Pharmacy Drug Class Review

Pharmacy Drug Class Review January 22, 2014 Authored By: Christina Manciocchi, Pharm.D. BCACP Disclaimer: Specific agents may have variations Edited By: Richard J. Kraft, Pharm.D.BCPS NEW CHOLESTEROL GUIDELINES FOCUS ON TARGET STATIN DOSES Abandon LDL, Non-HDL Goals Introduction: What s New in These Guidelines Compared to ATP-III? What is the New Global Risk Assessment for Primary Prevention? Pooled Cohort Equation- Focus on 10yr ASCVD Risk What are the 4 Statin Benefit Groups? Abandoning LDL and Non-HDL Treatment Goals? High & Moderate Intensity Statin Therapy for use in Primary Prevention Where Do Non-Statin Therapies Play a Role? What are the Statin Monitoring Recommendations? Clinical Questions Still Missing? HMG-CoA Reductase Inhibitors High Intensity: Atorvastatin 40-80 mg (Lipitor) Rosuvastatin 20-40 mg (Crestor) Moderate Intensity: Atorvastatin 10-20 mg (Lipitor) Rosuvastatin 5-10 mg (Crestor) Simvastatin 20-40 mg (Zocor) Pravastatin 40-80 mg (Pravachol) Lovastatin 40 mg (Mevacor) Fluvastatin 80 mg (Lescol) Pitavastatin 2-4 mg (Livalo) Statin Benefit Groups- Quick Reference Sheet (1 page front/back) Highlights: The Quick Read Information 1. How often should ASCVD risk factors be evaluated? a.) Every year (age >50) b) Every 10 years (age >30) c) Every 4-6 years (age >20) d) Every 1 year (any age) 2. The Pooled Cohort Equation can be used for which age group to Assess 10yr ASCVD risk? a) Age >20 b) Age 20-59 c) Age 40-79 d) Age > 79 3. What endpoint has been added to the risk calculation that was not in ATP-III? a) Fatal/nonfatal stroke b) Fatal/nonfatal MI c) CHD death d) Heart Failure 4. Which one of the following is NOT one of the 4 Statin Benefit groups? a.) Clinical ASCVD b.) Primary LDL >190 mg/dl c.) Diabetes type 1 or 2 d.) 10-yr ASCVD risk score < 2.5% 5. What is the LDL target for a high-risk patient according to the new guidelines? a.) LDL <70mg/dl b.) LDL < 100mg/dl c.) LDL <130 mg/dl d.) No LDL target specified 6. Which of the following is recommended as a High Intensity statin? a.) Simvastatin 80mg daily b.) Rosuvastatin 20mg daily c.) Atorvastatin 20mg daily d.) Pitavastatin 4mg daily 7. True or False: Non-Statin cholesterol medications have shown to further reduce ASCVD events when combined with statin therapy? a.) True b.)false QUIZ ANSWERS

Introduction: What s New in These Guidelines Compared to ATP-III? In November of 2013, the American College of Cardiology (ACC) and American Heart Association (AHA) in collaboration with the National Heart, Lung, and Blood Institute (NHLBI) published four evidence based clinical practice guidelines for the prevention and management of cardiovascular disease: 1. Assessment of Cardiovascular Risk Link to Guidelines 2. Lifestyle Modifications to Reduce Cardiovascular Risk Link to Guidelines 3. Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (> 21 years old) Link to Guidelines 4. Management of Overweight and Obesity in Adults Link to Guidelines Note: The Blood Cholesterol Expert Panel was originally convened as the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel [ATP] IV) appointed by the NHLBI. All members of the NHLBI ATP IV Panel transitioned to the ACC/AHA guideline Expert Panel. Important Changes from Adult Treatment Panel (ATP) III Reviewed ATP III NEW GUIDELINES ATP III NEW GUIDELINES ATP III NEW GUIDELINES ATP III NEW GUIDELINES Treatment of cholesterol to reduce Myocardial infarction /CHD death endpoints only Treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease (ASCVD): myocardial infarction, CHD death and now includes fatal/nonfatal stroke as well 10 year CHD risk calculator for primary prevention using the Framingham Equation (origin of data starting in mid 1900s) NEW 10 year ASCVD risk calculator for primary prevention using the Pooled Cohort Equations (accounts for more recent population data) Focus on treatment with statin and/or non-statin to achieve cholesterol parameters based on low, moderate, or high risk classification. Focus on Statin therapy - Identification of 4 groups most likely to benefit. Less focus on Non-statin therapies which have not shown acceptable ASCVD risk reduction compared to their potential for adverse effect Focus on titrating cholesterol medications to specific LDL and non-hdl targets Focus on using target dose intensity statins for percent LDL reduction from baseline- Moderate Intensity (30-49% LDL reduction) OR High Intensity (>50% LDL reduction)

What is the New Global Risk Assessment for Primary Prevention? A new risk calculator (The Pooled Cohort Equations) underwent development to address the concerns and limitations of previous risk assessments including: Non-representative/historically dated populations Limited ethnic diversity (Framingham evaluated exclusively white sample population) Narrowly defined endpoints (Framingham evaluated CHD only) Endpoints influenced by provider preferences and endpoints with poor reliability (ex: angina and heart failure) 10 year ASCVD Risk: The Work Group derived risk equations from community-based cohorts that is broadly representative of the U.S. population of Whites & African Americans 40-79 years of age. The new guidelines focus on patients who will benefit from statin therapy the most. Therefore, the equation estimates 10 year risk of first hard ASCVD event (defined as Nonfatal myocardial infarction, CHD death, or fatal or nonfatal stroke) as the outcome of interest -as heart attack and stroke are the first and second leading causes of death worldwide. This is consistent with evidence reviewed in a statement from the AHA/American Stroke Association calling for the inclusion of ischemic stroke in the outcome of interest for CVD risk assessment. Lifetime Risk: The equation also provides a lifetime risk assessment for individuals aged 20-59. This equation was not intended to replace the 10 year assessment but as a means to assess risk factors and quantify long-term risk starting at the age of 20. The precursor of ASCVD, occurs over decades and is related to long-term and cumulative exposure to causal, modifiable risk factors. Therefore, the primary value is to indentify individuals with an extreme value of risk factors and to provide context regarding the potential benefits of lifestyle modification and prevention (see guideline). Evidence was NOT found regarding the utility of lifetime risk assessment for guiding pharmacologic therapy decisions.

The Pooled Cohort Equations: Web based calculator available at http://my.americanheart.org/cvriskcalculator Lifetime Equation is applicable to: Male/females Age 20-59 without clinical ASCVD or LDL >190mg/dl (lifestyle only) Equation (10 yr) is Applicable to: African-American and non-hispanic white men and women 40-79 years of age who do NOT already have clinical ASCVD or LDL > 190mg/dl (already qualify for statin- see benefit groups). o For other Ethnic Groups: Use of the equations may be considered (recommendation based on Expert opinion from the guideline) o May underestimate the risk for: American Indians, Asian Americans (e.g. South Asian ancestry), and Hispanics (e.g., Puerto Ricans) o May overestimate the risk for: Asian Americans (e.g., East Asian Ancestry) and Hispanics (e.g., Mexican Americans) The information required to estimate ASCVD risk includes (Traditional Risk Factors): 1. Age/Sex/ Race 2. Total cholesterol, HDL cholesterol (* pre-treatment cholesterol values if patient already on statin) 3. Systolic blood pressure, blood pressure lowering medication use 4. Diabetes status 5. Smoking status If after quantitative risk assessment treatment is uncertain: >1 of the following can aid in risk-based treatment decision for patients who do not meet criteria for one of four statin benefit groups- See Below (these Non- traditional risk factors not included in Pooled Cohort Equation): Measure Factor which may indicate elevated ASCVD Risk Genetic Hyperlipidemias Family history of premature ASCVD High sensitivity C reactive protein CAC score LDL > 160mg/dl Male < 55 years of age, Female <65 years of age (1 st degree relative) >2mg/L >300 Agatston units or >75 th percentile for age, sex, and ethnicity Ankle-brachial index (ABI) <0.9 Treatment should be based on a risk discussion which includes the assessment of ASCVD risk, and potential benefits, negative aspects, risks, and patient preferences regarding initiation of preventive therapies. **The calculator should be used as a starting point to help identify those who may benefit from statin therapy the most and thus a discussion with their physician.

What are the FOUR STATIN Benefit Groups? The Expert panel has identified 4 major statin benefit groups (and at what intensity) for whom the ASCVD risk reduction clearly outweighs the risk of adverse events. The guideline reports that the absolute benefit in terms of CVD risk reduction is proportional to the baseline risk of the individual. SECONDARY PREVENTION Group #1 Recommendation (Age <75): ** Not necessary to Calculate ASCVD risk for this group Recommendation (Age >75): Clinical ASCVD High intensity statin should be initiated/continued Moderate intensity statin (or maximum tolerated statin intensity) should be used as the second option if high intensity statin not tolerated Continuing moderate/high intensity statin therapy in those who are tolerating it is reasonable Initiating moderate intensity statin is reasonable after evaluating ASCVD risk-reduction benefits, adverse effects, drug-drug interactions, and patient preferences PRIMARY PREVENTION Group #2 Recommendation (Age >21): ** Not necessary to Calculate ASCVD risk for this group Group #3 AND 7.5% ASCVD risk): Primary Elevations of LDL > 190mg/dl High intensity statin should be initiated/ continued Moderate intensity statin (or maximum tolerated statin intensity) should be used as second option if high intensity statin not tolerated Addition of non-statin medication may be considered if additional LDL lowering is necessary (provider discretion-no guidance available) after maximum tolerated statin has been achieved Diabetes Type 1 or 2 (LDL 70-189mg/dl) High intensity statin should be initiated/ continued AND < 7.5% ASCVD risk): Recommendation (Age <40 or >75): Moderate intensity statin should be initiated/ continued Reasonable to evaluate the potential for ASCVD benefits and for adverse effects, drug-drug interactions, and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy Note: American Diabetes Association recommends (Age >40 without overt CVD) with 1 additional risk factor (family history of CVD, HTN, dyslipidemia, albuminuria) be initiated on a statin providing at least 30-40% reduction in LDL Group #4 AND 7.5% ASCVD risk): AND 5-7.5% ASCVD risk): 10-year ASCVD risk of 7.5% or higher (Without DM, clinical ASCVD, or LDL >190) Moderate to high intensity statin should be initiated/ continued Moderate intensity statin is reasonable to consider With the exception of the following groups in which NO Recommendations were made for or against initiation/continuation of statin therapy due to limited evidence. o NYHA class II IV ischemic systolic heart failure OR Maintenance Hemodialysis

Abandoning LDL and Non-HDL Treatment Goals? For patients taking statins, the new guidelines state that patients no longer need LDL cholesterol levels down to a specific target number (ex: LDL <100mg/dl). This is a significant difference from previous guidelines and treatment approaches over the years which provided risk based cholesterol goals or used the approach that lower cholesterol is better. While research clearly shows that lowering LDL lowers the risk for heart attack and stroke, the expert panel could not find evidence to prove that one target number is best. NEW APPROACH PERCENT LDL REDUCTION FROM BASELINE The new guidelines base the new statin intensity recommendations on the only approach that has been evaluated in randomized control trial data. These trials were NOT designed to evaluate the effect of titrated (doseadjusted) statin treatment to achieve pre-specified LDL or non-hdl goals, as recommended by ATP-III. To date, Randomized Controlled Trials have either compared: 1. Fixed doses of statins with placebo or untreated controls 2. Fixed doses of higher-intensity statins with moderate-intensity statins The new approach indicates that the goal of treatment is to utilize a specific statin dose for PERCENT REDUCTION in LDL from baseline rather than to titrate to LDL and non-hdl targets o Guidelines suggest initiating patients at the appropriate statin dosages as there is no proof that slowly increasing a statin dose will prevent side effects. High- Intensity: Daily Dose Lowers LDL by > 50% Moderate Intensity: Daily Dose Lowers LDL by 30-49% Low Intensity: Daily Dose Lowers LDL by < 30% Atorvastatin 40*-80mg Atorvastatin 10-20mg Simvastatin 10mg Rosuvastatin 20-40mg Rosuvastatin 5-10mg Pravastatin 10-20mg Simvastatin 20-40mg Lovastatin 20mg *Only 1 RCT evaluated atorvastatin 40mg for >50% reduction; down titration if Pravastatin 40-80mg Fluvastatin 20-40mg unable to tolerate 80mg Lovastatin 40mg Pitavastatin 1mg Fluvastatin 80mg Pitavastatin 2-4mg ***Simvastatin 80mg No Longer Recommended by FDA Since 2012 Label Change

Where Do Non-Statin Therapies Play a Role? The new guidelines focus on statin therapy in addition to lifestyle modifications (See guidelines) as the foundation for ASCVD reduction. Currently, there is no evidence to support routine use of nonstatin therapy added to statin therapy to reduce ASCVS events further. No randomized control trial evidence is available to assess ASCVD outcome in statin intolerant patients. Routine Use of Non-Statin therapies NOT recommended Non statin therapies may be considered in the following situations ( expert opinion ): o High risk patients with less than anticipated response to statin intensity o High risk patients unable to tolerate a less than recommended intensity of statin o High risk patients completely intolerant to statins o May be considered in the treatment of hypertriglyceridemia (>500mg/dl) High risk patients include (from statin benefit groups): o Clinical ASCVD o LDL > 190mg/dl Diabetes (age 40-75) Important Safety Recommendations for Non-Statins: Therapy Recommendations/ Safety Gemfibrozil Should NOT be initiated in patients on statin therapy due to increased risk of muscle symptoms / rhabdomyolysis Fenofibrate Omega-3 fatty Acids Niacin Ezetimibe Bile Acid Sequestrants May be considered with low or moderate statin if benefits from ASCVD risk reduction or TG >500mg/dl outweigh the potential for adverse effects Do not use in renal impairment GFR<30 ml/min, GFR 30-59 ml/min dosage should not exceed 54mg/day No dosage restrictions in conjunction with statin therapy May be considered for the management of severe hypertriglyceridemia (>500mg/dl) NO dosage restrictions in conjunction with statin therapy Should not be used if hepatic transaminase 2-3x ULN, persistent severe cutaneuous reactions, acute gout NO dosage restrictions in conjunction with statin therapy Discontinue if ALT elevations >3x ULN NO dosage restrictions in conjunction with statin therapy Do not use with baseline TG level >300mg/dl, caution TG 250-299mg/dl

What are the Statin Monitoring Recommendations? Laboratory Monitoring: Measure Prior to Initiation of Statin (Baseline) During Statin Treatment Fasting Lipid Panel Recommended 4-12 weeks after initiation or dose adjustment; every 3-12 months thereafter Hepatic Transaminase Levels Recommended Not Routine; reasonable if symptoms suggesting of hepatotoxicity arise (e.g. unusual fatigue, loss of appetite, abdominal pain, dark colored urine, yellowing of the skin/sclera) CK Not Routine; Baseline Levels is reasonable for individuals believed to be at increased risk for adverse muscle events Not Routine; reasonable to measure if muscle symptoms including pain, tenderness, stiffness, cramping, weakness, fatigue Fasting Lipid Panel should be obtained at baseline Initiate Statin (Intensity Based on Group) (May be started at maximal intensity- titration has not shown to decrease side effects) Assess Therapeutic Response to Statin (FLP) and Lifestyle Changes (4-12 wks) (High Intensity >50% reduction in LDL, Moderate Intensity 30-49% reduction in LDL) *Percent reduction should be used as an indication of response and adherence to therapy but is not a treatment goal* YES Anticipated Therapeutic Response NO Reinforce Continued Adherence (Follow up 3-12 months) Intolerance to recommended statin NO YES Reinforce medication/ lifestyle adherence (Follow up 4-12 wk) Management of Statin Intolerance YES Anticipated Therapeutic Response NO Lower intensity of statin or if not tolerated consider non-statin in high risk patient Reinforce Improved Adherence or Increase Statin Intensity or consider addition of Non-statin drug (follow up 4-12 wks)

Clinical Questions still Missing? The Expert Panel acknowledged that the guidelines focused on treatments proven to reduce ASCVD events. It does not, nor was it intended to be a comprehensive approach to lipid management. Future research and future guideline updates are needed. The New guidelines acknowledge the following evidence gaps. None or limited randomized controlled trial data is currently available in the following areas: 1. Statins in primary prevention of ASCVD in adults >75 years of age 2. Titration to specific cholesterol or apolipoprotein goals vs. fixed dose statins therapy 3. Whether combination of suboptimal statin doses combined with nonstatin therapies reduce ASCVD risk in statin intolerant patients 4. Evaluation of clinical outcomes with new onset diabetes and statin therapy 5. Treatment of hypertriglyceridemia 6. Use of non-hdl in treatment decisions 7. Whether Apo B, Lp (a), or LDL particles are useful for guiding treatment decisions 8. The best approach to using noninvasive imaging for refining risk estimates to guide treatment decisions 9. If individuals subgroups of patients with heart failure or undergoing hemodialysis might benefit from statin therapy. Although two RCTs have shown no benefit for each condition (e.g. GISSI-HF, ARORA, CORONA) there is still insufficient evidence to provide recommendations for or against treatment in all individuals with these conditions. 10. Efficacy and safety of statins in patients excluded from randomized controlled trials (ex. HIV positive, organ transplant) 11. Role of pharmacogenetic testing 12. How Lifetime ASCVD risk should be used to inform treatment decisions and the optimal age for initiating statin therapy to reduce lifetime risk of ASCVD Answers: 1.) c 2.) c 3.) a 4.) d 5.) d 6.) b 7.) b References: 1. Eckel, R.H., et al., 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation, 2013. 2. Goff, D.C., Jr., et al., 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation, 2013. 3. Grundy, S.M., et al., Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation, 2004. 110(2): p. 227-39. 4. Jensen, M.D., et al., 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation, 2013. 5. National Cholesterol Education Program Expert Panel on Detection, E. and A. Treatment of High Blood Cholesterol in, Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation, 2002. 106(25): p. 3143-421. 6. Stone, N.J., et al., 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation, 2013.

Quick Reference Laboratory Monitoring: Measure Prior to Initiation of Statin (Baseline) During Statin Treatment Fasting Lipid 4-12 weeks after initiation or dose adjustment; every 3-12 Recommended Panel months thereafter Not Routine; reasonable if symptoms suggesting of Hepatic hepatotoxicity arise (e.g. unusual fatigue, loss of appetite, Transaminase Recommended abdominal pain, dark colored urine, yellowing of the Levels skin/sclera CK Not Routine; Baseline Levels is reasonable for individuals believed to be at increased risk for adverse muscle events Not Routine; reasonable to measure if muscle symptoms including pain, tenderness, stiffness, cramping, weakness, fatigue

High- Intensity: Daily Dose Lowers LDL by > 50% Moderate Intensity: Daily Dose Lowers LDL by 30-49% Atorvastatin 40*-80mg Atorvastatin 10-20mg Rosuvastatin 20-40mg Rosuvastatin 5-10mg Simvastatin 20-40mg *Only 1 RCT evaluated atorvastatin 40mg for Pravastatin 40-80mg >50% reduction; down titration if unable to tolerate 80mg Lovastatin 40mg Fluvastatin 80mg Pitavastatin 2-4mg *** Simvastatin 80mg No Longer Recommended by FDA Since 2012 Label Change Low Intensity: Daily Dose Lowers LDL by < 30% Simvastatin 10mg Pravastatin 10-20mg Lovastatin 20mg Fluvastatin 20-40mg Pitavastatin 1mg SECONDARY PREVENTION Group #1 Recommendation (Age <75): ** Not necessary to Calculate ASCVD risk for this group Recommendation (Age >75): PRIMARY PREVENTION Group #2 Recommendation (Age >21): ** Not necessary to Calculate ASCVD risk for this group Group #3 AND 7.5% ASCVD risk): AND < 7.5% ASCVD risk): Recommendation (Age <40 or >75): Group #4 AND 7.5% ASCVD risk): AND 5-7.5% ASCVD risk): Clinical ASCVD High intensity statin should be initiated/continued Moderate intensity statin (or maximum tolerated statin intensity) should be used as the second option if high intensity statin not tolerated Continuing moderate/high intensity statin therapy in those who are tolerating it is reasonable Initiating moderate intensity statin is reasonable after evaluating ASCVD riskreduction benefits, adverse effects, drug-drug interactions, and patient preferences Primary Elevations of LDL > 190mg/dl High intensity statin should be initiated/ continued Moderate intensity statin (or maximum tolerated statin intensity) should be used as second option if high intensity statin not tolerated Addition of non-statin medication may be considered if additional LDL lowering is necessary (provider discretion -no guidance available) after maximum tolerated statin has been achieved Diabetes Type 1 or 2 (LDL 70-189mg/dl) High intensity statin should be initiated/ continued Moderate intensity statin should be initiated/ continued Reasonable to evaluate the potential for ASCVD benefits and for adverse effects, drug-drug interactions, and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy 10-year ASCVD risk of 7.5% or higher (Without DM, clinical ASCVD, or LDL >190) Moderate to high intensity statin should be initiated/ continued Moderate intensity statin is reasonable to consider