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An «  evidence based approach » to HRT?

An «  evidence based approach » to HRT?. Serge Rozenberg UMC ST Pieter Serge_rozenberg@stpierre-bru.be Serge.rozenberg@skynet.be. Q: Is HT right for my patient?.

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An «  evidence based approach » to HRT?

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  1. An « evidence based approach » to HRT? Serge Rozenberg UMC ST Pieter Serge_rozenberg@stpierre-bru.be Serge.rozenberg@skynet.be

  2. Q: Is HT right for my patient? • 52-year-old woman at average risk for breast cancer and osteoporosis who is having menopause-related hot flashes and disturbed sleep. • 58-year-old woman with osteopenia whose mother had breast cancer. • 65-year-old woman with a history of coronary revascularization and documented osteoporosis. Manson J and Martin K. N Engl J Med 2001 Deborah Grady, NEJM 2006

  3. Patients • 52-year-old woman at average risk for breast cancer and osteoporosis who is having menopause-related hot flashes and disturbed sleep. • 58-year-old woman with osteopenia whose mother had breast cancer. • 65-year-old woman with a history of coronary revascularization and documented osteoporosis. Manson J and Martin K. N Engl J Med 2001 Deborah Grady, NEJM 2006

  4. Patients • 52-year-old woman at average risk for breast cancer and osteoporosis who is having menopause-related hot flashes and disturbed sleep. • 58-year-old woman with osteopenia whose mother had breast cancer. • 65-year-old woman with a history of coronary revascularization and documented osteoporosis. Manson J and Martin K. NEJM 2001 Deborah Grady, NEJM 2006

  5. Evidence Based Medicine • The process of systematically finding, appraising, and using contemporaneous research findings as the basis for clinical decisions. …

  6. Evidence Based Medicine • Evidence-based medicine follows 4 steps: • I. formulate a clear clinical question • II. search the literature • III. evaluate (critically appraise) the evidence for its validity and usefulness; • IV. implement useful findings in clinical practice. • Adapted from BMJ 1995;310:1122

  7. Patient 1 • 52-year-old woman at average risk for breast cancer and osteoporosis who is having menopause-related hot flashes and disturbed sleep.

  8. Search the literature • Favor RCT

  9. Symptom severity was also significantly reduced compared with placebo OR= 0.13, 95% CI 0.08-0.22. MacLennan et al Climacteric. 2001 Mar;4(1):58-74./Cochrane review

  10. )

  11. Search the literature • Favor RCT • Find representative population • Most randomised studies addressed elderly populations • Problem of subanalyses and heterogeneity

  12. WHI CEE n = 5310 CEE+MPA n = 8506 Placebon = 5429 Placebo n = 8102 Characteristic Age group at screening 50-59 years 60-69 years 70-79 years 1637 (30.8) 1673 (30.8) 2387 (45.0) 2465 (45.4) 1286 (24.2) 1291 (23.8) 2839 (33.4) 2683 (33.1) 3853 (45.3) 3657 (45.1) 1814 (21.3) 1762 (21.7) Data are number (%) of patients; HRT and placebo groups were similar. Baseline Characteristics: Age Groups Writing Group for the Women's Health Initiative Investigators. JAMA 2002;288:321-33. Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

  13. WHI: Total Mortality by Age at Baseline CHD Stroke Total Mortality CHD Stroke Total Mortality CHD Stroke Total Mortality Rossouw, et al. JAMA 2007;297:1465-1477.

  14. WHI: Total Mortality by Age at Baseline CHD Stroke Total Mortality CHD Stroke Total Mortality CHD Stroke Total Mortality Rossouw, et al. JAMA 2007;297:1465-1477.

  15. CHD Events by Age in WHI-E 50-59 Years 60-69 Years 70-79 Years CHD HR HR HR Event (95% CI) (95% CI) (95% CI) CHD 0.63 0.94 1.11 (MI or CD) (0.36-1.08) (0.71-1.24) (0.82-1.52) Angina 0.59 1.03 1.12 (0.34-1.02) (0.76-1.41) (0.78-1.60) CABG or PCI 0.55 0.99 1.04 (0.35-0.86) (0.78-1.27) (0.78-1.39) MI,CD,CABG,PCI 0.66 1.02 1.08 (0.44-0.97) (0.83-1.25) (0.85-1.38) MI,CD,CABG,PCI, 0.66 0.98 1.05 and angina (0.45-0.96) (0.80-1.20) (0.84-1.33) Angina confirmed with hospitalization and confirmatory stress test or coronary artery disease by angiography Hsia, et al. Arch Intern Med 2006;166:357-365.

  16. WHI: Total Mortality by Age at Baseline CHD Stroke Total Mortality CHD Stroke Total Mortality CHD Stroke Total Mortality Rossouw, et al. JAMA 2007;297:1465-1477.

  17. Absolute Risk of Stroke According to Years Since Menopause (WHI-EP Trial) and Age (WHI-E Trial) when Randomized Absolute Risk Number of Strokes per 10,000 Women per Year No. of Additional Cases of Stroke per 10,000 Women per Year of Therapy Placebo (n=8102) CEE+MPA (n=8506) Years Since1 Menopause <5 7 10 3 5 to <10 11 17 6 10 to 15 17 27 10 >15 42 48 6 Age2 50-59 17 15 -2 60-69 31 51 20 70-79 59 76 16 Placebo (n=5429) CEE (n=5310) 1Wassertheil-Smoller S, et al. JAMA 2003;289:2673-2684. 2Rossouw J, et al. JAMA 2007;297:1465-1477.

  18. Absolute Risk of Venous Thrombolic Events (VTEs) According to Age when Randomized to WHI Trials Absolute Risk Number of VTEs per 10,000 Women per Year No. of Additional Cases of VTEs per 10,000 Women per Year of Therapy Placebo (n=8102) CEE+MPA (n=8506) Age1 50-59 8 19 11 60-69 19 35 16 70-79 27 62 35 Age2 50-59 12 16 4 60-69 25 32 7 70-79 31 42 11 Placebo (n=5429) CEE (n=5310) 1Cushman M, et al. JAMA 2004;292:1573-1580. 2Curb JD, et al. Arch Intern Med 2006;166:772-780.

  19. Rossouw et al JAMA. 2007;297:1465-1477

  20. Rossouw et al JAMA. 2007;297:1465-1477

  21. Rossouw et al JAMA. 2007;297:1465-1477

  22. Rossouw et al JAMA. 2007;297:1465-1477

  23. Sare et al Eur Heart J. 2008 August; 29(16): 2031–2041.

  24. )

  25. Anderson et al Maturitas 55 (2006) 103–115

  26. Anderson et al Maturitas 55 (2006) 103–115

  27. Patient 2 • 58-year-old woman with osteopenia whose mother had breast cancer. • 58 – year • Osteopenia • Family history of breast cancer

  28. Hip Fractures Placebo HRT WHI Fracture Results Writing Group for the WHI Investigators JAMA 2002;288:321-33 & JAMA 2004 291;1701

  29. Cumulative Incidence of the Primary Outcomes of invasive breast cancers RUTH trial Barrett-Connor E et al. N Engl J Med 2006;355:125-137

  30. Vogel, V. G. et al. JAMA 2006;295:2727-2741.

  31. Cumulative Incidence of Invasive and Noninvasive Breast Cancer Vogel, V. G. et al. JAMA 2006;295:2727-2741.

  32. Factors modyfying the association between HT & breast cancer • Population-based case–control study with 688 breast cancer cases /724 controls • Subgroup of women with a positive family history of breast cancer, each year of HRT use increased the risk by 1.22 (95% CI, 1.02-1.47). • Pesch et al Europ J Epidemiol 2005

  33. Factors modifying the association between HT & breast cancer Pesch et al Europ J Epidemiol 2005

  34. Pubmed search “HRT /ERT and breast cancer and family history”: CT, Meta-Analysis, Practice Guideline, RCT • For women at increased breast cancer risk due to a family history or high-risk benign breast conditions, clinical trial data are limited but suggest a lack of an additive effect of HRT on risk. • Rippy L &Marsden JClimacteric. 2006 Dec;9(6):404-15

  35. Patient 3 • 65-year-old woman with a history of coronary revascularization and documented osteoporosis.

  36. WHI: Total Mortality by Age at Baseline CHD Stroke Total Mortality CHD Stroke Total Mortality CHD Stroke Total Mortality Rossouw, et al. JAMA 2007;297:1465-1477.

  37. Endothelial Dysfunction in Atherosclerosis Ross NEJM 1999

  38. Endothelial Dysfunction in Atherosclerosis Ross NEJM 1999

  39. Lift study Cumulative Percentages of Patients with Breast Cancer and Stroke. At 4 years, tibolone was associated with with increased stroke risk (RH 2.19; 95% CI, 1.14 to 4.23; P=0.02) (Panel B). Cummings,et al NEJM 2008

  40. Absolute & attributablerisks calculated per 10.000 persons-years assuming an RR of 1.4 for current HT compared with never hormone use. (Adapted from the NHS Grodestein et al 2008,) per 10.000 persons-years alternate analyses, (absolute risk, and attributable)including both the confirmed and probable cases,

  41. Col et al 2004

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