Women's Cardiovascular Health Guidelines and Recommendations

National Lipid Association National Lipid Association Recommendations for Patient Recommendations for Patient- -Centered Management of Dyslipidemia Part 2: Women s Health Dyslipidemia Part 2: Women s Health Centered Management of JACOBSON TA, ET AL JOURNAL OF CLINICAL LIPIDOLOGY DOI: 10.1016/JACL.2015.09.002

National Lipid Association National Lipid Association Recommendations for Recommendations for Centered Management of Dyslipidemia Part 2 Patient Patient- -Centered Management of Dyslipidemia Part 2 Women s Health Slide Deck Prepared by Merle Myerson MD, Ed D, FACC, FNLA

National Lipid Association National Lipid Association Recommendations for Patient Recommendations for Patient- -Centered Management of Dyslipidemia Part 2 Management of Dyslipidemia Part 2 - -Lifespan Centered Lifespan Writing Committee Gender Differences Pam Morris, MD, FNLA Unique women s issues Robert A Wild, MD, MPH, PHD, FNLA, NCMP Thomas Dayspring, MD, FNLA,NCMP James A Underberg, MD, MS, FNLA

National Lipid Association (NLA) National Lipid Association (NLA) The National Lipid Association (NLA) was created as an extension of the success established by the Southeast Lipid Association formed in 1997 by a group of pioneering lipid researchers and clinicians from the Southeastern United States. The NLA was formed in 2000 to advance the practice of clinical lipidology. The NLA is a multi-disciplinary society. Members include physicians, nurse practitioners, nurses, physician assistants, PhD researchers, pharmacists, dieticians and all professionals who desire to advance improvement in the practice of clinical lipidology.

Womens Health Women s Health More women than men die from cardiovascular disease (CVD) Women have traditionally been under-represented in all research designs addressing CVD findings are often generalized to women Paucity of research age < 40 years Unique female issues: Polycystic ovary syndrome Pregnancy Breast feeding Menopause Contraception

Background on Development of Clinical Guidelines and Recommendations

Cholesterol Guidelines Development Cholesterol Guidelines Development 2001: National Cholesterol Education Program Adult Treatment Panel (ATP) III issued 2007: NHLBI convened an expert panel to update the guidelines 2008: ATP IV members appointed June 2013: NHLBI announced that the work of the panel would not be published as ATP IV. NHLBI asks American College of Cardiology (ACC) & American Heart Association (AHA) to complete and publish a guideline November 12, 2013: 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults

2013 ACC/AHA Guideline 2013 ACC/AHA Guideline 4 Statin Benefit Groups: Individuals who should engage in a risk: benefit discussion with their provider Those with history atherosclerotic CV events Those with LDLC > 190 age 21 - 75 Those with diabetes 1 or 2 age 40 75 Those with no diabetes, age 40-75, 10 yr. ASCVD risk 7.5% Depending on risk, initiate risk-benefit discussion for use of moderate or high dose statin therapy There was insufficient evidence to support the use of LDL-C targets or goals No studies showing adding non statin drugs (fibric acids, niacin, ezetimibe, bile-acid binders) to statins add preventive benefit No LDL-C treatment targets

2013 ACC/AHA Guideline 2013 ACC/AHA Guideline Risk Calculator This guideline recommends using the new Pooled Cohort Risk Assessment Equations developed by the Risk Assessment Work Group to estimate the 10- year ASCVD risk . . . for the identification of candidates for statin therapy. Web-based and includes: sex, age, race (White or African-American), total cholesterol, HDL-cholesterol, systolic blood pressure, treatment for high blood pressure (if SBP > 120), diabetes, smoking

National Lipid Association National Lipid Association Clinical Recommendations for Patient Clinical Recommendations for Patient- -Centered Management of Dyslipidemia Management of Dyslipidemia Centered Part 1 Executive summary released in 2014 with the Full Report released in 2015. Document serves as a guide for clinicians for treating patients with dyslipidemia. LDL-C and non-HDL-C goals were retained for their importance in the prevention of heart attack and stroke. Evidence from randomized clinical trials (including primary, subgroup, and pooled analyses), epidemiological, metabolic, mechanistic, and genetic studies included Part 2 Released in 2015 and serve to provide a unique set of recommendations for management of dyslipidemia in special populations.

National Lipid Association National Lipid Association Recommendations for Patient Recommendations for Patient- -Centered Management of Dyslipidemia Centered Management of Dyslipidemia Target of therapy: non-HDL-cholesterol and LDL-Cholesterol Non-HDL-C and LDL-C goals depend on absolute ASCVD risk Apolipoprotein B is a secondary, optional target of treatment In selected patients with two major risk factors, any of the three risk calculators may be used to determine absolute ASCVD risk. If 3 major risk factors are present, the patient is considered at high risk and without need to calculate risk. Statins first line therapy Triglycerides are target of therapy when very high ( 500 mg/dL) Goals: Non-HDL-C < 130 for all risk groups except < 100 for very high risk LDL-C < 100 for all risk groups except < 70 for very high risk Jacobson TA, et al. Journal of Clinical Lipidology. 2015;9:129-169

Risk Calculators Risk Calculators NLA Part 1 Recommendations: use quantitative risk scoring as an option for patients with 2 major ASCVD risk factors, in the absence of any high or very high risk conditions, to facilitate treatment decisions. Thresholds for high risk are 10 year risk for a hard CHD event using NCEP ATP III, 15% 10-year risk using ACC/AHA Pooled Cohort Equations, and 45% risk for CVD using Framingham long-term 30-year risk.

CVD Risk Calculators POOLED COHORT EQUATIONS (ACC/AHA) REYNOLDS RISK Framingham Risk Score General population from one area. Framingham MA (USA) Population-based cohort studies funded by NHLBI Men and Women from USA, no known CVD (men were non-diabetic) Population Age 30-74 years Men 57-80?; Women 45 Men: 1995 2008, followed for median of 10.8 years Women: 1992-2004, followed for a median of 10.2 years 1968-1971 original Framingham cohort, 1971- 1975 and 1984-1987 Offspring Studies Data collection 1967-1992 Years risk prediction 10-year risk of CHD events 30-year risk of CHD and stroke 10-year risk of ASCVD 10-year risk for CVD Sex, age, race (White or Black), total cholesterol, HDL-C, Systolic blood pressure, treatment for high blood pressure (if systolic > 120 mmHg), Diabetes, smoking status Sex, age, smoking status, total cholesterol, HDL-C, CRPhs, parental history of MI < 60 years of age, HbA1c (if diabetic) sex, age, total cholesterol, HDL-C, smoking status, systolic blood pressure (treated/not treated), diabetes Variables 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults National Lipid Association Recommendations NCEP ATP III Canadian Cardiovascular Society International Atherosclerosis Society National Lipid Association Recommendations Guidelines using score National Lipid Association Recommendations c-statistic: 0.65, 0.71 O/E: 1.20; may be better than FRS at higher categories of predicted risk Discrimination and Calibration c-statistic: 0.65, 0.71, 0.77 O/E: 1.18, 1.51 unknown Risk scores account for White and Black Race Eliminated targets for LDL-C Men were in the Physicians Health Study and Women in the Women s Health Study Notes

National Lipid Association Recommendations: National Lipid Association Recommendations: Lipid Goals by Risk Category Lipid Goals by Risk Category Risk Category, (# major ASCVD risk factors) LDL-C mg/dL Non-HDL-C mg/dL Apo B mg/dL Criteria ASCVD DM type 1 or 2 2 other major risk factors Evidence of end organ damage <100 < 80 Very High < 70 DM type 1 or 2 CKD stage 3B or 4 LDL-C 190 mg/dL Quantitative risk score reaches highest level <130 < 100 <90 High ( 3) 2 major risk factors Consider quantitative risk scoring Consider other risk indicators Moderate (2) <130 <90 <100 Consider other risk indicators if known Low (0-1) <100 <130 <90 Jacoboson, TA, et al. Journal of Clincial Lipidology. 2015:9:129

Management Plan Initiate Lifestyle Modification Therapy Management Plan Initiate Lifestyle Modification Therapy Therapeutic lifestyle changes are advised for all patients regardless of level of risk Diet: heart-healthy, Mediterranean, DASH diet Weight reduction if indicated Increased physical activity Smoking cessation Blood pressure control Reduction of elevated fasting blood glucose

Management Plan Pharmacologic Management Plan Pharmacologic Reduction of atherogenic cholesterol (non-HDL-C and LDL-C) is a first priority Non-HDL-C and LDL-C are co-primary targets of therapy with non-HDL-C the primary target in patients who s Triglycerides are < 500 mg/dL. If Triglycerides 500 they are the primary target of therapy Statin drugs are first line (if no contraindications) for atherogenic cholesterol lowering. Slide #23: Tables for degree of potency and expected lowering. Other LDL-C lowering drugs: intestine absorption inhibitor, bile acid sequestrants, niacin Triglycerides: fibrates, fish oil, and niacin HDL-C is not a target of therapy

Primary Prevention of Atherosclerotic Cardiovascular Disease (ASCVD Primary Prevention of Atherosclerotic Cardiovascular Disease (ASCVD) Primary prevention strategies are critical to reduce morbidity and mortality for women at risk for ASCVD Relatively fewer women have been included in trials of primary prevention. Available data support the conclusion that women and men of comparable ASCVD risk experience similar reductions in events when treated with statin therapy Women without ASCVD should undergo risk assessment and stratification and the intensity of lipid-lowering therapy should be matched to the level of risk as described in the NLA Recommendations for Patient-Centered Management of Dyslipidemia Part 1

Secondary Prevention Secondary Prevention Women with manifest ASCVD benefit from statin therapy . . . The NLA Expert Panel recommends consideration for the use of moderate-or high- intensity statin therapy, irrespective of baseline atherogenic cholesterol levels, for patients with ASCVD or diabetes mellitus . . . National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 1

Gender Differences in Statin Lipid Gender Differences in Statin Lipid- -Lowering Therapy Lowering Therapy Research has shown that benefits extend similarly to both men and women Relatively less data available for gender-specific adverse events in women It has been estimated that women tend to be 1.5-1.7 times greater risk for clinically significant adverse drug reactions compared to men Tran C. J Clin Pharmacol. 1998;38:1003 Bhardwaj S. Clin Interv Aging. 2013;8:47 Wenger NK. Heart. 2008;94:434 Mora S. Circulation. 2010;121:1069 Recommendation: Clinicians should be aware of the potential for elevated adverse events with taking statins, particularly glucose elevations and myalgia which may be due to differences in age, comorbidities, BMI and body fat, muscle mass, and polypharmacy

Lipid Lipid- -Lowering Therapy Lowering Therapy Statins Statins Most researched lipid medication in terms of efficacy, safety, morbidity and mortality Felt to have pleiotropic effects benefits other than LDLC-lowering: anti- inflammatory, anti-thrombotic Lower Triglycerides, particularly in high doses Minimal raise in HDL-C Relatively potent vs. other LDL-C lowering medications

Statin Drugs Statin Drugs Drug Atorvastatin (Lipitor) Fluvastatin (Lescol) Lovastatin (Mevacor) Pitavastatin (Livalo) Pravastatin (Pravachol) Rosuvastatin (Crestor) Comments available as a generic available as a generic available as a generic available as a generic Simvastatin (Zocor) Available as a generic Avoid with doses > 40 mg/day

Statins Doses Statins Doses 2013 ACC/AHA Guideline 2013 ACC/AHA Guideline High Intensity LDL-C 50% Rosuva (Crestor) 20 - 40 Atorva (Lipitor) 40 80 Moderate Intensity LDL-C 30% to < 50% Atorva 10 20 Rosuva 5 - 10 Simva 20 40 Pitava (Livalo) 2 - 4 Prava 40 - 80 Lovastatin 40 Fluva (Lescol) XL 40 mg twice daily or XL 80 mg once daily Low Intensity: any dose lower than moderate

FDA DRUG SAFETY COMMUNICATION FDA DRUG SAFETY COMMUNICATION Statins Statins February 28, 2012 February 28, 2012 Liver enzyme tests Should be performed before starting statin therapy and as clinically indicated thereafter. FDA has concluded that serious liver injury with statins is rare and unpredictable in individual patients and that routine monitoring does not appear to be effective in detecting or preventing serious liver injury. Diabetes FDA s review of studies: While statin randomized controlled trials and epidemiological studies show an increase in HbA1c and incident Type 2 diabetes with statin therapy as compared to placebo, the risk for incident diabetes is low (odds ratio 1.09 95% CI 1.02- 1.17) and the benefits of statin therapy in appropriate patients exceeds risk. (Maki KC, et al. Journal of Clinical Lipidology. 2014;8(3S).

FDA DRUG SAFETY COMMUNICATION FDA DRUG SAFETY COMMUNICATION Statins Statins Cognitive Adverse Events Post-marketing adverse event reports and data from observational and clinical studies did not suggest that cognitive changes associated with statin use are common or lead to clinically significant cognitive decline Patients should know that although cognitive symptoms have been reported by some statin users, information from such case reports cannot be considered to be reliable, is not conclusive, and has not been proven in a cause-and-effect manner. Rojas-Fernandez. Journal of Clinical Lipidology. 2014;8(3S) Lovastatin and Simvastatin Both metabolized via CYP450, increased risk of myopathy and interaction with other medications

Lipid Lipid- -lowering Therapy lowering Therapy Statins Statins Myopathy Muscle soreness is the most common side effect of statins. This may occur with or without elevation in serum creatine kinase. The statin can be stopped to see if symptoms resolve and then have a retrial to see if symptoms return. Options can include reducing the dose, trial of a different statin, alternate-day dosing of a statin with a long half life or use of non-statin drugs.

Non Non- -statin lipid statin lipid- -lowering therapy lowering therapy There is limited gender-specific evidence for the benefit of non-statin drugs in the prevention of ASCVD events. 2013 ACC/AHA Guidelines: No studies showing adding nonstatin drugs (fibric acids, niacin, ezetimibe, bile-acid binders) to statins add preventive benefit

Non Non- -Statin Drugs Statin Drugs IMPROVE-IT Randomized double blind controlled trial: High risk secondary prevention, participants followed for 6-7 years Simvastatin 40 mg + ezetimibe vs. Simvastatin 40 + placebo No effect on total mortality but reduced rate of stroke and MI LDL-C 69 54 in intervention group No safety signal of harm Lower is better (maybe goals do matter) Value of non-statins Cannon CP. N Engl J Med. 2015 Jun 18;372(25):2387-97.

Non Non- -Statin Drugs Statin Drugs LDL-C Lowering Triglyceride Lowering Bile Acid Sequestrants Fibrates Cholesterol Absorption Inhibitor Omega-3 fatty acids Niacin Niacin (high dose) Mipomersen [HoFH only] Lomitapide [HOFH only ] PCSK-9 Inhibitors

Non Non- -Statin Drugs Statin Drugs Recommendations for use of non-statin drugs for women are the same as those outlined in the NLA Recommendations Part 1: Non statin drug therapy may be considered for patients with contraindications for, or intolerance to, statin therapy Non statin drug therapy can be added to statin therapy when non-HDL-C and LDL-C levels remain above goal Note that: Women treated with niacin and laropiprant in the HPS2 -THRIVE study had an excess of events and trend toward harm compared to men. HPS2-THRIVE Collaborative Group. N Engl J Med. 2014;371:203.

Lipid Lipid- -lowering Therapy lowering Therapy Statins Statins Pregnancy All women should have lipid testing prior to pregnancy or early in pregnancy (at least before the end of the first trimester). For women on lipid-lowering medication prior to pregnancy, all medications except bile acid sequestrants should be stopped. Omega -3-FA are currently recommended to be stopped in preparation for pregnancy. Certain women with FH may also be treated with LDL apheresis Very high triglycerides ( 500 mg/dL with risk for pancreatitis) may be treated with diet/lifestyle management, omega-3-fatty acids, fenofibrate or gemfibrozil beginning in the 2nd trimester based on clinical judgement.

Lipid Lipid- -lowering Therapy in Pregnancy lowering Therapy in Pregnancy statin drugs are contraindicated Animal reproduction studies have shown adverse effects with use of fibrates, ezetimibe, cholestyramine, and omega 3 fatty acids but there are no studies on pregnant human subjects Use of these agents should therefore be employed only after careful consideration of the risk- benefit ratio Lomitapide is contraindicated in pregnancy Animal reproduction studies using colesevelam have shown no evidence of risk but no studies have been done on pregnant human subjects using this drug. At present there is no definitive information on use of PCSK9 Inhibitors or mipomersin in pregnancy

Lipid Lipid- -lowering Therapy for Women Who are Breast Feeding lowering Therapy for Women Who are Breast Feeding Colesevelam can be used. For other bile acid sequestrants, use can be considered after weighing all risks and benefits For patients with severe hypertriglyceridemia use of omega-3-fatty acids and fibrates can be considered after weighing all risks and benefits. It is advisable to avoid estrogenic oral contraception as this may increase triglyceride levels

Lipid Lipid- -lowering Therapy lowering Therapy Pregnancy: FDA Classification Pregnancy: FDA Classification FDA Categories were removed from drug labeling per the new FDA labeling guidance effective June 30, 2015. Instead, drug labeling will include a summary of the risks of using a drug during pregnancy and lactation, discussion of data supporting that summary and relevant information to assist health care providers in treatment decisions.

Lipid Lipid- -lowering Therapy lowering Therapy Pregnancy and Familial Hypercholesterolemia Pregnancy and Familial Hypercholesterolemia Familial Hypercholesterolemia manifests as markedly elevated LDL-C levels due to genetic mutations, most commonly with the LDL receptor. Most patients are heterozygous (1/300) while the homozygous condition is very rare. Patients with FH are at increased risk for premature atherosclerosis. Despite high circulating levels of atherogenic lipoproteins, data do not support an association between maternal lipid levels and maternal or perinatal outcomes. Inadequately studied Vrijkotte TG. J Clin Endocrinol Metab. 2012;97:3917 No definitive data are available to guide stopping treatment but it is felt that statins and other systematically absorbed lipid drug therapy should be stopped a minimum of one month and possibly as long as 3 months prior to attempted conception.

Lipid Lipid- -lowering Therapy lowering Therapy Lactation Lactation Patients with FH can receive bile acid sequestrants Patients with severe hypertriglyceridemia can receive fibrates and omega-3 fatty acids and should avoid estrogenic contraception even with late breast feeding.

Dyslipidemia in Pregnancy Dyslipidemia in Pregnancy Pregnancy is a metabolic stress test Best time to screen is before or during first trimester Hypertriglyceridemia associated with preeclampsia and gestational diabetes Preeclampsia and Gestational diabetes are risk factors for later CVD as strong or stronger than smoking Lack of awareness among Primary Care Physicians and Obstetricians

Polycystic Ovarian Syndrome (PCOS) Polycystic Ovarian Syndrome (PCOS) Diagnosis is by identifying at least two of the following criteria: androgen excess (clinical or in the blood) , ovulatory dysfunction, and/or presence of polycystic ovaries by ultrasound. Affects 7-22% of reproductive-age women. Women with PCOs are at increased risk for metabolic syndrome, diabetes mellitus, and complications of pregnancy. Majority have insulin resistance aggravated by obesity. Patients with PCOS should be evaluated for dyslipidemia and diabetes. The pattern seen is generally that of insulin resistance (elevated Triglycerides and low HDL-C along with a predominance of small, dense LDL particles). If baseline values are normal, testing should be repeated at least every two years.

Polycystic Ovarian Syndrome (PCOS) Polycystic Ovarian Syndrome (PCOS) The accuracy of risk assessment remains uncertain for women with PCOS but risk stratification and treatment goals should be the same as described for the general population in the NLA Recommendations Part 1 Treatment of the dyslipidemia should be focused on reversing all components of the metabolic syndrome through diet, exercise, and medication if needed. Implications for those at high risk for maternal and/or fetal complications should be considered Combined oral contraceptives are often used to control menses, reduce endometrial and ovarian cancer risk and reduce hirsutism. Use of combined oral contraceptive may result in increase in Triglycerides and thrombotic risk and patients should be monitored.

Oral Contraception Oral Contraception Estrogen in combined oral contraceptives may increase Triglycerides and HDL-C and lower LDL-C. The more estrogen, the greater the TG-raising effect and may cause marked elevations (> 500 mg/dL) in women with high baseline TG. Androgenic progestins (norgestrel and levonorgestrel) can raise LDL-C and lower HDL-C. Others are usually lipid neutral. Transdermal contraceptive may be less prone to producing clinically important elevations in TG concentration with similar thrombotic risk as compared to oral contraceptives.

Lipid Changes with the Menopause Lipid Changes with the Menopause Both LDL-C and apolipoprotein B increase in the few years prior to menopausal symptoms, peak, and then plateau. HDL-C tends to decrease after menopause. These changes are related to declining ovarian production of estradiol and population average weight gain. The absolute risk of ASCVD increases substantially during and after the menopause.

Hormone Replacement Therapy Hormone Replacement Therapy Hormone replacement therapy is primarily indicated to control menopause-related quality of life issues. Results from the Women s Health Initiative suggest that women at higher risk for ASCVD events are more likely to have even higher risk when they take oral hormone replacement therapy. Risk for CVD increases with age Wild RA. Semin Reprod Med. 2014;32:433

Hormone Replacement Therapy Hormone Replacement Therapy Recommendations: Prescribe the lowest effective dose of HRT Doses lower than 0.3 mg of oral conjugated estrogen or equivalent given at night will not control hot flashes for most women. Transdermal or vaginal delivery may be associated with fewer adverse events than the oral route Vaginal and transdermal preparations have smaller effects on clotting factors, lipid metabolism, inflammatory biomarkers, and sex hormone binding globulin synthesis.

Recommendations for Womens Health Recommendations for Women s Health In general, women should be treated according to the National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia Part 1 with the following special considerations. First-line cholesterol-lowering drug therapy, unless contraindicated, is moderate-to high-intensity statin. If goal levels of atherogenic cholesterol are not achieved, statin dose may be increased or the patient switched to a more efficacious agent. Statin therapy should be considered for patients at very high risk (known ASCVD, or diabetes with 2 major risk factors) even if pre- treatment levels are below the treatment goals.

Recommendations for Womens Health Recommendations for Women s Health Non-statin drug therapy may be considered for women with contraindications or intolerance to statin therapy, or in combination with statin therapy for patients who need additional lowering of atherogenic cholesterol to achieve treatment goals. Women taking statins may be at increased risk for certain adverse events, particularly myalgia.

Recommendations for Pregnancy to Menopause Recommendations for Pregnancy to Menopause Women should be screened for dyslipidemia before pregnancy or as part of the routine obstetrical laboratory examination For women taking lipid-lowering medications prior to pregnancy, all except bile acid sequestrants should be stopped when the woman becomes pregnant, or is trying to become pregnant Women should be educated on the importance of pregnancy avoidance when lipid-altering therapies other than bile acid sequestrants are used.

Recommendations for Pregnancy to Menopause Recommendations for Pregnancy to Menopause Total cholesterol and Triglyceride levels in women with normal pregnancies should generally not exceed 250 mg/dL. If they do, the clinician should evaluate for preexisting or acquired secondary causes. Hypercholesterolemia during pregnancy and breast feeding, especially in women with FH may be treated with bile acid sequestrants. Women with homozygous FH may be considered for treatment with LDL apheresis LDL apheresis may also be considered in heterozygous FH patients with ASCVD. Very high Triglycerides ( 500 mg/dL) may be treated during pregnancy with diet and lifestyle plus prescription omega-3 fatty acid. Fenofibrate and gemfibrozil may be given starting early in the 2nd trimester based on clinical judgement. These agents can be used during breast feeding.

Recommendations for Pregnancy to Menopause Recommendations for Pregnancy to Menopause PCOS is a high-risk condition for dyslipidemia, metabolic syndrome, preeclampsia, hypertension, diabetes, and premature delivery. All patients with PCOS should be screened for these and followed carefully. Contraceptive choice impacts dyslipidemia. COC should generally not be used by women 35 years of age who smoke because of risk for stroke and MI. Sex hormone therapy should not be used for prevention of ASCVD. Menopause sex hormone therapy is an option for treatment of significant menopause symptoms during menopause transition for women at minimal risk for ASCVD.