thereafter : •  1 yr of HRT 4.2 (2.3 - 7.6) • > 1 yr 2.2 (1.3 - 3.8) • Dose response relationship : doubling of risk in CEE users < 0.6 vs > 0.6 (Daly and Jick) Any unopposed opposed oral transdermal RR 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) Castellsague J et al, Drug Safety 1998;18:117

  5. HRT AND RISK OF VTE : RANDOMIZED THERAPEUTIC TRIALS (RCTs) • WHI study HR = 2.11 (1.58 - 2.82) - (3.29if compliance adj.) (E+P) (idem PE or DVT; adj or not) 5.2 yrs FU - 2xmore 1st year of use ("healthy survivors“ ?) • HERS study HR = 2.7 (1.4 - 5.0) p = 0.003 4.1 yrs FU - 2x more 2 first years of use, mainly for PE rather than DVT Risk was decreased with Aspirin or Statins ! HR 0.5 (0.2 – 0.9) • Tamoxifen and Raloxifene RCTs : RR  2.3 (Fisher 1998; Cummings 1999) • BERAL's meta-analysis of RCTs : RR 2.2 (1.5 - 3.2) Beral V et al, Lancet 2002;360:942

  6. Venous Thromboembolic disease outcomes in WHI-E-only arm (*) DVT significant only for nominal CI 95% p 0.03 (**) P value for interaction NS (0.39) WHI Steering Committee JAMA 2004;291:1701

  7. RISK OF VTE DURING USE OF TRANSDERMAL HRT • Oral E (+P)   in AT, PC, PS  in APCR (APTT and ETP based), F VIII, IX, XI  tPA, PAI1 FPA and F1+2 • Dose-related effects Sidelmann JJ et al, BJOG 2003;110:541 Oger E et al, ATVB 2003;23:1671 • Transdermal E (+P) no change Scarabin PY et al, ATVB 1997;17:3071 Scarabin PY et al, Lancet 2003;362:428

  8. DIFFERENTIAL ASSOCIATION OF ORAL AND TRANSDERMAL E-RT WITH VTE (ESTHER STUDY) • Oral ERT :  blood coagulation and  risk of VTE • Transdermal ERT : little effect on coag; ? VTE  Multicentre, hospital-based, case control study of PMW : 155 documented idiopathic VTE (92 PE + 63 DVT) vs 381 controls matched for centre, age, time of recruitment  Adj O.R. oral-ERTvs no use 3.5 (1.8 - 6.8) TTS-ERT vs no use 0.9 (0.5 - 1.6) • oral-ERT vs TTS-ERT estimated risk4.0 (1.9 - 8.3)  Transdermal safer than oral estrogen for VTE risk Scarabin P.Y. et al, Lancet 2003;362:428

  9. II. STROKE AND HRT USE NURSE'S HEALTH STUDY AND STROKE • Observational cohort study of 70.533 PMW followed up from 1976 to 1996; 767 strokes identified • Risk of stroke in HRT users vs non users : CEE  0.625mg/d RR 1.35 (1.08-1.68) CEE  1.25mg/d RR 1.63 (1.18-2.26) CEE + progestin RR 1.45 (1.10-1.92) • No increase in risk if CEE 0.3mg/d Grodstein F et al, Ann Intern Med 2000;133:933

  10. WHI (E+P): UPDATE ON STROKE IN PM WOMEN - n = 8506 CEE + MPA + 8102 placebo 50 - 79y.o.; F.U. 5.6yrs a) Overall strokes n = 151 (1.8%) treated and 107 (1.3%) placebo = +31% Overall HR 1.31 (1.08-2.08) : • ischemic (80%) 1.44 (1.09 - 1.90) • hemorrhagic (15%) 0.82 (0.43 - 1.56) Risk of ischemic stroke only is increased in all age subgroups. Risk factors are not modified by EE + MPA b) Case-control study : 140 strokes (cases) vs 513 controls; assessment of biomarkers of inflammation, thrombosis, lipids : increased risk of stroke NOT modified by E+P intake Significant increase in thrombotic stroke if CEE+MPA; reinforce initial results of WHI (JAMA 2002). Wassertheil-Smoller S - JAMA 2003;289:2673

  11. STROKE OUTCOMES IN WHI E-ONLY ARM (*) Excess risk of stroke only significant for nominal CI 95% (44 strokes in users vs 32 placebo per 10.000 WY; Z = - 2.72. Monitoring boundary was set at Z = - 2.69 WHI Steering Committee, JAMA 2004;291:1701

  12. WHI : STROKE RISK HR HR Stroke (E) Stroke (E+P) 5-10 10-15 Age (years) Years postmenopause Wassertheil-Smoller et al. JAMA 2003;289:2673-84 The Women’s Health Initiative Steering Committee. JAMA 2004;291:1701-12 (Courtesy J.C. Stevenson, Nov 2004)

  13. WOMEN'S ESTROGEN FOR STROKE TRIAL (WEST STUDY) • 664 PMW (mean age 71 years) with TIA or stroke • RCT E2 1mg/d vs placebo x 2-8 years • Overall RR E2 1.1 (0.8-1.4) for death or new stroke  E2 does not reduce mortality or recurrence of stroke in PMW with cerebrovascular disease. E2 not indicated for secondary prevention of cerebrovascular disease Viscoli CM et al, NEJM 2001;345:1243

  14. III. CHD/MI AND HRT USE • MI incidence 50-54yrs 50/100.000WY 60-64yrs 200/100,000WY • Ratio M/F 55-65yrs 3.3 : 1.0 Possible reasons for  risk with age =  atherosclerosis +  classical risk factors +  markers of inflammation, impaired thrombotic and rheological variables • Smoking impact calculated in PM women (studies from Grodstein, Sidney, Rosenberg and Psaty) overall RR 3.3 (2.9-3.7) • Hypertension impact overall RR 2.6 (2.3-2.9) Lowe GDO, Maturitas 2004; Farley T et al, Maturitas 2004

  15. NURSES’HEALTH STUDY :RISK OF CHD • Observational cohort study of 70533 postmenopausal women • Follow-up : 1976 to 1996 • 1258 non fatal MI or CHD death RR in current users of HRT 0.61 (0.52-0.71) • Evidence of primary prevention of CHD (MI) by E + P or E alone vs former or never use (*) • Recent Danish Nurses Obs Study : no beneficial effect of HT (*) Similar results for secondary prevention in that study Grodstein F et al, Ann Intern Med 2000;133:933 Lokkegaard E et al, BMJ 2003;326:426

  16. CHD OUTCOMES IN WHI (E + P) (*) Adjusted for age, coronary events/therapy and for sequential monitoring Manson JE et al NEJM 2003;349:523

  17. WOMEN’S HEALTH INITIATIVE • increased CHD events in early years • ? increased thrombogenesis / adverse remodelling • age skewed to older women • ? oestrogen dose too high • ? effect of MPA (E-alone arm had early “harm”) • ? healthy survivor effect CHD events trend p=0.02 Manson et al. N Engl J Med 2003; 349: 523-34 (Courtesy J.C. Stevenson, Nov 2004)

  18. CHD OUTCOMES IN WHI E-ONLY ARM WHI Steering Committee, JAMA 2004;291:1701-1712

  19. WHI: CHD RISK HR HR CHD events (E+P) CHD events (E) 10-19 age (years) years postmenopause Writing Group for the Women’s Health Initiative Investigators. JAMA 2002; 288: 321-33 The Women’s Health Initiative Steering Committee. JAMA 2004; 291: 1701-12 (Courtesy J.C. Stevenson, Nov 2004)

  20. HERS (I) TRIAL • 2763 women (1380 E+P vs 1383 placebo) • mean age 66.7 years • >6 months from cardiac event • conjugated equine oestrogens 0.625 mg + MPA 2.5 mg • event rate 3.3% (estimated 5%) • mean follow-up 4.1 years (estimated 4.75 years) • no overall benefit seen RH = 0.99 (0.82 – 1.14) CHD events trend p=0.009 (Courtesy J.C. Stevenson, Nov 2004) Hulley et al. J Am Med Assoc 1998; 260: 605-13

  21. ARE HRT’s EFFECTS ON CHD AGE-DEPENDENT ? • Nijmegen study : later age at menopause =  CV mortality (De Kleijn MJJ et al, Am J Epidemiol 2002;155:339) • Brachial artery flow-mediated dilation : in healthy and young HRT users w/o CHD Θin older women and HRT users with CHD (Herrington D et al, ATVB 2001;21:1955) • Clarkson non-human primates : Age, stage of atherosclerosis,  artery wall ER,  plaque inflammation suppress efficacy of HRT for decreasing plaque area.  Clarkson’s model : Window of opportunity for HRT benefit = 6 years postmenopause (Clarkson, Gynaec Forum 2004;9:11) • E  MMPs. Statins  MMPs - WHI (E+P):Statins +HRT : HR for CHD = 0,99;HRT and no statins HR=1.27 (Manson JE et al, NEJM 2003;349:523)

  22. MMP-9 Adventitia Media InternalElastic Lamina FibrousCap Fibrous Cap FibrousCap Plaque Plaque Fatty Streak/Plaque Plaque Necrotic Core Necrotic Core <35-45 yrs 45-55 yrs 55-65 yrs >65 yrs Relation of Age Distribution in WHI* to Stage of Progression of Coronary Artery Atherosclerosis 70% 20% 55-59 10% 50-54 0% 45% 60-69 25% 70-79 yrs Clarkson, 2002.

  23. Timing of HT and Prevention of Atherothrombosis Hypothetical Pathogenic Sequence No HRT MMP-9 Fibrous Cap Fibrous Cap Fibrous Cap Adventitia Media Internal Elastic Lamina Plaque Necrotic Core Necrotic Core Fatty Streak/Plaque HRT Early & Continued HRT Mural Thrombus HRT Late HRT 35–45 yrs 45–55 yrs > 65 yrs 55–65 yrs Clarkson, 2002.

  24. Hormone Therapy and Plaque Reduction A. Early Intervention B. Late Intervention 0.40 0.30 0.20 0.10 0 P=N.S. 70% P<0.05 Coronary Artery Plaque Size (mm2) Placebo CEE Baseline Placebo CEE CEE+ MPA Surgical Menopausal Monkeys Rx with Conjugated Estrogen With and Without MPA. Clarkson 2002. INT. J. FERTIL. 47:61

  25. DIFFERENCES BETWEEN OBSERVATIONAL AND CLINICAL TRIAL PARTICIPANTS Adapted from Clarkson TB et al, Gynaec Forum 2004;9:11

  26. Some problems with interpretation of RCTs in perimenopausal women • WHI was ten-fold underpowered to show cardioprotection of women starting HRT during menopausal transition (Naftolin, Fertil Steril, 2004) • Importance of timing 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 yrs HR 0.56 CEE alone vs placebo 60-69 yrs 0.92 70-79 yrs 0.94 Anderson G, 2003

  27. CONCLUSIONS : HT AND CVD (I) • Confirmation of increased risk of venousthromboembolism 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 • CHD : no primary prevention in older women by E+P and potentially E-alone; cardio-prevention if < 10 years postmenop not ruled out. No secondary prevention demonstrated. E-dose implied ?? Stevenson JC, Pract CV risk man 2003;1:7 Herrington DM et al, Atherosclerosis 2003;166:203

  28. CONCLUSIONS : HT AND CVD (II) • For risk of CHD we need to study a youngpostmenopausal 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) • The comparative study of Scarabin et al (Lancet 2003;362:428) on E2 oral vs transdermal has to be expanded/initiated not only in case of VTE but also for stroke and CHD • The estrogen dose and route, and the progestin type dose and regimen should be carefully selected (or different regimens compared) in these new randomized trials

  29. MOTOR CARS Lamborghini Both are motor cars……. …….but performance differs! Compare with HRT! (Courtesy J.C. Stevenson, Nov. 2004)

  30. ESTIMATING THE RISK-BENEFIT BALANCE FROM 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, 2003

  31. Global index of ALL clinical outcomes of WHI studies Stevenson J.C., 2004

  32. HT AND VTE IN POSTMENOPAUSALWOMEN : SUMMARY 1 • RR = 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 No primary or secondary prevention ? Explanation : Prothrombotic effect of E ? (dose/route)

  33. HRT AND STROKE IN POSTMENOPAUSAL WOMEN : SUMMARY 2 • RR =1.31-1.45 (OBS and RCT studies agree) • RR : not dependent of age or time since menopause Incidence increases from 2nd year of HT onwards • E-dose related; thrombotic stroke only • 2nd Prevention (WEST study) RR = 1.1 HT or ET : increased risk of thrombotic stroke in PMW No primary or secondary prevention ? Explanation : Prothrombotic effect of E ? (dose)

  34. HT AND CHD IN POSTMENOPAUSAL WOMEN : SUMMARY 3 • OBS and RCT studies disagree (healthy user bias in OBS a.o.) • OBS studies (eg NHS) : RR = 0.61 (I and II Prevention) • RCT studies - Older women + one high dose regimen of CEE + MPA - RR dependent of age and time since menopause • E+P RR = 1.24 : only significant 1st year (1.8) RR = 0.89 if < 10 years postmenop RR = 1.71 if > 20 years postmenop • E-only RR = 0.91 RR = 0.56 if PMW = 50-59 years of age • Secondary Prevention (HERS I + II) RR = 0.99 RR 1st year = 1.5 HT or ET : slightly increased risk of CHD in older women. Probability of LOWER risk in early postmenop(primaryprevention).No secondary prevention. ? Explanation : Prothrombotic and Proinflammatory effects of E,  in older women (unstable plaques) ?

  35. Effect of ET on coronary atherosclerosis in monkeys : timing of initiation Thomas B. Clarkson,Gynaecology Forum;Vol.9,n°3, 2004

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

  37. HERS II TRIAL • HERS – I : Higher risk of CHD events during the first year in E+P users Decreased risk during years 3 to 5 (significant trend)  HERS – II : Unblinded follow up for 2.7 additional years (93% of those surviving) • HERS-I overall RH 0.99 (0.81-1.22) HERS-II overall RH 1.00 (0.77-1.29) HERS-I + II overall RH 0.99 (0.84-1.17) (similar results after adjustment for confounders and use of statins) • CONCLUSION : HERS-I : early harm = prothrombotic effect of E+P ? late benefit : improvement due to HRT or healthy survivor effect ? HERS-II : benefit did not persist at 6.8years  E+P did not reduce risk of recurrent CHD in PM women with CHD Grady D et al, JAMA 2002;288:49

  38. Association Française pour l'Etude de la Ménopause 1979-2004 XXVesJournées

More Related