CPE Session 7. Update on Clinical Practice Guidelines and Best Evidence in the Management of Hyperlipidemia and Cardiovascular Risk Reduction

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1 CPE Session 7 Update on Clinical Practice Guidelines and Best Evidence in the Management of Hyperlipidemia and Cardiovascular Risk Reduction Saturday, April 25, 2015 ACPE UAN L01-P 1.0 CPE Hour Lourdes Heuermann, PharmD, BCACP Dr. Lourdes Heuermann is a 1982 graduate of the University of Nebraska Medical Center College of Pharmacy. She worked as a geriatric consultant pharmacist for many years prior to working at the VA in She is currently an ambulatory care clinical pharmacist at the Grand Island VA. She is adjunct assistant professor with UNMC and was the 2009 Preceptor of the Year for the University of Nebraska Medical Center College of Pharmacy. She is the lead preceptor for students at the Grand Island VA Ambulatory Care rotation site and is also a preceptor for Pharmacy Residents. In 2011, she attained Board Certifi cation in Ambulatory Care by the Pharmacy Board of Specialties. At the VA, she serves on the Pharmacy and Therapeutics Committee as well as the Clinical Pharmacy Practice Council. She and her husband Fred have 4 children, 2 of which are pursuing careers in pharmacy. Dr. Heuermann has no fi nancial interests or arrangements that would be considered a confl ict of interest for the presentation of this program. NPA 2015 Annual Convention

2 CPE Session 7 Update on Clinical Practice Guidelines and Best Evidence in the Management of Hyperlipidemia and Cardiovascular Risk Reduction Saturday, April 25, 2015 ACPE UAN L01-P 1.0 CPE Hour Janelle Sellers, PharmD Dr. Janelle Sellers is a 2005 graduate from the Nebraska Medical Center College of Pharmacy. She completed a PGY-1 and PGY-2 residency at the Grand Island VA specializing in ambulatory care. Dr. Sellers served as the Grand Island PGY-1 Residency director from 2008 to She is now practicing as a VA clinical pharmacy specialist in her home town of North Platte, Nebraska. Her areas of practice include chronic disease management, chronic pain and anticoagulation. She is the 2012 recipient of the NPA s Distinguished Young Pharmacist Award. Dr. Sellers and her husband, Bill, have a 5 year old son, Lake. They enjoy participating in outdoor activities and recently hiked Piestewa Peak in Arizona. Dr. Sellers has no fi nancial interests or arrangements that would be considered a confl ict of interest for the presentation of this program. NPA 2015 Annual Convention

3 Reducing Cardiovascular Risk Through Dyslipidemia Management Chemical structure of a lipid molecule LOURDES HEUERMANN PHARMD, BCACP JANELLE SELLERS, PHARMD CLINICAL PHARMACY SPECIALISTS VA NEBRASKA/WESTERN IOWA HEATH CARE SYSTEM Faculty Disclosures: Lourdes Heuermann, PharmD, BCACP Dr. Heuermann has listed no financial interest/arrangement that would be considered a conflict of interest Janelle Sellers, PharmD Dr. Sellers has listed no financial interest/arrangement that would be considered a conflict of interest Program Objectives Describe the four statin benefit groups as identified in the ACC/AHA guidelines Identify low, moderate, and high intensity statin doses for the various statin medications Identify basic similarities and difference between ACC/AHA and NLA treatment guidelines for cholesterol Describe safety considerations for the use of statin and other cholesterol lowering therapies, including combination therapies Cholesterol Treatment Guidelines ATP I 1988 ATP II 1993 ATP III 2002 ATP III Update 2004 America College of Cardiology/American Heart Association Blood Cholesterol Guidelines National Lipid Association Executive Summary ACC/AHA Blood Cholesterol Guidelines Why Statin Therapy? Evidence to support statin use for the prevention of ASCVD in all secondary prevention & high risk primary prevention Excludes NYHA class II IV HF and hemodialysis Expert Panel without industry bias Expert Panel unable to find RCT evidence to support titrating cholesterol lowering drug therapy to achieve LDL C or Non HDL targets as per ATP III Can reduce burden of disability from nonfatal stroke and nonfatal CHD events. RTC s show reduced burden Primary and secondary prevention of ASCVD with statins can positively impact rising healthcare costs Evidence shows reduction in total mortality in individuals using statins as both primary and secondary prevention 1

4 ACC/AHA 2013 What is New Use of Pooled Cohort Equations to estimate 10 year risk of ASCVD events in Caucasian and African American men and women Identification of 4 statin benefit groups Recommendations based on statin benefit identification and intensity, not LDL and non HDL goals Safety and monitoring recommendations for statin and non statin therapies identified LDL and Non HDL Treatment Goals ACC/AHA could not find RCT data available to support specific target Magnitude of additional ASCVD risk reduction achieved with one target lower than another is unknown Targets do not take into account potential ADRs from polypharmacy that might be needed to achieve a specific goals Pooled Cohort Risk equation Pooled Cohort Risk Equation Calculates 10 year and lifetime risk Eliminates risk factor counting Limitations: some factors not included in equations LDL C 160 mg/dl Genetic hyperlipidemias Family history High sensitivity C reactive protein >2 mg/l Not all ethnicities represented Aged > 75 years old 2013 ACC/AHA Blood Cholesterol Guidelines: The 4 Statin Benefit Groups Picture of statin medication bottles The 4 Statin Benefit Groups 1. Individuals with clinical ASCVD 2. Individuals with primary elevations of LDL C 190 mg/dl 3. Individuals ages 40 to 75 with diabetes with LDL C mg/dl 4. Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL C mg/dl & an estimated 10 year ASCVD risk of 7.5% or higher 2

5 Statin Benefit Group 1: Individuals with Clinical ASCVD (Secondary Prevention) Age < 75 Age > 75 Statin Benefit Group 2: Primary elevations of LDL C 190 mg/dl Adults > 21 years old Recommend High Intensity Statin therapy Moderate Intensity Statin therapy used if intolerance or safety issues present Statin Therapy should be individualized based on risk vs benefit, adverse reaction potential, DDI, and patient preference Recommend High Intensity Statin therapy to achieve at least a 50% risk reduction Non statin medications may be needed in addition to statin therapy Family screening is important in this patient population (familial hypercholesterolemia) Statin Benefit Group 3: y/o with diabetes with LDL C mg/dl Recommend Moderate Intensity Statin therapy High Intensity Statin therapy is reasonable for patients with diabetes and a 7.5% estimated 10 year ASCVD risk Patients < 40 or > 75 years of age, statin therapy should be individualized (risk reduction benefits, adverse effects, DDI s, and patient choice) Statin Benefit Group 4: W/o clinical ASCVD, w/o diabetes, y/o with LDL C mg/dl & estimated 10 year ASCVD risk >7.5% Moderate or High Intensity Statin Pooled Cohort Equation to estimate 10 year ASCVD risk With 10 year risk of < 7.5% or 5% < 7.5%, assess risk vs. benefit, adverse effects, DDI s, and patient choice Statin Doses Based on Intensity High Intensity Statin Therapy Daily dose lowers LDL C on average by 50% Atorvasta n (40 ) 80 mg Rosuvastatin 20 (40) mg Moderate Intensity Statin Therapy Daily dose lowers LDL C on average, by 30% to 50% Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin mg Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2 4 mg Low Intensity Statin Therapy Daily dose lowers LDL C on average, by <30% Simvastatin 10 mg Pravastatin mg Lovastatin 20 mg Fluvastatin mg Pitavastatin 1 mg Statin selection LDL < 40 Safety Recommendations Risk of Type II Diabetes > 75 with comorbidities Creatinine Kinase LFTs Photo of a caution sign 3

6 Statin Selection: Metabolism Differences Major Pathway Statin Interactions Statin Selection: Lipophilicity Cyt P450 2C9 Cyt P450 3A4 P Glycoprotein Substrates Fluvastatin Rosuvastatin Lovastatin Simvastatin Atorvastatin Pravastatin Diclofenac, Tolbutamide, Warfarin Erythromycin, Cyclosporine, Itraconazole, Verapamil Few interactions, possibly Cyclosporine Cerivistatin Simvastatin Lovastatin Atorvastatin Fluvastatin Rosuvastatin Pravastatin Increased Lipophilicity Glucoronide Conjugation Pitavastatin Cyclosporine, Erythromycin Statin Selection Extremely low LDL s < 40 Multiple or serious comorbidities, including impaired renal or hepatic function History of previous statin intolerance or muscle disorders Unexplained ALT elevations >3 times ULN Patient characteristics or concomitant use of drugs affecting statin metabolism Reasonable to decrease dose of statin if two consecutive LDL C values of < 40 mg/dl No data available to suggest adverse events below this point Type 2 Diabetes Risk Patients > 75 Years Old Benefits outweigh risks in all but low risk patients If diabetes develops, remain on statin therapy plus adhere to healthy lifestyle The rate of excess diabetes varies by statin intensity. Moderate intensity: 0.1 excess case of diabetes per 100 statin treated individuals per year; 0.3 excess w/high intensity Picture of person testing glucose level Use caution in this patient population Be aware of: Taking multiple drugs Possible DDI s Polypharmacy Complex drug regimen (HIV or transplant patients) Few data were available for individuals >75 years of age, more RCT s needed for elderly! 4

7 Creatinine Kinase (CPK) Should NOT be routinely measured Check with symptoms: pain, tenderness, stiffness, cramping, weakness, fatigue Baseline for those at risk for adverse muscle events: Personal or family history of statin intolerance or muscle disease Clinical presentation Concomitant drug therapy could increase chance of myopathy Liver Function Tests Recommend baseline ALT before statin initiation Reasonable to test liver function of symptoms of hepatotoxicity occur: Unusual fatigue or weakness Loss of appetite Abdominal pain Dark colored urine Yellowing of the skin or sclera Monitoring Statin Therapy Non Statin Pharmacotherapy Initial fasting lipid panel 2 nd lipid panel to assess adherence in 4 12 weeks Assess lipids every 3 12 months thereafter as necessary Fibrates Niacin Bile Acid Sequesterants Omega 3 Ezetimibe Non Statin Medications: Fibrates Do not add Gemfibrozil to statin Tx Can add Fenofibrate to Low moderate intensity statins when TG s > 500 mg/dl Renal status at baseline, in 3 months and q6 months thereafter Reduce Fenofibrate dose for egfr ml/min D/C Fenofibrate if egfr drops below 30 ml/min Non Statin Medications: Niacin Prior to initiation: baseline LFT s, glucose, A1c and uric acid and q6 months Stop if LFT s > 2 3x ULN, severe cutaneous Sx, persistent hyperglycemia, acute gout, severe GI distress Extended release can titrate up to 2 g Immediate release titrate up to 3 g Pre medicate w/asa 325 mg for flushing 5

8 Non Statin Medications: Bile Acid Sequesterants National Lipid Association Guidelines 2014 Should not be used with baseline triglycerides > 300 mg/dl Severe triglyceride elevations might occur A fasting lipid panel should be obtained prior to BAS initiation, 3 months after initiation, and every 6 12 months thereafter National Lipid Association logo Risk Category Criteria Treatment goal Consider Drug Therapy High or Very High Risk Groups Low 0 1 major ASCVD risk factors Consider other risk indicators, if unknown Moderate 2 major ASCVD risk factors Consider quantitative risk scoring Consider other risk indicators High 3 major ASCVD risk factors Diabetes (type 1 or 2) 0 1 other major ASCVD risk factors and No evidence of end organ damage CKD stage 3B or 4 LDL C 190 mg/dl (severe hypercholesterolemia) Quantitative risk score reaching the high risk threshold Very High ASCVD Diabetes (type 1 or 2) 2 other major ASCVD risk factors or Evidence of end organ damage < 130 < 100 < 130 < 100 < 130 < 100 < 100 < 70 Non HDL Cmg/dL LDL C mg/dl National lipid association logo No risk scoring for initial assessment in the following patients: DM (type 1 or 2) CKD stage 3B LDL C 190 mg/dl (severe hypercholesterolemia phenotype, includes FH) ASCVD These patients are high or very high risk for ASCVD and recommend moderate to high intensity statin No bottom limit on LDL National lipid association logo What about the Non Statin meds? Niacin + Statins AIM HIGH HPS2 THRIVE? Niacin ER + statin = reduced adverse cardiovascular events Stopped early (36 months) Lack of benefit over statins alone Increased risk of stroke, infection? Niacin/laropirant + statin = reduced adverse cardiovascular events Lack of benefit in the treatment arm Increase significant risk of serious ADR s in niacin/laropirant + statin group compared to statins Glucose metabolism, myopathy, bleeding, infections 6

9 Monotherapy Niacin patients who cannot take or have contraindication to statins High risk for vascular events and have a high LDL or non HDL Severe hypertriglyceridemia (TG 500mg/dL) Discuss potential side effects Treating Elevated TG s TG s 500 mg/dl Monotherapy Statin or fibrate may be beneficial Adding 2 nd drug to high risk patients treated with statins Limited data to support AHA Scientific statement 2011 Omega 3 Fatty Acids Ezetimbe TG s 500 mg/dl ARBITER 6 HALTS ENHANCE AHA recommends 2 4 g of EPA + DHA per day Marine derived EPA and/or DHA is best Picture of fish oil capsules AHA Scientific statement 2011 Statin + Niacin ER vs. Statin + Ezetimibe = regression of carotid intima media thickness? Niacin ER group significant for primary end point and major cardiovascular events Simvastatin vs. Simvastatin + Ezetimibe = change in mean carotid artery intimamedia thickness? Familial hypercholesterolemia No significant difference in changes in intimamedia thickness in the simvastatin + ezetimibe group Ezetimibe Summary IMPROVE IT Patients with recent ACS CV death/mi/ua/coronary revascularization/stroke) p=0.016 Ezetimibe + Simvastatin vs. Simvastatin Mean LDL C 53.7 vs mg/dl 2013 ACC/AHA Guidelines in adults based on RTC s: 4 statin benefit groups identified Does not take the place of clinical judgment on a case by case basis Therapeutic Lifestyle changes remain a cornerstone of therapy Departure from Arbitrary LDL and non HDL targets and risk factor counting 7

10 Summary: National Lipid Association (NLA) guidelines: NLA Expert panel modest refinements to ATP III Elevated levels of atherogenic cholesterol carried by APO B (LDL and non HDL) is a root cause of atherosclerosis leading to most clinical ASCVD Non HDL is a better marker for ASVD than LDL Target for Low to High risk patients: non HDL < 130 & LDL < 100; Apo B< 90 Target for Very High risk Patients: non HDL< 100 & LDL < 70; Apo B< 80 Although concur that RCT s represent the best evidence, they report limitations thus support arbitrary targets Assessment Question 1: What is what is an appropriate pharmacological intervention per ACC/AHA for a 65 year old diabetic male with a history of Myocardial Infarction? a. Atorvastatin 40 mg per day b. Simvastatin 20 mg per day d. Ezetimibe 10 mg per day d. Niacin 1000 mg per day Assessment Question 2: Assessment Question 3: What is the primary target for this same patient using the NLA guidelines? a. Atorvastatin 10 mg per day b. Targeting LDL to less than 100 c. Targeting non HDL to less than 100 d. Simvastatin 10/Ezetimibe 10 (1) daily What statin benefit group does a 22 year old male who is primary prevention with a baseline LDL of 193 mg/dl fall under per the ACC/AHA guidelines? a. LDL less than 100 b. Moderate intensity statin c. Non HDL less than 100 d. High intensity statin Assessment Question 4: Which of the following statins is the least lipophilic: a. Simvastatin b. Fluvastatin c. Pravastatin d. Atorvastatin Assessment Question 5: All of the following things must be considered when determining the safe use of a statin except for: a. Liver function tests b. Elderly with multiple comorbidities c. LDL less than 40 d. Triglycerides less than 200 8

11 Assessment Question 6: Which Clinical trial was stopped early due to no benefit in the Niacin+Statin group (versus statin alone) and possible increased stroke risk? a. AIM High b.. HPS2 Thrive c. ARBITER 6 HALTS d. IMPROVE IT Assessment Question 7: According to the ACC/AHA blood cholesterol guidelines, for safety reasons, bile acid sequestrants should not be used in patients who: a. Have triglyceride levels over 100 b. Have LDL less than 100 c. Have triglyceride levels over 300 d. Have a high HS CRP Assessment Question 8: Questions and Discussion The following is not a lab parameters that should be monitored at baseline and every 6 months with niacin therapy according to ACC/AHA? Picture of question marks a. Liver function tests b. Uric acid level c. A 1 c and glucose d. Basic metabolic panel References: American College of Cardiology/American Heart Association Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Circulation National Lipid Association Recommendations for Patient Centered Management of Dyslipidemia: Part 1 Executive Summary. Journal of Clinical Lipidology (2014)8,