1. Uncertain but Determined Let’s talk about WHO, WHI and WHY Peter van de Weijer MD PHD The Netherlands 1 March 2005 Hongkong

2. Clinicians Women © PHMvdW 2005 Health care for Women Researchers Not an issue for just one group Policy makers Healthcare industry Health Educators Epidemiologists Healthcare administrators Nurses

3. Clinician Women © PHMvdW 2005 Provide Medical Practice relationship ongoingpersonal Experience Health care for Women health care Medical Knowledge, based on the best available evidence to understand and evaluate research findings to apply “true” research evidence to clinical practice The need to be taken care of t t o communicate about evidence, risks and benefits

4. 1960Symptom relief – preservation of “youth” © PHMvdW 2005 History 1970 1980 Unopposed estrogen - endometrial cancer Prevention of osteoporosis ; coronary heart disease ; Alzheimer’s disease Progestins eliminate risk endometrial cancer 1993 Women’s Health Initiative to evaluate putative protective effects of HT on chronic diseases of aging National Institutes of Health 700 million dollar – public funding

5. Women’s Health Initiative (WHI) Study Outline Examination of long-term strategies for the prevention of morbidity and mortality in postmenopausal women. The WHI program includes 4 clinical studies more than 100.000 women participating 1) Effects of PremPro® (0.625mg CEE/2.5mg MPA) on CHD 2) Effects of Premarin® (0.625 mg CEE) on CHD 3) Effects of a low-fat and high-fiber diet 4) Effects of vitamin D + calcium To Understand and Evaluate Research Findings CHD: Coronary Heart Disease 12-year duration

6. Women’s Health Initiative (WHI) Study Outline To Understand and Evaluate Research Findings Two large, randomized, placebo-controlled clinical trials planned duration 8.5 years. Prempro® (0.625 mg CEE, 2.5 mg MPA) vs. placebo –16,608 women –50-79 years of age (mean age 63.2 years) Premarin® (0.625 mg CEE) vs. placebo –10,739 women with prior hysterectomy, –50-79 years of age (mean age 63.6 years) Outcomes Primary outcome Coronary heart diseases (CHD) non-fatal myocardial infarction and CHD death Secondary outcome Stroke, Venous Thromboembolism, Colorectal Cancer, Osteoporosis-related fractures, all-cause Mortality Primary adverse outcome Invasive breast cancer

7. © PHMvdW 2005 I. Study design and level of evidence II. Results ; Absolute risks IV. Population studied similar to your practice population III. Time of initiation of therapy and duration V. Decision analysis based on all health outcomes To Understand and Evaluate Research Findings

8. Observation Estimation Hypothesis Test Randomised double blind placebo controlled Test does not support hypothesis Test does support hypothesis revise Observational studies RCT MWS WHI © PHMvdW 2005 Clinical research HERS NHS

9. Types of Studies Used in Investigating HT Observational studies Studies in defined groups of the population. They observe factors determining and influencing the frequency (incidence) and distribution of health-related events. Observed factors are instrumental in defining endpoints for further randomised clinical studies. Only RR > 3 are probably causational; RR: 1-2 attributable to bias Nurses’ Health Study (NHS); Million Women Study

10. Types of Studies Used in Investigating HT Randomised controlled trials Studies on individuals to evaluate the efficacy of HT in comparison with a control group (e.g. vs. placebo). Women’s Health Initiative (WHI) Heart and Estrogen/Progestogen Replacement Study (HERS)

11. Description of the levels of evidence Level Iproperly randomized, controlled trial Level II-1well-designed controlled trial, no randomization Level II-2well-designed cohort or case-control analytic study preferably from more than one centre or group Level II-3Multiple time series with or without the intervention (cross-sectional, uncontrolled investigational ) Level IIIOpinions of respected authorities that are based on clinical experience, reports from expert committees Report of the US Preventive Services Task Force. Guide to Cinician Preventive Services 2 nd edition Baltimore Williams & Wilkins 1996 Research findings © PHMvdW 2005 FDA

12. Level III Women’s Health Initiative HERS Level II-2 Level II-3 Level II-1 Level I Nurses Health Study Million Women Study Expert opinion / reviews / NAMS position papers / meta-analysis HERS II Research findingslevel of evidence © PHMvdW 2005

13. Women’s Health Initiative (WHI) Results To Understand and Evaluate Research Findings Level I © PHMvdW 2005 Placebo CEE MPA RR 95% CI Breastcancer33411.26 1.00-1.59 4 Chlebowski JAMA 2003;289:3243-53 CHD33391.24 1.00-1.54 3 Manson N Engl J Med 2003;349:523-9 Stroke24311.44 1.09-1.90 4 Rossouw JAMA 2002;288:321-333 Deep Ven Thr13262.11 1.58-2.82 9 Rossouw JAMA 2002 Coloncancer16100.63 0.43-0.92 -3 Rossouw JAMA 2002 Endom. Cancer6.95.60.81 0.48-1.36 -0,7 Anderson JAMA 2003;290:1739-48 Ovarian Cancer2.74.21.58 0.77-3.24 0,8 Anderson JAMA 2003 Hipfracture16110.67 0.47-0.96 -2,5 Cauley JAMA 2003;290:1729-38 Tot fractures1991520.76 0.69-0.83 -23,5 Cauley JAMA 2003 Tot Mortality53520.98 0.82-1.18 -0,5 Rossouw JAMA 2002 Absolute risk N / 10000 /yr Relative riskReference CEE /MPA extra 5 yrs risk per 1000 women

14. Women’s Health Initiative (WHI) Results To Understand and Evaluate Research Findings Level I © PHMvdW 2005 Placebo CEE MPA Breastcancer33414 CHD33393 Stroke24314 Deep Ven Thr13269 Coloncancer1610-3 Endom. Cancer6.95.6-0,7 Ovarian Cancer2.74.20,8 Hipfracture1611-2,5 Tot fractures199152-23,5 Tot Mortality5352-0,5 Absolute risk N / 10000 /yr CEE /MPA extra 5 yrs risk per 1000 women HT should not be started or continued for Primary prevention of CHD Secundary prevention of CHD HT for the treatment of osteoporosis will require balancing risks and benefits including Risks and benefits of alternatives to HT

15. Women’s Health Initiative (WHI) Results To Understand and Evaluate Research Findings Level I © PHMvdW 2005 Placebo CEE MPA RR 95% CI Breastcancer33260.77 0.59-1.01 -3.5 WHI Steering JAMA 2004;291:1701-12 CHD54490.91 0.75-1.12 -2,5 WHI Steering JAMA 2004 Stroke32441.39 1.10-1.77 6 WHI Steering JAMA 2004 Deep Ven Thr21281.33 0.99-1.79 3,5 WHI Steering JAMA 2004 Coloncancer16171.08 0.75-1.55 0.5 WHI Steering JAMA 2004 Endom. Cancer Ovarian Cancer Hipfracture17110.61 0.41-0.91 -3 WHI Steering JAMA 2004 Tot fractures1951390.70 0.63-0.79 -28 WHI Steering JAMA 2004 Tot Mortality78811.04 0.88-1.22 1,5 WHI Steering JAMA 2004 Absolute risk N / 10000 /yr Relative riskReference CEE extra 5 yrs risk per 1000 women

16. Women’s Health Initiative (WHI) Results To Understand and Evaluate Research Findings Level I © PHMvdW 2005 Placebo CEE MPA RR 95% CI Breastcancer33260.77 0.59-1.01 -3.5 WHI Steering JAMA 2004;291:1701-12 CHD54490.91 0.75-1.12 -2,5 WHI Steering JAMA 2004 Stroke32441.39 1.10-1.77 6 WHI Steering JAMA 2004 Deep Ven Thr21281.33 0.99-1.79 3,5 WHI Steering JAMA 2004 Coloncancer16171.08 0.75-1.55 0.5 WHI Steering JAMA 2004 Endom. Cancer Ovarian Cancer Hipfracture17110.61 0.41-0.91 -3 WHI Steering JAMA 2004 Tot fractures1951390.70 0.63-0.79 -28 WHI Steering JAMA 2004 Tot Mortality78811.04 0.88-1.22 1,5 WHI Steering JAMA 2004 Absolute risk N / 10000 /yr Relative riskReference CEE extra 5 yrs risk per 1000 women HT should not be started or continued for Primary prevention of CHD Secundary prevention of CHD HT for the treatment of osteoporosis will require balancing risks and benefits including Risks and benefits of alternatives to HT Low dose therapy less risk for stroke and DVT

17. © PHMvdW 2005 I. Study design and level of evidence II. Results ; Absolute risks To Understand and Evaluate Research Findings Absolute risks are relevant for general practice

18. Risk factorAccounts for …percent of breastcancer Modifiable Risk factor ? Age (increasing)70% -80%No Familial (multiple genetic/environmental factors)15%-20%Possible Herediatary Predisposition (single gene mutation)5% - 10%No BREAST CANCER ACOG Bulletin Breastcancer Obstet Gynecol 2004: 104; 11-16 © PHMvdW 2005 Most of the recognized risk factors for breastcancer are not modifiable

19. Risk factorAccounts for …percent of breastcancer Modifiable Risk factor ? Age (increasing)70% -80%No Familial (multiple genetic/environmental factors)15%-20%Possible Herediatary Predisposition (single gene mutation)5% - 10%No BREAST CANCER ACOG Bulletin Breastcancer Obstet Gynecol 2004: 104; 11-16 © PHMvdW 2005 Risk factorRelative riskModifiable ? Age at menarche 14 yrs vs 11 yrs1 : 1.3No Parity multiparous : nulliparous1 : 1.3possible Age at first birth 20 yrs vs 30 yrs1 : 1.5possible Age at menopause 42 yrs vs 52 yrs1 : 2.0possible Body weight normal weight : obesity1 : 1.5yes Serum lipids normal vs raised1 : 1.6yes Antibiotic use never vs 1-50 days/life1 : 1.5yes Alcohol consumption none vs ≥20 g daily1 : 1.3yes Hormone Therapy none vs CEE/MPA/5yrs1 : 1.3yes Physical Activity active vs non-active1 : 1.2yes

20. E+P 8506 8378 8277 8150 7000 4234 2064 801 P 8102 8037 7891 7772 6819 3922 1740 523 Writing Group for the WHI Investigators. JAMA. 2002;288:321-33 Previous HRTcc-HTPlacebo Never73,9 %74,4 % Past19,7 %19,6 % RR 1.26 95% CI 1.01-1.54 53yr 124 166 Chlebowski et al JAMA 2003;289:3243-53 No extra increase in breastcancer the first 4-5 yrs of first time CEE / MPA use © PHMvdW 2005

21. Lesson No extra increase in breastcancer the first 4-5 yrs of first CEE / MPA use started after the age of 50 years Level I Evidence Time of initiation of treatmentDuration of therapy

22. © PHMvdW 2005 I. Study design and level of evidence II. Results ; Absolute risks To Understand and Evaluate Research Findings Absolute risks are relevant for general practice Time of initiation of therapy and duration

23. © PHMvdW 2005 I. Study design and level of evidence II. Results, Absolute risks III. Time of initiation of therapy and duration “Study findings indicate that combined HT is associated with an increased risk of breast cancer. Women considering HT should be counseled that the absolute risk of breastcancer for any individual remains relatively low“ ACOG Breastcancer Obstet Gynecol 2004;104: 11-16 To Understand and Evaluate Research Findings

24. © PHMvdW 2005 Applicability to general practice I. Study design and level of evidence II. Results; Absolute risks IV. Population studied similar to your practice population III. Time of initiation of therapy and duration To Understand and Evaluate Research Findings

25. Women’s Health Initiative (WHI) Study Population Mean age at recruitment: 63 years Past or current smokers: 50% Women treated for hypertension: 36-48% Women on lipid lowering medications: 13-15% BMI > 25: 70-79% Women treated for diabetes: 4-8%

26. © PHMvdW 2005 I. Study design and level of evidence II. Results; Absolute risks IV. Population studied similar to your practice population III. Time of initiation of therapy and duration V. Decision analysis based on all health outcomes To Understand and Evaluate Research Findings

27. © PHMvdW 2005 Decision analysis based on all health outcomes Global index Coronary heart disease Stroke Pulmonary embolism Breastcancer Colorectal cancer Hip-fracture Death Prevention CEE + MPA CEE 10 serious adverse events for every 10000 women using HT for 1 year 1 2 serious adverse events for every 10000 women using HT for 1 year 2 NS 1.Grady D. N Engl J Med 2003; 348:1835-7 (level III) 2.Anderson GL et al. JAMA 2004;291:1701-12 (level I) 3.Col et al. Arch Intern Med 2004;164: 1634-40 (decision analysis) Symptomatic 3 Asymptomatic / HT 2 yrs Quality adjusted life expectancy Mild symptoms / HT 2 yrs Severe symptoms / HT 2 yrs - 1-3 months + 3 - 4 months + 7 -8 months

28. Clinician Women © PHMvdW 2005 Health care for Women Provide Medical Practice The need to be taken care of relationship ongoingpersonal health care

29. 45 yrs5055 yrs Fertility Menstrual cycle problems Flushes / night sweats Urogenital atrophy Osteoporosis Diabetes CVD Contraception PMS Pre Arthritis Carcinoma Breast Colon Ovarian Cervical PerimenopausePost Eyesight Hearing ? ? Climacteric Medicine Uterine Bleeding © PHMvdW 2004 Cognitive function » Strength Menopause

30. 45 yrs5055 yrs Menstrual cycle problems Flushes / night sweats PrePerimenopausePost Climacteric Medicine © PHMvdW 2004 Menopause HT No randomised trials for risks Progestagens No risk demonstrated OC No randomised trials No change in practice necessary

31. 45 yrs5055 yrs Flushes / night sweats PrePerimenopausePost Climacteric Medicine © PHMvdW 2004 Menopause First 5 yrs HT use No increase for Br Ca QALY > Symptomatic No change in practice necessary

32. 45 yrs5055 yrs PrePerimenopausePost Climacteric Medicine © PHMvdW 2004 Menopause HT should not be started or continued for Primary prevention of CHD Secundary prevention of CHD HT for the treatment of osteoporosis will require balancing risks and benefits including Risks and benefits of alternatives to HT

33. Menopause 45 yrs50 yrs55 yrs Menstrual cycle problems Bleeding problems Flushes Night sweats Urogenital atrophy DUPHASTON ® 10 / 20 FEMOSTON ® 1 / 10 FEMOSTON ® 1 / 5 Low dose for estrogens Proper dose for progestagen s

34. Clinician Women © PHMvdW 2004 Health care for Women Medical Practice relationship ongoingpersonal The Art of Medicine the unique combination of Experience Medical Knowledge Intuition Judgment Communication Curiosity Compassion Epidemiologists Health care industry Policymakers Administrators Researchers