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Top Newsmakers in Women’s Health

Pelin Batur, MD, FACP, NCMP

Education Director, Education Director, Primary Care Women’s HealthPrimary Care Women’s Health

Deputy Editor, Deputy Editor, Cleveland Clinic Journal of MedicineCleveland Clinic Journal of Medicine

baturp@ccf.org

What’s new with:HORMONE THERAPY

0 1.0

<10

10-19

>20

0.5

Years SinceMenopause

0.88

1.23

1.66

1.5 2.0 2.5

Effect of HT on CHD: Timing hypothesis

Rossouw JE, JAMA 2007;297:1465-1477

WHI-E+PAbsolute Risk /10,000 women

<10

10-19

>20

0.48

0.96

1.12

<10

10-19

>20

0.76

1.10

1.28

WHI-E

WHI-Combined

-4

7

30

-14

-1

7

-6

4

16

Decreased mortality with HT: DOPS studyBMJ 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: 4% with DM

WHI: 36% with hypertension

Fig 3 Risk with HT vs control

Schierbeck L L et al. BMJ 2012;345

©2012 by British Medical Journal Publishing Group

16 vs 33 women

15 vs 26 women

 Risk with HT vs control

Schierbeck L L et al. BMJ 2012;345

©2012 by British Medical Journal Publishing Group

10 vs 17 women11 vs 14 women

2 vs 1 woman

22 vs 40 women

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 studyBMJ 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 2002-2011

• 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 HTNeurology. 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 HTNeurology. 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?

Date of download: 7/5/2013 Copyright © The American College of Physicians.

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

•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 low-dose 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: What is the optimal screening interval in older women?

• Methods: – 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 riskJ 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 riskJ 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 pregnancywww.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 mid-2007) vs vaccination period (mid-2007 to end of 2011)

• Women < age 21 year old ↓ 92.6%– 11.5% in 2007 to 0.85% in 2011 (P<0.001)

• Women age 21-30 year old ↓ 72.6%– 11.3% in 2007 to 3.1% in 2011 (P<0.001)

• Women age >30– No change

BMJ April 2013; 346

51.1%

81.8%

What’s new with:OSTEOPOROSIS

•Source: Jokes R Us

EPIC-Heldelberg StudyHeart. 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 studyJAMA 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 studyPLoS 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 studyPLoS 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!