9/5/2016. Faculty. Cardiometabolic Risk Prevention in Women. Crash Test Dummies. Pregnancy: The First Physiologic Stress Test

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1 Faculty Cardiometabolic Risk Prevention in Women Margo B. Minissian, PhDc, ACNP, CLS, AACC, FAHA Nurse Scientist, Cardiology Nurse Practitioner Clinical Lipid Specialist Cedars-Sinai Heart Institute Women's Heart Center Los Angeles, California Chrisandra Shufelt, MD, MS, FACP Associate Director, Barbra Streisand Women s Heart Center & Preventive Rehabilitative Cardiac Center Director, Women s Hormone and Menopause Program Cedars-Sinai Heart Institute Associate Professor, Cedars-Sinai Medical Center Los Angeles, California Disclosures Learning Objectives Margo B. Minissian: Consultant Sanofi Regeneron; Grant/Research Support American Heart Association, NIH, National Lipid Foundation Chrisandra Shufelt has disclosed no relevant financial relationships with any commercial interests. Assess the cardiovascular system during pregnancy Analyze adverse pregnancy outcomes (APOs) as a risk for future maternal heart disease Prepare a detailed history and physical including pregnancy and APO history for female patients Explain the timing hypothesis and role that estrogen plays on a healthy blood vessel as compared to diseased blood vessel Identify the indications for starting hormone replacement therapy in women and describe how to use ASCVD risk to guide treatment options Analyze non-hormonal treatment options to systemic hormone therapy for menopausal symptoms and how to counsel patients on usage APO = adverse pregnancy outcome; ASCVD = atherosclerotic cardiovascular disease. Crash Test Dummies Pregnancy: The First Physiologic Stress Test 1

2 Recognition of Hypertension in Medicine vs Obstetric-Gynecology Clinics APOs Pregnancy complications = Identification of CVD risk Physiologic stress tests in 85% of US women Identify women who would most benefit from primary prevention efforts to reduce the risk of CVD Schmittdiel J, et al. Hypertension Apr; 57(4): CVD = cardiovascular disease. Sattar N, et al. BMJ. 2002;325(7356): Hemodynamic Changes in Pregnancy Unintended Consequences of Pregnancy 80% of women are parous 25% to 35% will have at least one complex pregnancy >20% of women carry pregnancy history indicative of CVD Especially black mothers Low birthweight: 7% Preterm delivery: 12% Hypertensive disorders: 15% Liu L, et al. Cardiovas Res. 2014; 101: GDM: 5% GDM = gestational diabetes mellitus. Denton AB, et al. West Indian Med J. 1994;43(3): Mosher WD, et al. National Health Statistics Reports. July 24, Number 55. US Department of Health and Human Services. Centers for Disease Control and Prevention. National Center for Health Statistics. APOs with Increased CVD Risk GDM Gestational hypertension Pre-eclampsia Preterm delivery >80% of women bear at least 1 child ~30% of women have APOs ~25% of women carry a predictor of their future CVD risk Gestational Diabetes Mellitus 5% of pregnancies History of GDM CVD risk: adjusted odds ratio = 1.85 CVD events 7 years earlier than non-gdm 7-fold increase in risk of later type 2 diabetes Compared with women without diabetes mellitus, women with diabetes mellitus have a 3- to 7-fold increased CVD risk in contrast to a 2- to 4-fold increase in risk for men with diabetes mellitus Rich-Edwards JW, et al. Epidemiol Rev. 2014;36: Bellamy L, et al. Lancet. 2009;373(9677): Gregg EW, et al. Ann Intern Med. 2007;147: Carr DB, et al. Diabetes Care. 2006;29(9):

3 Gestational Hypertension 3% to 14% of pregnancies Strong association of gestational hypertension with development of chronic hypertension Increased ischemic heart disease and stroke mortality Associated with higher BMI, systolic and diastolic blood pressures and unfavorable lipid profile Attenuated by adjustment for pre-pregnancy measurements Increased CVD risk may be largely attributed to risk factors that were present before pregnancy Pre-Eclampsia ~25% of preterm births; 2%-5% of all births 4-fold higher incidence of hypertension Preceded by increased left ventricular mass and diastolic blood pressure at postpartum screening 3-fold higher incidence of type 2 diabetes mellitus 2-fold elevated risk of CVD death Risk of CVD is higher in women exposed to early pre-eclampsia than in women diagnosed with pre-eclampsia later in pregnancy regardless of pre-eclampsia severity Lykke JA, et al. Hypertension. 2009;53(6): Wilson BJ, et al. BMJ. 2003;326:845. Romundstad PR, et al. Circulation. 2010;122: Hernandez-Diaz S, et al. BMJ. 2009;338:b2255. Irgens HU, et al. BMJ. 2001;323: McDonald SD, et al. Am Heart J. 2008;156(5): Preterm Delivery (<37 Weeks) Preterm Delivery, Especially if Pre-Eclamptic, Predicts Total Mortality in the Mother 6% to 12% of deliveries in the developed world HR for CVD 1.3 to 2.6 compared with term births Even in normotensive preterm deliveries Even in spontaneous preterm delivery (compared to medically indicated preterm delivery) Maternal intrauterine environment and health HR CVD mortality Pre-eclamptic: 1.7 Preterm: 3.0 Preterm pre-eclamptic: 8.1 HR = hazard ratio. Beck S, et al. Bull World Health Organ. 2010;88(1): Catov JM, et al. Ann Epidemiol. 2010;20(8): Norway registry, n~600,000 first births Irgens HU, et al. BMJ. 2001;323(7323): Incorporating Spontaneous Preterm Delivery into Evaluation of Risk for Future Maternal CVD Spontaneous Preterm Delivery Is Associated with Clustering of MatErnal Risk Markers: The SPACE study NIH Sponsored Recruited women who delivered spontaneously 34 weeks Matched normal control subjects by age, ethnicity, mode of delivery Each women received non-invasive vascular testing, lipids, inflammatory markers, and emerging exploratory biomarkers Vascular dysfunction Spontaneous Preterm delivery Endothelial dysfunction Minissian & Doering, Park K, et al. Cardiovasc Drugs Ther. 2015;29: doi: /s Inflammation 3

4 The Positive Impact of Early Screening on CVD Risk Population with complicated pregnancy (eg, pre-eclampsia) Healthy population Threshold for clinical vascular or metabolic disease Vascular Dysfunction Targeted screening, lifestyle modification, early treatment Cedars-Sinai. Barbra Streisand Women s Heart Center [website]. Heart-Center/. Accessed September 2, Courtesy of Dr. Janet Rich Edwards. Pregnancies Middle Age What s the Take Home? Pregnancy can tell us about a woman s future risk of heart disease A detailed history and physical examination, including APOs, are important in stratifying the risk of heart disease Women with an APO are 2 to 8 times more likely to develop heart disease later in life Identifying and treating known heart disease risk markers, such as blood pressure and cholesterol, and leading a healthy active lifestyle can reduce the risk of heart disease Menopause, Hormones, and the Heart Chrisandra Shufelt, MD, MS, NCMP APO = adverse pregnancy outcome. 550 Cardiovascular Disease Deaths in the United States ( ) Women s Health Initiative Ages years Randomized Double-Blinded Trial Deaths (in thousands) Women Men Women who had no uterus at start of study Hysterectomy Women who had a uterus at start of study YES N= 10,739 NO N= 16,608 CEE mg/d Placebo CEE mg/d + MPA 2.5 mg/d Placebo Go AS, et al. Circulation. 2014;129:e28-e292. CEE = conjugated equine estrogen; MPA = medroxyprogesterone acetate. Manson JE, et al. N Engl J Med. 2003;349: Women s Health Initiative Steering Committee. Anderson GL, et al. JAMA Apr 14;291(14):

5 WHI Hormone Therapy Trials Goal was to assess the effect of HT on diseases of aging This was a study of disease prevention rather than a treatment trial Average age WHI 61.8 years WHI Events per 10,000 Women/Year of CEE Use WHI = Women s Health Initiative; HT = hormonal therapy. Accessed September 2, Rossouw JE, et al. JAMA Apr 4; 297(13): Hodis HN, et al. Clin Obstet Gynecol Sept;51(3): Timing Hypothesis Estrogen s Action on Endothelium Timing Hypothesis: The beneficial effects of HT in preventing atherosclerosis may occur only when the therapy is initiated before advanced atherosclerosis develops HT is NOT beneficial when given to older women, because the underlying biologic characteristics of the vessel wall and vascular response to HRT are altered in older, more atherosclerotic vessels. HRT = hormone replacement therapy. Rossouw JE, et al. JAMA Apr 4; 297(13): Ouyang et al. J Am Coll Cardiol May 2;47(9): CVD Risk >10 Years (ACC/AHA Risk Prediction Score) MenoPro/NAMS Algorithm and Free Mobile Application Moderate-to-severe hot flashes and/or night sweats? (and inadequate response to behavioral/lifestyle modifications) <5 Years Since Menopause Onset 6 to 10 >10 HT OK HT OK Avoid Low (<5%) HT Moderate (5% to 10%) High (>10%) Assess CVD risk and time since menopause onset HT OK (choose transdermal) HT OK (choose transdermal) Avoid HT Avoid HT Avoid HT Avoid HT DECISION ABOUT DURATION OF USE: Continued moderate-to-severe symptoms; patient preference; weigh baseline risks of breast cancer, CVD, and osteoporosis. NAMS = North American Menopause Society; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor. Manson J, et al. Menopause. 2015;22(3): Yes Yes Interested in HT and free of breast cancer, endometrial cancer, DVT/PE, CHD, stroke/tia, and other contraindications to HT? No Consider non-hormonal therapy: paroxetine, other SSRI/SNRIs, gabapentin, pregabalin, clonidine ASCVD Risk Estimator Gender Race Systolic blood pressure Diabetes mellitus Age Total cholesterol HDL Treatment for hypertension Smoker Estimator/#/ASCVD-Risk-Estimator/ ASCVD Risk Estimator. American College of Cardiology. American Heart Association Accessed September 2,

6 Transdermal vs Oral Estrogen MenoPro/NAMS Algorithm and Free Mobile Application Moderate-to-severe hot flashes and/or night sweats? (and inadequate response to behavioral/lifestyle modifications) Genitourinary symptoms such as vaginal dryness or pain with intercourse/sexual activity? No Patch Yes Free of breast, endometrial, or hormone-sensitive cancers? No No indication for HT Yes Vaginal lubricants, moisturizers; consider lowdose vaginal estrogen Lacut K, et al. Thromb Haemost Jul;90(1): Brosnan JF, et al. Thromb Haemost. 2007;97(4):558. Straczek F, et al. Circulation. 2005;112: Zegura B, et al. Menopause. 2006;13(4): Shifren JL, et al. J Clin Endocrinol Metab May;93(5): Powers MS, et al. Am J Obstet Gynecol Aug;152(8): Manson J, et al. Menopause. 2015;22(3): Local Vaginal Estrogen 80% of Women Experience Vasomotor Symptoms during Menopause Local vaginal therapy given at routine doses does not achieve systemic levels and does not stimulate the endometrium Systemic progestin is not indicated Surveillance is required if a woman is having vaginal spotting or breakthrough bleeding and must be followed to resolution FDA hearing to change the box warning on vaginal estrogens Warnings apply to the systemic estrogen and not local treatment FDA = US Food and Drug Administration. NAMS Position Statement, Accessed September 2, Simunic V, et al. Int J Gyn Ob. 2003;82: High-Risk Patients for HT Known coronary artery disease History of an MI, CVA, VTE - PE accounts for one-third of excess fatal events from HT History of estrogen-sensitive cancers Clotting and protein deficiency - Factor V Leiden or prothrombin with oral E increases VTE risk 25-fold Multiple cardiac risk factors: Hypertension, hyperlipidemia, diabetes mellitus, family history of premature heart disease - LDL >130, CHD risk OR 1.46 ( ) - Metabolic syndrome YES CHD risk OR 2.26 ( ) - LDL/HDL ratio >2.5, OR 1.73 ( ) MI = myocardial infarction; VTE = venous thromboembolism; PE = pulmonary embolism; HT = hypertension; LDL = low-density lipoprotein; OR = odds ratio; HDL = high-density lipoprotein. Bray PF, et al. Am J Cardiol Wild RA, et al. Menopause Canonico M, et al. Circulation. 2007;115(7): Straczek C, et al. Circulation. 2005;112: AHA Scientific Statement: Acute MI in Women, 2011 ACCF/AHA CABG Guidelines, * 2004 AHA STEMI Guidelines, * 2007 UA/NSTEMI Guidelines * HRT precipitates acute CHD events in older women Evidenced-based guidelines, HRT is NOT recommended for primary or secondary CVD prevention Recommend against initiating HRT and not continuing HRT for women taking E-alone or E+P after CVD event HRT should not be initiated and discontinuation should be considered in those women to reduce risk of VTE *Updated guidelines removed and do not address HRT. Antman EM, et al. Circulation. 2004;110:e82-e292. Anderson JL, et al. Circulation. 2007;116:e148-e304. Hillis LD, et al. Circulation. 2011; 124: e652- e735. Stanislav S, et al. Circulation. 2016: Jan 26 [Epub ahead of print]. 6

7 SSRIs, SNRIs Non-Hormonal Options for Menopause Symptoms - First FDA-approved SSRI for treatment of menopausal symptoms (paroxetine) - Venlafaxine at the lowest dose of 37.5 mg/d had a 40% reduction in hot flashes after 1 week and a 60% reduction at 75-mg dose Gabapentin - 50% to 60% reduction in HF Take with meals and titrate up slowly - Most studies dose 900 mg/d - Studies are underway with pre-gabalin Clonidine - Less effective than SSRI/gabapentin First Non-Hormonal Treatment for Hot Flashes Paroxetine Paroxetine salt 7.5 mg Paroxetine North American Menopause Society. Menopause. 2015;22(11):1-18. Nonhormonal management of menopause-associated vasomotor symptoms: 2015 NAMS position statement. doi: /GME Brisdelle [prescribing information]. Miami, FL: Noven Therapeutics, LLC; Mechanism for SNRI/SSRI on Vasomotor Symptoms Kvell K, et al. Molecular and Clinical Basics of Gerontology. University of Pécs, Pécs, Over-the-Counter Supplements and Herbal Therapies NAMS statement: Negative, insufficient, or inconclusive data to recommend supplements Black cohosh: Active ingredients are unknown 30 reports of liver toxicity Soy foods and soy extracts: Isoflavone, no more effective than placebo Evening primrose: Ineffective with decline in hot flashes by 1 vs placebo 2.6 Flaxseed: When acted on by gut flora, produce weal estrogenic sterols No support for use of hot flashes Vitamin E: Not clinically useful Shown increase and decreases in hot flashes Non-hormonal management of menopause-associated vasomotor symptoms: 2015 NAMS position statement. doi: /GME What s the Take Home? Best candidates for HT are symptomatic women, recently menopausal, and at low-baseline CVD risk HT should NOT be initiated or continued for the primary or secondary prevention of CVD or other chronic diseases Low-dose transdermal estrogen may have decreased effects on CHD Studies are ongoing Non-hormonal options are available and effective for women who are not candidates for HT Deaths (in thousands) Cardiovascular Disease Deaths in the United States ( ) NHLBI WISE Study, NHLBI and AHA Red Dress Awareness and Guidelines Campaigns Women Men WHI stopped Go AS, et al. Circulation. 2014;129:e28-e292. 7

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