Behavioral Objectives

Management of Cholesterol M. Dominique Ashen PhD, CRNP The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease NPAM October 2015..Guidelines should inform clinical judgment, but not replace it.. Neil Stone, MD, Chair, 2013 ACC/AHA Guidelines on Management of Blood Cholesterol to Reduce Cardiovascular Risk Behavioral Objectives 1. Review 2013 ACC/AHA Guideline on Treatment of Blood Cholesterol, learn how to put it into practice and understand the limitations. Lifestyle management remains the cornerstone for reducing CVD risk including achieving and maintaining optimal lipid levels 2. Discuss the use of non-traditional risk assessment tools, non-statin therapy, and new drug therapies. New Guidelines: Atherosclerotic Cardiovascular Disease (ASCVD) even modest weight loss (3-5% of body weight) can result in clinically meaningful benefits for triglycerides, blood glucose, glycated hemoglobin, and development of diabetes (type 2). 1

4 Statin Benefit Groups: reduce risk in those most likely to benefit 1. With clinical ASCVD without NYHA class II-IV heart failure or hemodialysis. 2. With primary elevations of LDL-C 190. 3. 40-75 yo with DM, and LDL-C 70-189 without clinical ASCVD. 4. Without clinical ASCVD or DM, who are 40-75 yo with LDL-C 70-189 and have an estimated 10-year ASCVD risk of >7.5% Highlights: 2013 Cholesterol Guideline 1) New Pooled Cohort Equation for ASCVD risk assessment in primary prevention patients 2) Strong evidence for Statin Rx in 4 groups (reduction of morbidity and mortality) 3) No LDL-C or non-hdl-c treatment targets 4) Non-traditional risk assessment: optional use of coronary artery calcium scan (CAC ) or hscrp in selected individuals in whom risk is uncertain When 10-year risk <7.5% or decision is unclear: Other factors to enhance treatment making decisions include: Family history of premature ASCVD LDL-C >160 High-sensitivity C-reactive protein 2 CAC score 300 or 75th % for age, sex, ethnicity Ankle-brachial index <0.9 Elevated lifetime risk of ASCVD Pooled Cohort Equations for Risk Assessment Equations predict 10-yr risk of CVA/MI Former guidelines focused only on MI; now incudes CVA Highlights the large burden of disability from nonfatal events Lowered treatment threshold to 7.5% Former threshold of 20% or >10% with 2 traditional RF Separate equations for non-white populations Importance of race/ethnicity in risk of ASCVD www.clincalc.com Lifestyle Modifications both prior to and with drug therapies Regular Exercise: regular, aerobic, 3-4 sessions per week, 40 min per session, moderate- to vigorous Heart Healthy Diet: (DASH, USDA or AHA diets) 5-6% from saturated fat; reduce trans fat High in vegetables, fruits, whole grains, low-fat dairy, fish, legumes, poultry, vegetable oils, nuts; limited sugar-sweetened beverages and red meat Avoidance of tobacco Healthy weight 12 2

Primary Prevention and the Use of Statins JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hscrp No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dl hscrp >2 mg/l 4-week run-in Ridker et al, NEJM 2008359:2195-07 Rosuvastatin 20 mg (N=8901) Placebo (N=8901) Baseline LDLC Baseline HDLC Baseline hscrp 104 mg/dl 49 mg/dl 4.2 mg/l Women 6,800 Non-Caucasian 5,000 MI Stroke Unstable Angina CVD Death CABG/PTCA No Cholesterol Treatment Target Goals Appropriate intensity statin Rx recommended to reduce ASCVD risk by lowering LDL-C and non-hdl-c High intensity statin: daily dose lowers LDL by > 50% Moderate intensity statin: daily dose lowers LDL-C by approx 30% to <50% Treat to target is no longer advocated More trials needed to prove this approach HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) 17,802 men (>50 yrs) and women (>60) with LDL-C <130 mg/dl and hs-crp >2 mg/l randomized to rosuvastatin (20 mg) or placebo for up to 5 yrs* Cumulative incidence of CV death, MI, stroke, hospitalization for unstable angina, and arterial revascularization 0.00 0.04 0.08 Rosuvastatin Placebo 0 1 2 3 4 Follow-up (years) 44% RRR P<0.00001, NNT=25 Statin benefits those with mean age of 66 and elevated hscrp *The study was stopped prematurely after 1.9 years Ridker PM et al. NEJM 2008;359:2195-2207 HMG-CoA Reductase Inhibitor: Reduction in LDL-C Statin Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin 10 mg/d 69 (37) 29 (15) 39 (21) 37 (20) 80 (43) 51 (27) FDA=Food and Drug Administration, LDL-C=Low density lipoprotein cholesterol, Rx=Treatment Law MR et al. BMJ 2003;326:1423-1427 20 mg/d 80 (43) 39 (21) 54 (29) 45 (24) 90 (48) 60 (32) 40 mg/d 91 (49) 50 (27) 68 (37) 53 (29) 99 (53) 69 (37) 80 mg/d 102 (55) 61 (33) 83 (45) 62 (33) 108 (58) 78 (42) Data presented as absolute reductions in LDL-C* (mg/dl) and percent reductions in LDL-C (in parentheses) *Standardized to LDL-C 186 mg/dl (mean concentration in trials) before Rx. Independent of pre-rx LDL-C Maximum dose of 80 mg/d administered as two 40-mg tablets Not FDA approved at 80 mg/d A Meta-analysis of 164 Trials* HMG-CoA Reductase Inhibitor: Secondary Prevention Relationship between LDL-C Levels and Event Rates in Secondary Prevention Statin Trials of Patients with Stable CHD 30 Statin Placebo 4S 25 20 15 4S LIPID LIPID CARE CARE 10 HPS HPS TNT (atorvastatin 10 mg/d) 5 TNT (atorvastatin 80 mg/d) 0 0 70 90 110 130 150 170 190 210 LDL-C (mg/dl) Event (%) CARE=Cholesterol and Recurrent Events Trial, HPS=Heart Protection Study, LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study, TNT=Treating to New Targets LDL-C=Low density lipoprotein cholesterol LaRosa JC et al. NEJM 2005;352:1425-1435 Non-Traditional Risk Assessment 2013 guidelines emphasize the importance of chronologic age People age differently health age ( vascular age ) may not always correlate with chronologic age Assessing a person s vascular age (using a CAC) may allow for a more accurate CVD risk assessment and appropriate management decisions especially in presence of normal lipids 3

When to use CAC? Agree with ATP III report: indiscriminate CAC screening NOT recommended Optional for advanced risk assessment by physicians who understand its strengths and limitations Often considered in patients not judged to be at high risk who are > 40 years old with a family history of premature CVD or MetSyn Coronary Artery Calcium for the Prediction of Mortality: Are you as old as your arteries? Tota Maharaj R, Blaha MJ, Nasir K, et al. Eur Heart J 2012;33:2955-62 ~1 msv October 6, 2015 23 Coronary Artery Calcification as Assessed by EBCT No Calcification Severe Calcification Clinicain-Patient Decision Making: The Big Picture LAD Scientific evidence Patient preference Left Main LCX Agatston scores of 0 to 100 indicate mild plaque burden, scores of 100 to 400 indicate moderate plaque burden, and scores greater than 400 indicate high plaque burden. Clinical Judgment 4

Case Study: CS 63 yo caucasian female Personal History: HTN and dyslipidemia Current Meds: Amlodipine 2.5 mg qd Lipids: TC 240, TG 54, HDL 68, LDL 156 Height/Weight/BMI: 5 1.5 ;120 lbs; 22 BP: 128/74 Guidelines: Concerns and Improvements Concerns: Even greater dependence on chronologic age Death of the Intermediate Risk group Risk overestimation Improvements: Provide guidance on evaluation of cholesterol More formally acknowledge lower is better Allow for optional non-hdl-c goals Align with international guidelines to try to achieve consensus Case Study (cont): CS 63 yo female Lifestyle: Diet: tendency for high saturated fat foods (especially cheese); 1-2 glasses of wine qhs Exercise: Regular for many years; 5 days per week walking/biking outdoors Smoking: Former; 9 years, quit 1981 Family history: Brother (alive)dyslipidemia; mother died at age 90; father died at age 73 of pancreatic cancer ASCVD Risk Prediction: Application with the use of Case Studies 10-year ASCVD risk (%) = 6.1% 10-year ASCVD risk (%) for someone the same age with optimal risk factors levels = 3.2% 5

Does she belong to one of the Statin Benefit Groups? With clinical ASCVD without NYHA class II- IV heart failure or hemodialysis. NO With primary elevations of LDL-C 190. NO 40-75 yo with DM, and LDL-C 70-189 without clinical ASCVD. NO Without clinical ASCVD or DM, who are 40-75 yo with LDL-C 70-189 and have an estimated 10-year ASCVD risk of >7.5% NO Process of Risk Reduction for Patient: Statin was suggested given high LDL (156) Pt very resistant to use of statin; requested initial trial of lifestyle. Whether she uses a statin or not, she needs to improve her dietary habits (lower saturated fat). 3 Month follow-up: With reduction in saturated fats in her diet she reduced LDL to 142 What lifestyle modifications could be made? Regular Exercise: regular, aerobic, 3-4 sessions per week, 40 min per session, moderate to vigorous Heart Healthy Diet: (DASH, USDA or AHA diets) 5-6% of calories from saturated fat; reduction in trans fat reduce saturated fat consumption in her diet (cheese) High in vegetables, fruits, whole grains, low-fat dairy, fish, legumes, poultry, vegetable oils, nuts; limited sugar-sweetened beverages and red meat Avoidance of tobacco Healthy weight Process of Risk Reduction cont.: Discussed CAC scan pros and cons 1 msv radiation exposure (3 msv/yr from naturally occurring radioactive materials, cosmic radiation) Evaluates calcified plaque, not soft plaque Cost not covered by insurance Identifies subclinical atherosclerosis; optimizies risk stratification; can de-risk: Result of CAC: Agatston score 10 ( mild ); 85 th percentile for age, gender, ethnicity ( above average ) Her 10-year ASCVD risk is less than 7.5%. What can help make the decision? Family history of premature ASCVD NO LDL-C >160 NO High-sensitivity C-reactive protein 2 Not evaluated CAC score 300 or 75th % for age, sex, ethnicity Not evaluated Ankle-brachial index <0.9 Did not discuss Elevated lifetime risk of ASCVD Cannot calculate >59 yo Discussion Points: Use of risk assessment tool in women Likely to be below 7.5%; use scores 5-7.5% for discussion of CVD prevention and tools for treatment making decisions What drives risk with this tool Age, high SBP (and treatment), cholesterol Role of non-traditional tools to detect subclinical disease Risk discussion with the patient 6

Case Study #2 MA 66 yo male PMH: HTN, Family History: No CVD history in first degree relatives Lifestyle: Denies cigarette smoking, exercises regularly, follows healthy dietary habits Medications: Lisinopril 40 mg qd Lab Results: Total cholesterol 185 mg/dl, LDL-C 122 mg/dl, HDL-C 42 mg/dl, triglycerides 102 mg/dl, glucose 96 mg/dl liver and kidney function wnl PE: BP 132/78, BMI 24, waist circumference 38 HMG-CoA Reductase Inhibitor: Reduction in LDL-C Statin Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin 10 mg/d 69 (37) 29 (15) 39 (21) 37 (20) 80 (43) 51 (27) 20 mg/d 80 (43) 39 (21) 54 (29) 45 (24) 90 (48) 60 (32) 40 mg/d 91 (49) 50 (27) 68 (37) 53 (29) 99 (53) 69 (37) 80 mg/d 102 (55) 61 (33) 83 (45) 62 (33) 108 (58) 78 (42) Data presented as absolute reductions in LDL-C* (mg/dl) and percent reductions in LDL-C (in parentheses) *Standardized to LDL-C 186 mg/dl (mean concentration in trials) before Rx. Independent of pre-rx LDL-C Maximum dose of 80 mg/d administered as two 40-mg tablets Not FDA approved at 80 mg/d A Meta-analysis of 164 Trials* FDA=Food and Drug Administration, LDL-C=Low density lipoprotein cholesterol, Rx=Treatment Law MR et al. BMJ 2003;326:1423-1427 ASCVD Risk Prediction: 10-year ASCVD risk (%) = 17.4% 10-year ASCVD risk (%) for someone the same age with optimal risk factors levels = 9.6% HMG-CoA Reductase Inhibitor: Adverse Effects Elevated LFTs: 0.5-2.0% incidence of elevated hepatic transaminases Dose-dependent phenomenon Usually reversible and rarely leads to progressive hepatic failure Hepatocyte Myalgias: 5% incidence of myalgias (rare significant rise in CPK) 0.1% incidence of myositis (with CPK up Skeletal myocyte to 10 times the upper limit of normal) 0.0001% incidence of fatal rhabdomyolysis. Pasternak RC et al. Circulation 2002;106:1024-1028 HMG-CoA Reductase Inhibitor Evidence:Primary Prevention Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) 17,802 men (>50 yrs) and women (>60) with LDL-C <130 mg/dl and hs-crp >2 mg/l randomized to rosuvastatin (20 mg) or placebo for up to 5 yrs* Cumulative incidence of CV death, MI, stroke, hospitalization for unstable angina, and arterial revascularization 0.00 0.04 0.08 Rosuvastatin Placebo 0 1 2 3 4 Follow-up (years) 44% RRR P<0.00001, NNT=25 Statin benefits those with mean age of 66 and elevated hscrp Strategies for Statin Intolerant Patients: Switching to a different statin Reducing the frequency of statin administration Substituting statins with other LDL-Clowering agents (e.g. ezetimibe, colesevelam or nicotinic acid) Combining low-dose statin treatment with other lipid-modifying drugs. *The study was stopped prematurely after 1.9 years Ridker PM et al. NEJM 2008;359:2195-2207 7

Case Study #3 KL 57yo male PMH: HIV, Above average coronary calcification for his age. Family History: Adopted Lifestyle: Former cigarette smoker; does not exercise; is very careful about his diet (low saturated fat); drinks 2-3 alcoholic beverages 3-4x per week Medications: HIV meds, Lipitor 40 mg Lab Results: TC168, TG322, HDL24, LDL80, glucose 105 PE: BP 136/68, BMI 24, waist circumference 36 Case Study #4 TH 48 yo male PMH: dyslipidemia, family hx of high cholesterol (mother and all siblings) Medications: None; encouraged by his PCP to start a statin; he does not want to Lifestyle: Denies cigarette smoking, basketball 4x per week and treadmill on weekends, low saturated fat diet, healthy choices Laboratory results: total cholesterol 315 mg/dl, triglycerides 135 mg/dl, HDL-C 42 mg/dl, LDL-C 246 mg/dl, glucose 92 mg/dl, liver and kidney function wnl PE: 112/74 mmhg HR: 60 bpm BMI: 22 AIM HIGH Results: Statin + Niacin 3414 subjects; > 45 yo; in patients with established vascular disease and atherogenic dyslipidemia; 34% with T2DM and 71% with MetS; 94% prior statins Randomized to Simvastatin to reduce LDL-C < 80 mg/dl; then Niacin ER 2 gm added in 1718 or PBO in 1696 Baseline lipids: LDL-C 71 TG 161 HDL 35 Primary endpoint composite: No difference in primary end points (CHD Death, MI, or hi-risk ACS hospitalization after 32 months). Increased stroke (1.6% vs. 6.7%); trial stopped early. IMProved Reduction of Outcomes: Vytorin Efficacy International Trial IMPROVE-IT A Multicenter, Double-Blind, Randomized Study to Establish the Clinical Benefit and Safety of Vytorin (Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-Risk Subjects Presenting With Acute Coronary Syndrome Lifestyle Management of High Triglycerides 1. Regular aerobic exercise 2. Decrease consumption of simple sugars and white carbs (bread, rice, pasta and potatos) 3. Moderate alcohol consumption 4. Weight reduction 5. Fish oil VERY EFFECTIVE!! Ezetimibe: Background Ezetimibe inhibits Niemann-Pick C1-like 1 (NPC1L1) protein located primarily on the epithelial brush border of the GI tract resulting in reduced cholesterol absorption Two recent human genetic analyses have correlated polymorphisms in NPC1L1 with lower levels of LDL-C and lower risk of CV events* *MI Genetics Consortium Investigators NEJM 2014; online Nov 12; Ference BA et al AHA 2014 8

Patient Population Inclusion Criteria: Hospitalization for STEMI, NSTEMI/UA < 10 days Age 50 years, and 1 high-risk feature: New ST chg, + troponin, DM, prior MI, PAD, cerebrovasc, prior CABG > 3 years, multivessel CAD LDL-C 50-125 mg/dl (50 100 mg/dl if prior lipidlowering Rx) Major Exclusion Criteria: CABG for treatment of qualifying ACS Current statin Rx more potent than simva 40mg Creat Cl < 30mL/min, active liver disease IMPROVE-IT: Ezetimibe + Simvastatin Simvastatin + Ezetimibe produced a statistically significant 2% absolute risk reduction in combined CV outcomes compared with Simvastatin alone in patients with ACS Both statin in monotherapy and the combination of statin + ezetimibe decreased relative risk of CVD the same amount (20%) for each mmol/l of LDL-C reduction. CVD benefit associated with LDL cholesterol lowering to at least 53 mg/dl (benefit is independent of the LDL cholesterol at baseline, if over 50 mg/dl). LDL cholesterol concentrations far below 70 mg/dl during follow-up of six years are not associated with any increase in side effects. LDL-C and Lipid Changes 1 Yr Mean LDL-C TC TG HDL hscrp Simva 69.9 145.1 137.1 48.1 3.8 EZ/Simva 53.2 125.8 120.4 48.7 3.3 Δ in mg/dl -16.7-19.3-16.7 +0.6-0.5 Median Time avg 69.5 vs. 53.7 mg/dl Conclusions IMPROVE-IT: First trial demonstrating incremental clinical benefit when adding a non-statin agent (ezetimibe) to statin therapy: YES: Non-statin lowering LDL-C with ezetimibe reduces cardiovascular events YES: Even Lower is Even Better (achieved mean LDL-C 53 vs. 70 mg/dl at 1 year) YES: Confirms ezetimibe safety profile Reaffirms the LDL hypothesis, that reducing LDL-C prevents cardiovascular events Results could be considered for future guidelines CV Death, Non-fatal MI, or Non-fatal Stroke HR 0.90 CI (0.84, 0.97) p=0.003 NNT= 56 Simva 22.2% 1704 events EZ/Simva 20.4% 1544 events NEW Therapy Option: PCSK9 Inhibitor for treatment of Familial Hypercholesterolemia PCSK9 is a protein that modulates plasma LDL-C PCSK9 promotes LDLR degredation within the hepatocyte and reduces concentration of LDLR on the hepatocyte surface resulting in increased plasma LDL-C levels PCSK9 gain of function gene mutations increases the level of PCSK9 which reduces LDLR and increases circulating LDL-C 7-year event rates 9

Treatment of Familial Hypercholesterolemia: PCSK9 Inhibitor Case Study #5 DC 41 yo male PMH: dyslipidemia, hypertension, obesity, s/p MI age 37; family hx of CVD (father, 2 uncles paternal grandfather and brother died of MI in late 40 s) Medications: aspirin 81 mg qd, altace 10 mg qd, toprol XL 100 mg qd, lipitor 20 mg qd, tricor 145 mg qd Lifestyle: Denies cigarette smoking, physically inactive, diet high in saturated fat and carbohydrates Laboratory results: total cholesterol 155 mg/dl, triglycerides 207 mg/dl, HDL-C 25 mg/dl, LDL-C 89 mg/dl, glucose 116 mg/dl, liver and kidney function wnl PE: 132/82 mmhg HR: 66 bpm BMI: 32 10