Top Newsmakers in Women’s Health
Pelin Batur, MD, FACP, NCMP
Education Director,
Primary Care Women’s Health
Deputy Editor,
Cleveland Clinic Journal of Medicine
No Financial Disclosures or Conflicts of Interest
baturp@ccf.org
What’s new with:
HORMONE THERAPY
Effect of HT on CHD: Timing hypothesis
Years Since
Menopause
Absolute Risk /
10,000 women
WHI-E+P
0.88
<10
-4
1.23
10-19
7
1.66
>20
30
WHI-E
0.48
-14
<10
0.96
-1
10-19
1.12
7
>20
0.76
WHI-Combined
-6
<10
1.10
4
10-19
1.28
16
>20
0
0.5
1.0
1.5
2.0
2.5
Rossouw JE, JAMA 2007;297:1465-1477
Decreased mortality with HT: DOPS study
BMJ Oct 2012; 345
Study Design:
•
•
•
•
Open label, randomized, 1006 healthy Danish women
Aged 45-58, between 1990-1993
500+ HT vs control, stopped after 11 yr , followed for 16 yr
Primary end point death, heart failure, and MI
Results
Characteristics
Hormone Therapy
(N = 502)
No Therapy
(N= 504)
Age (years)
50.0
49.5
BMI
25.2
25.3
Total cholesterol
244mg
242mg/dl
LDL cholesterol
148mg/dl
148mg/dl
Systolic BP
130 mm Hg
129 mm Hg
Years since
menopause
0.61
0.58
Fasting glucose
84mg/dl
84mg/dl
WHI: mean age 63
WHI: 13% with
increased lipids
WHI: 36% with
hypertension
WHI: 4% with DM
Fig 3 Risk with HT vs control
16 vs 33 women
15 vs 26 women
Schierbeck L L et al. BMJ 2012;345
©2012 by British Medical Journal Publishing Group
Risk with HT vs control
2 vs 1 woman
11 vs 14 women
10 vs 17 women
22 vs 40 women
Schierbeck L L et al. BMJ 2012;345
©2012 by British Medical Journal Publishing Group
Conclusions
• Young, healthy, recently menopausal women
who received HT for 10 years for the primary
prevention of osteoporotic fractures
experienced a ↓ risk for death, MI or heart
failure
• There was no associated increase in stroke,
breast cancer, DVT, or PE
Decreased mortality with HT: DOPS study
BMJ Oct 2012; 345
Limitations:
• Open label trial, not blinded
• The number of participants is small
• Different estrogen & progestin (estradiol/norethisterone)
Take home message:
• Not ment to prescribe for primary prevention
• Reassuring news about HT in symptomatic healthy menopausal women
Excess Deaths Among Hysterectomized
Women Aged 50-59 yrs
Am J Public Health. Sept 2013;103(9):1583-1588
• Study Design:
– Derived formula to assess mortality among hysterectomized women
aged 50 - 59 years assigned to placebo in WHI vs the entire population
of comparable women in the US
– Incorporated the decline in estrogen use observed between 20022011
• Results:
– Since 2002, between 18,601 – 91,610 postmenopausal women died
prematurely because of ET avoidance
– Estrogen use in this population is low and continuing to fall
– Informed discussion between these women and their health care
providers about the effects of ET is a matter of considerable urgency
Reduced Alzheimer’s with Early HT
Neurology. 2012 Oct 30;79(18):1846-52
• What we already know:
– Observational studies ↓ risk of Alzheimer in HT users
– Randomized studies (WHIMS, WHI) show ↑ risk
• Study Design:
– 1,768 women in Cache County, from 1995-2006
– Detailed history on age at menopause and use of HT
– 176 women developed incident AD
• Findings:
– HT use within 5 years of menopause 30% ↓ AD [CI 0.49-0.99]
– 10+ years of use, HT showed 37% ↓ AD.
– ET & EPT had similar magnitude of reduced risk
• only ET reached statistical significance
– AD risk not reduced when HT initiated ≥5 yr after menopause
• Older women initiating EPT had ↑ risk, HR 1.93 [CI 0.94-3.96]
Reduced Alzheimer’s with Early HT
Neurology. 2012 Oct 30;79(18):1846-52
• Summary:
– Association of HT use and AD risk may depend on timing of use
• HT possibly beneficial if taken during a critical window near menopause
• HT (especially EPT) initiated in later life may be associated with ↑ risk
• Limitations:
– Observational study
• Only one looking at appropriate age group
• Level of risk in older women similar to prior randomized trials
• What this contributes:
– We should not be offering HT for prevention of Alzheimer’s, but
reassurance for for newly menopausal, younger women
Transdermal HT preferred over oral
ACOG Committee Opinion #556
• What we already know:
– First-pass metabolism of oral estrogen might ↑ pro-thrombotic /inflammatory effects
– Estradiol-acetate vaginal ring does not seem to raise risk for VTE
• The ACOG Committee Opinion #556 states:
– transdermal estrogen better approximates physiologic estrogen levels
– The transdermal route might be safer
– In healthy women with negative risk histories, the "probability of VTE is generally low."
• Possible exceptions:
– Avoid transbuccal lozenges and troches
– Individualize!
– Oral regimen is preferred in hirsutism
• To avoid confusion:
– Don’t confuse with contraceptive dose hormones
– Does this apply to stroke risk?
Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: U.S. Preventive
Services Task Force Recommendation Statement
Ann Intern Med. 2013;158(1):47-54. doi:10.7326/0003-4819-158-1-201301010-00553
Date of download:
7/5/2013
Copyright © The American College of Physicians.
•http://www.menopause.org/docs/default-document-library/htsolidarity12.pdf?sfvrsn=4
• Systemic HT is the most effective treatment
• Progestin therapy is needed if uterus intact
• HT an acceptable option for young healthy women
– Up to age 59, or within 10 years of menopause
• Consider QOL when making decision
• Local estrogen therapy (vaginal-only) if only
symptoms are vaginal dryness or discomfort
•http://www.menopause.org/docs/default-document-library/htsolidarity12.pdf?sfvrsn=4
Take Home Messages
• Try to limit EPT to 3-5 years, whereas ET can be used for
a longer duration of time
• Women with premature menopause can use HRT until at
least the age of 51
• Observational studies suggest that transdermal and lowdose oral estrogen are associated with lower risks for VTE
and CVA
– RCT evidence is still not available
New approvals
• Ospemifene (Osphena™)
• Paroxetine 7.5 mg (Brisdelle ™)
Ospemifene (Osphena™)
• Estrogen agonist/antagonist
• Stroke (per 1000 women):
– Thromboembolic: 0.72 vs 1.04 in placebo
– Hemorrhagic: 1.45 vs 0 in placebo
• DVT (per 1000 women):
– 1.45 vs 1.04 in placebo
• At 1 yr:
– No endometrial cancer
– Endometrial thickening >5mm (per 1000 women)
• 60 Osphena vs 21 placebo
– Uterine polyps
• 5.9 Osphena vs 1.8 placebo
– Proliferative endometrium
• 86 Osphena vs 13 placebo
Ospemifene (Osphena™)
• “Long term” studies are 1 yr:
– Goldstein SR et al. Climacteric; Aug 2013
• n=349
– Simon JA et al. Menopause; April 2013
• n=180
• Watch for drug interactions
–
–
–
–
Fluconazole (↑ 2.7x)
Ketoconazole (↑ 1.4x)
Highly protein bound
Watch inhibitors CYP3A4 and CYP2C9
Brisdelle ™
paroxetine mesylate
• 7.5 mg QD
• ↓ 1-2 hotflashes/day
• Side effects occur despite lower dose
What’s new with:
BREAST CANCER
www.truthaboutnursing.org
What we already know
• There is more scientific evidence supporting screening
for breast cancer than for any other cancer
– Trials performed when more effective treatments not
available
• Strong consensus exists for screening women 50-69
– Consensus not as strong for screening age 40-49, or >70
• Effective screening programs should lead to a
reduction in the diagnosis of late stage cancers
– Increase in breast cancer incidence in 1990 is mostly due to
in situ, DCIS, early stage cancers
The News
• Kerlikowske et al. JAMA Inter Med 2013;
173:807
• Braithwaite, et al. J Natl Cancer Inst 2013;
105:334
• UK Panel. Lancet 2012; 380: 1778
• Bleyer et al. NEJM 2012; 367: 1998
Effect of three decades of screening
mammography on breast cancer incidence
Bleyer et al. NEJM 2012; 367: 1998
• Question: Has the ↑ in detection of early stage
breast cancer led to a ↓in the incidence of late stage
cancer?
• Methods: Analyzed SEER Data between 1976-2008
• Results: Early-stage breast cancer diagnosis has
doubled, late stage presentation ↓ 8%
• Conclusions:
– 70,000 women overdiagnosed in 2008
– 1.3 million women overdiagnosed last 30 yrs
– Accounts for 31% of diagnosed breast cancer
Outcomes of Screening Mammography by Frequency,
Breast density, and Postmenopausal HT
Kerlikowske et al. JAMA Inter Med 2013; 173:807
• Question: Biennial vs annual screening, effect on advanced
stage breast cancer
• Methods: Prospective US data, 1994-2008, 900,000+ women
• Results:
– Age 50-74: No ↑ risk of advanced stage cancer with biennial
screening
– Age 40-49: ↑risk of advanced stage cancer for women with
dense breasts screened q2 yr [OR= 1.89; CI, 1.06-3.39]
– Risk of false positive ↑with annual screening
• 40-49 yo + dense breasts + annual screen = 65%
• 50-74 yo + dense breasts + biennial screen = 30%
• 50-74 yo + fatty breasts + biennial screen = 17%
Screening Outcomes in Older US Women Having
Multiple Mammograms in Community Practice.
Braithwaite, et al. J Natl Cancer Inst 2013; 105:334
• Question:
• Methods:
What is the optimal screening interval in older women?
– Prospective data, US women >65yo, 1990-’06
– 2993 with & 137 949 women without breast cancer
– Calculated odds of advanced stage and larger tumors, and 10-year
cumulative probability of false-positives by screening frequency (1 vs 2y),
age, and comorbidity score.
• Results:
– Adverse tumor characteristics did not differ by comorbidity score age, or
interval
– FP higher in annual screeners: 48 vs 29%
Benefits & harms of breast cancer screening.
Lancet 2012; 380: 1778
• Question: Quantify reduced breast cancer mortality vs harm of
overdiagnosis
• Methods: UK panel meta-analysis of 11 randomized trials
• Results:
– RR of breast cancer mortality 0.80 [CI 0·73-0·89]
– Excess incidence 11-19%
• Estimate, inaccuracies acknowledged
– For every 10,000 UK women, 50 yo, screened 20 yrs:
• Prevent 43 deaths from breast cancer
• 129 cases overdiagnosed (invasive and non-invasive)
• 1 breast cancer death prevented per 3 overdiagnosed cases
North American Guidelines
• Age 40-49
– Yearly:
• ACS, ACR, AMA, NCI,
ACOG
– Every 1-2 yr:
• AAFP
• ACP
– only for women who do
not wish to participate
in shared decision
making
– Never:
• Canadian Task Force
• Age 50+
– Yearly:
• ACOG, AMA, ACS,ACR,
NCCN
– Every 1-2yr:
• ACP, AAFP, NCI
– Every 2 yrs:
• USPSTF
– Every 2-3 yrs:
• Canadian Task Force
How does this affect my practice?
How does this affect my practice?
How does this affect my practice?
“Indecision is the key to flexibility”
Asa does not reduce breast cancer risk
J Clin Oncol. Oct 2012;30(28):3468-77
• What we already know:
• In 2008, a study had suggested a small decrease in the risk of ER+ breast
cancer in aspirin users
• Study design:
• Data prospectively collected from cancer-free postmenopausal women
• Biennial questionnaires looked at analgesic use, reproductive history, and
other lifestyle factors.
• 84,602 women, between 1980-2008
• Findings:
• 4,734 cases of incident invasive breast cancer
• Aspirin users (20+ yrs, ≥ 2/wk)
– RR 0.90 for ER/PR+ [CI 0.77-1.06]
– RR 0.91 for ER/PR- [CI 0.68-1.22]
Asa does not reduce breast cancer risk
J Clin Oncol. Oct 2012;30(28):3468-77
The big picture:
– Counseling should be be focused on more
established risk reduction strategies:
• Exercise
• Avoiding weight gain
• Stopping smoking
• Minimizing alcohol
• Raloxifene or tamoxifen
What’s new with:
CERVICAL CANCER SCREENING
•Funnycomics.com
What’s new with:
CERVICAL CANCER SCREENING
• Well-woman visit. Committee Opinion No.
534. ACOG Obstet Gynecol 2012;120:421–4
• ASCCP Updated Consensus Guidelines. J Lower
Genital Tract Disease. Vol 17(5), 2013
What’s new with:
CERVICAL CANCER SCREENING
• Initiate screening:
– Age 21, irrespective of sexual history or risk factors
• Screening interval:
– Age 21-29, q 3 yr, reflex HPV only
– Age 30-65 options:
• Pap/HPV q 5 yr (preferred method)
• Pap only q 3 yr
• Discontinuation:
– Age >65 and
• No history of CIN 2+ in the preceding 20 years
• Adequate prior negative screening
– 3 consecutive normal Paps OR 2 consecutive normal cotests
– Most recent in past 5 years
– After hysterectomy if all apply:
• No history of CIN 2+
• Cervix was removed
– Age > 65 with h/o CIN 2+
• Continue for at least 20 years, (even if > age 65 )
What’s new with:
Abnormal Pap Smear Follow up
• No endocervical cells = no early repeat needed
• Unsatisfactory specimen = always need repeat
• AGUS/ atypical endocervical cells
– Colposcopy
– Endocervical curettage
– HPV testing
– Endometrial biopsy for age > 35
– Possible endometrial biopsy <35 if RF
• abn bleeding, chronic anovulation, family history
What’s new with:
Abnormal Pap Smear Follow up
• ASCUS/HPV (-) = Routine screening
– 3 yrs, instead of 5
– If age >65, can’t exit screening
• ASCUS, unknown HPV = repeat at 12 months
– Colposcopy not an option unless + HPV
• Women age 21-24 with ASCUS/LGSIL:
– Leave them alone !
ASCCP.org
What’s new with :
VACCINATIONS
Updated Tdap needed during pregnancy
www.cdc.gov/vaccines/pubs/preg-guide.htm
• What we already know:
– 27,550 cases of pertussis in 2010
– ↑ over the last several years, resistant strains emerging
– severe illness and hospitalization reported in children up to 10 yo
– mothers responsible for 30–40% of infant infections
• New updates:
– Give a dose of Tdap during each pregnancy irrespective of prior hx of
vaccine
– Optimal timing 27-36 weeks of gestation
– If not given during pregnancy, administer immediately postpartum
– If unknown or incomplete tetanus vaccination
• Three vaccinations:
– 0, 4 weeks and 6 to 12 months
– Tdap should replace 1 dose of Td, preferably after 20 weeks
gestation
– Breastfeeding is not a contraindication
HPV VACCINATION:
Underutilized & well-tolerated
•
•
•
•
•
•
HPV vaccination ↑ every year 2007-2011
Unchanged 2011-2012
33% for all 3 doses
54% for one dose
Could have been 92% is given with other shots
Parents who did not intend to vaccinate stated:
–
–
–
–
–
Vaccine not needed
It was not recommended
Safety concerns
Lack of knowledge about vaccine/disease
Daughter not sexually active
•MMWR July 2013; 62 (29): 591
HPV VACCINATION
Underutilized & well-tolerated
• Vaccine adverse effect reporting system 2006-2013:
– 21,194 reports
– Reporting peaked in 2008, with subsequent decrease
• “Nonserious” (92.1%):
– Syncope, dizziness, nausea, headache, fever, hives
– Injection site reactions
• “Serious”(7.9%):
– Headache, nausea, vomiting, fatigue, dizziness/syncope, generalized
weakness
•MMWR July 2013; 62 (29): 591
HPV vaccination:
Is it effective?
• HPV prevalence in young women
– Age 14-19, 2003-2006 & 2007-2010
– National Health and Nutrition Examination Survey
• Prevalence of HPV 16, 18, 6, 11 infection ↓
– 11.5% to 5.1%
• No change in nonvaccine HPV types
• Effectiveness 82%, for those with ≥1
•J Infect Dis June 19 2013
HPV vaccination:
Is it effective?
• National Australian HPV vaccine program
– 2007-current
• Genital warts in the pre-vaccination period (2004 to mid2007) vs vaccination period (mid-2007 to end of 2011)
• Women < age 21 year old ↓ 92.6%
81.8%
– 11.5% in 2007 to 0.85% in 2011 (P<0.001)
• Women age 21-30 year old ↓ 72.6% 51.1%
– 11.3% in 2007 to 3.1% in 2011 (P<0.001)
• Women age >30
– No change
BMJ April 2013; 346
What’s new with:
OSTEOPOROSIS
•Source: Jokes R Us
EPIC-Heldelberg Study
Heart. 2012; 98(12):920-5
• 23, 980 Heidelberg cohort, aged 35-64 years , f/u 11 years
• Third quartile of dietary calcium decreased risk of MI
compared with first quartile
– HR of 0.69 (95% CI 0.50 - 0.94)
– No change in stroke risk or CVD mortality
• Users of calcium supplements had ↑ increased MI risk
compared to non-users
– HR 1.86 (95% CI 1.17- 2.96)
– More pronounced for calcium supplement only users (HR=2.39; 95% CI
1.12 to 5.12)
NIH-AARP diet and health study
JAMA Intern Med. Apr 2013;173(8):639-46
• Prospective study, 1995 - 1996
• 388 229 men and women, aged 50 - 71 years
• In men, supplemental calcium intake was associated with an elevated risk
of CVD death
– RR>1000 vs 0 mg/d, 1.20 (CI, 1.05-1.36),
– No change in cerebrovascular disease death (RR, 1.14; CI, 0.81-1.61).
• In women, supplemental calcium intake not associated with CVD death
– RR 1.06; CI, 0.96-1.18
– No change in cerebrovascular disease death (1.08; CI 0.87-1.33)
• Dietary calcium intake unrelated to CVD death in men or women
NHANES III study
PLoS One. Apr 2013;8(4)
• METHODS:
– Review of death certificate data, aged 17+, to estimate risk of :
• Overall CV death, Ischemic heart disease (IHD), MI, CHF, Cerebrovascular disease
• RESULTS:
– 10.0% of the population died of CV disease, majority (5.4%) died of IHD
– ↑risk of overall CV death in bottom 5% of serum Ca vs to those in the
mid 90%
• HR: 1.51 (95% CI: 1.03-2.22)
– Women ↑ risk of IHD death with serum ca in the top 5% vs mid 90 %
• HR: 1.72 (95%CI: 1.13-2.61)
– Men ↑ risk of IHD mortality with low serum calcium
• HR: 2.32 (95% CI 1.14-3.01)
– No clear association of CVD death w/ dietary or supplemental ca intake
NHANES III study
PLoS One. Apr 2013;8(4)
• CONCLUSION:
Calcium (as assessed by serum concentrations) is
involved in CV health, though differential effects by
sex may exist. No clear evidence was found for an
association between dietary or supplementary intake
of calcium and cardiovascular death
Canadian Multicentre Osteoporosis Study
J Clin Endocrinol Metab. Jul 2013;98(7)
• Methods:
• Longitudinal cohort of 9033 patients, 10-year follow-up (1995-2007)
• Assess all-cause mortality as a function recorded total calcium intake
(dietary and supplements) and total vitamin D intake
• Results:
• In women: Use of calcium supplements ↓ mortality (doses up to 1000
mg/d)
• HR 0.78 (CI, 0.66-0.92)
• Association not affected by levels of concurrent vitamin D intake.
• No definitive associations were found among men
Vitamin D/Ca Decrease Mortality:
Pooled analysis of 8 trials
J Clin Endocrinol Metab. 2012 Aug;97(8):2670-81.
METHODS:
•24 RCT reporting data on mortality in which vitamin D was given
either alone or with calcium
•8 trials included in analysis, death within 3 yr of treatment
•70,528 participants (86.8% females) , median age of 70
RESULTS:
•Vitamin D alone did not affect mortality, but mortality↓ if
vitamin D was given with Ca (HR= 0.91; CI 0.84-0.98)
•NNT= 151 need tx w/ vitamin D & Ca for 3 yr to prevent 1 death
Calcium summary:
Cleveland Clinic Patient Education Materials
The Role of Calcium in Preventing
Osteoporosis
•http://my.clevelandclinic.org/disorders/osteoporosis/hic_the
_role_of_calcium_in_preventing_osteoporosis.aspx#
Thank You!