OVERVIEW WOMEN S HEALTH: YEAR IN REVIEW

OVERVIEW WOMEN S HEALTH: YEAR IN REVIEW Judith Walsh, MD, MPH Professor of Medicine UCSF Update in Women s Health for SGIM Drs. Mary Beattie and Pam Charney Review of literature from March, 2008 through February, 2009 Journals, Cochrane, Medline search using medical subject heading sex factors Criteria Scientific rigor Potential to impact clinical practice TOPICS Cardiovascular disease Menopause and hormone therapy Breast cancer Osteoporosis Urinary Incontinence CARDIOVASCULAR DISEASE IN WOMEN 1

In whom would you consider ordering a hscrp? hscrp: Background 1. 75 year old diabetic woman with a glycohemoglobin of 9.5 and an LDL of 175 mg/dl 2. 52 year old healthy woman with an LDL of 190 mg/dl 3. 57 year old healthy woman with an LDL of 130 mg/dl 4. All of these individuals 5. 2 and 3 only 13% 35% 20% 30% CRP is an inflammatory biomarker that has been shown to predict cardiovascular events CRP is elevated in many inflammatory conditions hscrp can detect levels down to 0.3 mg/dl 2% 1 2 3 4 5 Clinical Questions Does hscrp add prognostic value to traditionally measured cardiovascular risk factors? Does treating an elevated hscrp affect clinical outcomes? hscrp and CHD outcomes Ridker PM et al for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. NEJM 2008: 359: 2195-207. Aim: To determine whether treating individuals with elevated CRP but normal LDL-cholesterol with statins can reduce the rate of first cardiovascular events 2

C reactive protein Randomized controlled trial with 17,802 individuals (6,801 women) who received rosuvastatin 20 mg or placebo LDL <130 mg/dl and hscrp 2.0 mg/dl Composite outcome: MI, stroke, revascularization, unstable angina, CV death Results Trial stopped early after 1.9 years LDL cholesterol lowered by 50% and hscrp by 37% Rosuvastatin treated individuals had a lower rate of the primary endpoint RH 0.56 (0.46, 0.69) 1.8% of placebo participants vs 0.9% of rosuvastatin treated had an MI, stroke or death RH 0.53 (0.40, 0.69) NNT 120 for 1.9 years Results in Women Similar effects when women analyzed separately High rate of physician reported diabetes in rosuvastatin treated group Impact for Practice JUPITER was a study of statin therapy, not of hscrp testing Highly select group of participants 89,000 screened; 80% excluded Consider measurement of hscrp in individuals with an intermediate level of risk, if the decision about drug therapy would change CDC and AHA, 2003 3

Key Articles Rosuvastatin therapy is also associated with a lower risk of VTE Ridker, NEJM 2009 Adherence to DASH diet associated with lower CHD risk in women after 24 year follow-up Fung, Arch Intern Med, 2008 Key Articles New recommendations for aspirin use in women Women aged 55-79 should use ASA when potential benefit of a reduction in ischemic strokes outweighs the potential harms of a gastrointestinal hemorrhage USPSTF 2008 Vasomotor Symptoms MENOPAUSE AND HORMONE THERAPY Minnie Pause is a 53 year old woman who had her last menstrual period 18 months ago. She is still having hot flashes and awakens at least twice a night with them. She is considering taking estrogen but wants to know how much longer this will last. What do you tell her? 4

What do you tell her about when they will go away? 1. Average duration is about 2 years and so they should be gone in about 6 months. 2. Average duration is about 4 years 3. They will never go away 47% 45% 7% BACKGROUND Treatment for menopausal symptoms is based on their transitory nature Many clinical guidelines suggest that symptom duration is approximately 2 years Many studies do not follow women more than 2 years Risks and benefits of hormone therapy depend on duration of use Use lowest dose for shortest duration 1 2 3 CLINICAL QUESTIONS What is the natural progression of vasomotor symptoms during the menopause transition? How long is it safe to use hormone therapy? DURATION OF VASOMOTOR SYMPTOMS Politi MC et al. Revisiting the duration of vasomotor symptoms of menopause: a meta-analysis. JGIM 2008:23: 1507-13 Objective: to estimate the natural progression of menopausal symptoms 5

Vasomotor symptoms Rigorous meta-analysis included 10 studies with over 35,000 participants Clear definition of vasomotor symptoms Assessed prevalence of symptoms and bothersome symptoms Results Percent of women with symptoms increased in the two years before the final menstrual period (FMP), peaked one year after the FMP and did not return to premenopausal levels until 8 years after the FMP 50% of women had symptoms during the 4 years after FMP 10% of women had symptoms up to 12 years after FMP Results: Bothersome Symptoms Impact for practice Menopausal symptoms last about 4 years Risks and benefits of hormone therapy must be considered within the longer period of use 6

Key articles New evidence based guidelines for the use of hormone therapy Risk defined as possibility or chance of harm Put level of risk in perspective HT should not be used as an antidepressant No data to support any particular route of administration or dosing regimen Use greater caution in women over 60 NAMS, Menopause, 2008 Key Articles Menopausal complaints are associated with a less favorable cardiovascular risk profile Gast, 2009 Hormone therapy associated with an increased risk of GERD Jacobson, 2008 Hormone therapy associated with an increased risk of stroke regardless of time of initiation Grodstein, 2008 Key Articles Hormone therapy is associated with improvement in some quality of life measures in women with vasomotor symptoms and may improve sexual function and vitality Hess, 2008; Welton, 2008 Hypnosis and exercise may improve vasomotor symptoms Elkins, 2008 Hormone Therapy and Breast Cancer: Background In the WHI, women who took hormone therapy had a higher incidence of breast cancer and the cancers were larger and more advanced Since the WHI, use of hormone therapy (HT) in the U.S. has decreased Breast cancer incidence has also decreased in the U.S. 7

Clinical Question Is the relationship between HT cessation and decreased breast cancer incidence causal? More frequent mammograms? Other factors? Hormone therapy and breast cancer Chlebowski RT et al for the WHI Investigators. Breast cancer after use of estrogen plus progestin in postmenopausal women. NEJM 2009:360: 573-87. AIM: To determine whether the decrease in breast cancer seen after discontinuing HT is causally related to HT discontinuation. Hormone Therapy and Breast Cancer 15,387 in WHI trial and 41,449 women in WHI Observational Study Detailed information about duration of hormone therapy use, mammographic frequency and breast cancer outcomes RESULTS In WHI trial, breast cancer risk was lower in hormone treated women in first two years Increased over 5.6 years of intervention then decreased after study pills discontinued No difference in mammography rate 8

RESULTS In observational study, women taking HT had a higher risk of breast cancer Risk decreased with year to year reductions in HT use IMPACT FOR PRACTICE The increased risk of breast cancer with hormone therapy use decreases with cessation This effect is not related to frequency of mammography KEY ARTICLES In WHI, HT use resulted in more than 1 in 10 women having otherwise avoidable mammographic abnormalities and more than 1 in 25 women having otherwise avoidable breast biopsies Chlebowski Arch Intern Med 2008 In a large cohort study, there was no overall association between caffeine consumption and breast cancer risk Ishitani et al. Arch Intern Med 2008 OSTEOPOROSIS 9

OSTEOPOROSIS Violet D. is a 69 year old woman who comes in for a health care maintenance exam. You order a bone mineral density. She tells you she also wants a Vitamin D level checked. What do you do? Vitamin D 1. Order a Vitamin D level 2. Don t order a Vitamin D level because you are not sure to 68% do with the results 3. Don t order it but start her on a calcium/vitamin D supplement 27% 5% 1 2 3 BACKGROUND Vitamin D deficiency is common in older adults, homebound individuals and women admitted with hip fracture Association between Vitamin D level and fracture risk is inconsistent Association could be influenced by renal function, muscle strength and estrogen receptors CLINICAL QUESTIONS What is the association between Vitamin D level and fracture? When should Vitamin D levels be checked? When and how should Vitamin D supplementation be given? 10

VITAMIN D AND FRACTURE RISK Cauley JA et al. Serum 25(OH) vitamin D concentrations and risk for hip fractures. Ann Intern Med 2008:149: 242-250. AIM: To determine whether serum 25 (OH) D concentration is associated with hip fracture in community dwelling older women METHODS Nested case-control study within the Women s Health Initiative Observational Study 400 cases and 400 controls followed for a median of 7.1 years Women had no prior history of hip fracture, were not on estrogen or other bone active therapies RESULTS: HIP FRACTURE RISK Odds Ratios of Risk for Hip Fracture* 25-Hydroxyvitamin D Level Unadjusted Odds Ratio (95% CI) Adjusted Odds Ratio (95% CI) Per 2.5-nmol/L decrease 1.03 (1.01-1.05) 1.03 (1.01-1.05) Per 25-nmol/L decrease 1.30 (1.07-1.58) 1.33 (1.06-1.68) Quartile (according to control group) First (9.2-47.5 nmol/l) 1.73 (1.13-2.66) 1.71 (1.05-2.79) Second (47.6-60.1 nmol/l) 1.08 (0.72-1.63) 1.09 (0.70-1.71) Third (60.2-70.6 nmol/l) 0.78 (0.50-1.20) 0.82 (0.51-1.31) Fourth (70.7-121.5 nmol/l) 1.00 (reference) 1.00 (reference) HIP FRACTURE RISK Association was linear Dose response effect No difference by age Independent of geographic location P for trend 0.009 for unadjusted and 0.015 for adjusted models 11

IMPACT FOR PRACTICE Low serum 25 (OH) vitamin D concentrations can help identify women at high risk for hip fracture Perhaps we should consider Vitamin D level in decision making about anti-resorptive therapies Vitamin D Evidence AHRQ Systematic Review of the efficacy and safety of Vitamin D in relation to bone health BMD-fair Fractures- inconsistent Performance measures (body sway, gait speed)- inconsistent Falls- fair, but few studies Harms- check levels www.ahrq.gov FRACTURE AND SUBSEQUENT RISK One year later, Violet trips over a suitcase in the hallway and fractures her wrist. She comes in to see you to start an osteoporosis medication and also wants to know whether there are any additional future consequences. What do you tell her? FRACTURE AND SUBSEQUENT RISK 1. She has no increased risk of future fracture 2. She has an increased risk of future fracture but no increased risk of mortality 3. She has an increased risk of future fracture as well as an increased mortality risk for 5-10 years 5% 15% 80% 1 2 3 12

BACKGROUND Osteoporotic fractures are increasing as the population ages Hip and vertebral fractures are associated with premature mortality CLINICAL QUESTIONS What is the mortality risk following an osteoporotic fracture? Does degree of trauma matter? Does subsequent fracture affect that risk? METHODS Prospective cohort study from Dubbo Osteoporosis Epidemiology Study Individuals who had a fracture between 1989 and 2007 Age and sex specific standardized mortality ratios compared with general population for hip, vertebral, major and minor fractures RESULTS IN WOMEN Fracture type Number of deaths Personyears SMR (95% C.I.) Hip 89 509 2.53 (2.04-3.13) Vertebral 93 994 1.76 (1.43-2.17) Major 48 591 1.60 (1.20-2.13) Minor 76 1349 1.38 (1.10-1.74) 13

SUBSEQUENT FRACTURE AND MORTALITY Subsequent fracture was associated with an increased risk of mortality in women HR 1.53 (1.15, 2.04) IMPACT FOR PRACTICE Any fracture is associated with an increased risk of 5-10 year mortality A subsequent fracture is associated with an increased mortality risk for 5 more years We should pay more attention to non-hip, non-vertebral fractures KEY ARTICLES FRAX: WHO Fracture assessment Calculate the 10 year probability of a hip fracture and the 10 year probability of any osteoporotic fracture Includes femoral neck BMD and risk factors Can be used only in previously untreated patients Algorithm adapted for the U.S. www.shef.ac.uk/frax WHO Fracture Risk Algorithm Most useful in identifying individuals in the osteopenic range who are most likely to benefit from treatment Treat when there is a 10 year risk of hip fracture 3% or a 10 year risk of a major osteoporosis-related fracture that is 20% based on the U.S. adapted WHO algorithm In the future some BMD machines may be able to provide a report with absolute fracture risk 14

KEY ARTICLES Individuals with diabetes, on thiazolidinediones and who have had gastric bypass surgery are at increased risk for osteoporosis Meier, 2008; Mastrandrea 2008; Fleischer, 2008 Tibolone reduced fracture and breast cancer risk but increased risk of stroke Cummings, 2008 URINARY INCONTINENCE Urinary Incontinence: Treatment Mrs. Ima Leeker is a 72 year old woman who comes to see you. She admits to increasing episodes of urinary incontinence when she rushes to get to the bathroom and just before she gets there she loses urine. What do you recommend for Mrs. Ima Leeker? 1. Behavioral therapy-(bladder training and Kegels exercises) 2. Drug therapy 3. Weight loss 4. All of the above 34% 58% 5% 3% 1 2 3 4 15

URINARY INCONTINENCE Urinary incontinence (UI) affects more than 13 million U.S. women and significant impacts quality of life Stress vs urge incontinence Behavioral treatments and drug therapy are useful for urge incontinence but compliance is a problem Clinical Questions Does weight loss result in improvement in incontinence? Can combining drug and behavioral treatment improve symptoms of incontinence and can these improvements be sustained after stopping drug therapy? Weight loss and incontinence Subak et al for the PRIDE investigators. Weight loss to treat urinary incontinence in overweight and obese women. NEJM 2009:360: 481-90. AIM: Can weight loss reduce incontinence episodes? KEY RESULTS Women in the intervention group lost an average of 7.8 kg Vs 1.5 kg in the control group At 6 month follow-up, intervention group had a 70% reduction in all incontinence episodes Stress and urge 16

Behavioral therapy Burgio KL et al for the Urinary Incontinence Treatment Network. Ann Intern Med 2008: 149: 161-169. AIM: To determine whether supervised behavioral training added to drug therapy improves incontinence and to determine whether the improvement can be sustained after stopping drug therapy KEY RESULTS Combined therapy resulted in a greater reduction in incontinence at 12 weeks Vs Drug therapy alone Effect was not sustained after stopping drug therapy IMPACT FOR PRACTICE One of the many benefits of weight loss is an improvement in urinary incontinence Although adding behavioral therapy to drug treatment can improve symptoms, it does not improve the ability to discontinue drug therapy CONCLUSIONS Consider measuring hscrp in intermediate risk women in whom management might change Menopausal symptoms last an average of 4 years The increased risk of breast cancer seen with hormone therapy decreases after cessation 17

CONCLUSIONS Low vitamin D levels can help identify women at high risk for hip fracture Any fracture is associated with an increase in 5-10 year mortality Weight loss leads to an improvement in urinary incontinence Behavioral therapy is helpful for urge incontinence but does not improve the ability to discontinue drug therapy 18