Strategies for Managing Dyslipidemia Patients with Residual CVD Risk

Strategies for Managing Dyslipidemia Patients with Residual CVD Risk

Acknowledgements We acknowledge the work of Lynne T. Braun, PhD, CNP, FAHA, FPCNA, FAAN in the development of this presentation. Disclosures: Consultant/advisory board on UpToDate Inc. Affiliated with Practice Point.

Presenter Speaker Disclosures

Objectives Outline secondary prevention strategies in CVD patients with residual risk despite taking the maximum tolerated dose of statin therapy. Describe the clinical steps taken to identify statin intolerance. Differentiate between the indications for statins, PCSK9 inhibitors and other LDL-lowering therapies. Identify the potential barriers to treatment adherence for patients requiring LDL-lowering therapies and solutions to address the barriers.

Case Study: Ms. Green Ms. Green is a 56-year-old Caucasian patient who recently had a NSTEMI. This is her follow-up appointment 2 weeks later. Risk factors: untreated hypertension, hypercholesterolemia, obesity (BMI is 30.6 kg/m2) Past medical history: pre-diabetes, degenerative disc disease Family history of premature CVD (father had MI at age 45) Discharge meds include atorvastatin 80 mg, lisinopril 20 mg, metoprolol XL 25 mg, and ASA 81 mg daily.

Stone NJ et al JACC 2014;63:2889-2934. Initiating Statin Therapy in Patients with Clinical ASCVD Clinical ASCVD Not on statin therapy Initial evaluation: Lipid panel, ALT, CK, others as needed to eval secondary causes Evaluate and treat lab abnormalities: TG > 500 LDL>190 ALT > 3 times ULN Age < 75 Without contraindication High-Intensity Statin Healthy lifestyle Age > 75 or statin safety concerns Moderate-Intensity Statin Healthy Lifestyle

Case Study: Ms. Green Continued Upon 2-week follow-up: Reported feeling achy and tired, attributed this to recently having a heart attack Referred to cardiac rehab One month later: Ms. Green scheduled an appointment because of severe leg and low back pain; she had difficulty exercising during cardiac rehab. HCP asked her to temporarily stop atorvastatin TSH, vitamin D, LFTs, and CK levels were ordered (a baseline CK was not available).

Ms. Green Continued Muscle pain resolved 2 weeks after stopping atorvastatin. CK mildly elevated; vitamin D low; LFTs and TSH normal. Atorvastatin restarted at 40 mg, Muscle symptoms occurred again after 1 month. Ms. Green experienced leg pain from simvastatin in the past. Hypercholesterolemia was untreated until the time of her heart attack. Atorvastatin was again stopped, and after resolution of symptoms, rosuvastatin 10 mg was begun. Thus far, Ms. Green has tolerated moderate-intensity rosuvastatin, but is hesitant to increase the dose. Her LDL-C is 90 mg/dl (vs 140 mg/dl untreated).

Evaluating Statin-Associated Muscle Effects

Statin-Associated Muscle Effects Myalgia Unexplained muscle discomfort Often described as flu-like symptoms with normal CK level Myopathy Muscle weakness Myositis Muscle inflammation Myonecrosis: muscle enzyme elevations or hyperckemia Mild > 3-fold above untreated baseline CK level Moderate 10-fold above untreated baseline CK level Severe 50-fold above untreated baseline CK level Myonecrosis with myoglobinuria or AKI Increase in serum creatinine 0.5 mg/dl (clinical rhabodomyolysis) Rosenson RS et al., J Clin Lipidol 2014;8:S58-S71

Assessing Muscle Symptoms Myalgia Often described as muscle aches, soreness, stiffness, tenderness, cramps with or shortly after exercise Muscles commonly affected Symmetric hip flexors/thigh aches Symmetric calf aches Symmetric upper arm aches Rosenson RS et al., J Clin Lipidol 2014;8:S58-S71

Options for the Patient Intolerant to Multiple Statins Use a systematic approach to evaluate statin intolerance Careful history of symptoms: description, timing Rule out other causes Hypothyroidism, vitamin D deficiency, recent exercise, rheumatologic disorders, vitamin D deficiency, primary muscle diseases) Evaluate for drug-drug interaction Lower the statin dose Switch to another statin Reduce the dose frequency to less than daily Consider using a nonstatin lipid-lowering agent Adding co-enzyme Q10 to statin (inconclusive results) Cannon CP et al., N Engl J Med 2015; DOI: 10.1056/NEJMoa1410489 Parker BA et al., J Clin Lipidol 2013;7:187-193

Statin Safety Recommendations: ACC/AHA Guidelines Use moderate-intensity statin therapy in patients who are predisposed to statin-associated adverse effects. Multiple or serious comorbidities, including impaired renal or hepatic function History of previous statin intolerance or muscle disorders Unexplained ALT elevations > 3 times ULN Concomitant use of drugs affecting statin metabolism > 75 years of age History of hemorrhagic stroke Asian ancestry CK should not be routinely measured, although it is reasonable to measure baseline CK in persons at increased risk for adverse muscle events Stone NJ et al., Circulation 2013, DOI: 10.1161/01.cir.0000437738.63853.7a

Monitoring Statin Therapy Obtain baseline lipid panel, ALT, CK. Repeat lipid panel in 4 to 12 weeks to determine adherence. Thereafter, assess every 3 to 12 months as clinically indicated. If dose adjustment, repeat lipid panel in 4 to 12 weeks.

Question/Discussion: What are some secondary prevention strategies that can be implemented in CVD patients with residual risk despite taking the maximum tolerated dose of statin therapy?

Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519

Decision Pathway: Patients with Clinical ASCVD with Comorbidities, on Statin for Secondary Prevention Patients with ASCVD with comorbidities on statin for secondary prevention Patient has > 50% LDL-C reduction or LDL-C < 70 mg/dl or Non HDL-C < 100 mg/dl Patient has < 50% LDL-C reduction and/or has not reached expected targets Continue to monitor adherence to meds, lifestyle, and LDL-C response to therapy Address statin adherence, Intensify lifestyle, Increase to high-intensity statin, evaluate for statin intolerance, control other risk factors Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519

Barriers to Adherence to Lipid-Lowering Therapies and Strategies to Overcome These Barriers

Factors That Place Patients at Rise of Non-Adherence Cost of medication Concern over adverse effects Complexity of medication regimen Taking multiple medications Silent conditions Forgetfulness Negative previous experience with drug therapies

Assess Adherence by Starting with a Single Question In the past 2 weeks, what percent of your cholesterol medicine would you say you have taken? (If less than 100%).. What is the main reason you might miss your medication?

Morisky Medication Adherence Scale: MMAS-4 Do you ever forget to take your medicine? Are you careless at times about taking your medicine? Sometimes if you feel worse when you take the medicine, do you stop taking it? When you feel better, do you sometimes stop taking your medicine? 0 = high adherence 1-2 = medium adherence 3-4 = low adherence Med Care. 1986;24:67-74

Strategies for Low Health Literacy Create a shame-free environment. All staff should be made aware of literacy issues. Speak slowly to foster a patient-centered approach. Use plain, nonmedical language. Use supplemental materials with visual images, video, and audio sources to improve recall. Limit the amount of information and repeat it. Med Care. 1986;24:67-74

Educating the Patient Assess patient s need for information (verbal explanation, written materials) Specifically relate the reason for prescribing a lipid modifying agent to an individual patient s condition: FH and + family history Recent cardiac event (in the case of Ms. Green) Diabetes as a high-risk condition Presence of CAC

Educating the Patient Address the importance of 3 forms of therapy to modify lipids and reduce CHD risk: Heart-healthy diet Regular physical activity Medication Use teach-back method to ensure patient s understanding Create a collaborative environment to encourage questions Stress the life-saving, event prevention nature of statins for high-risk patients

Discuss Potential Adverse Effects at Drug Initiation Discuss the potential for muscle aches and describe how muscle aches feel (statins). Tell patients you want to be called if they believe they are experiencing an adverse effect. Explain that although statins are one class of drugs, they are very different from one another; a problem with one doesn t usually mean every statin should be avoided.

Intensify Lifestyle Strategies

Lifestyle as the Foundation for Risk Reduction A critical component of health promotion and ASCVD risk reduction Heart-healthy diet Regular exercise Avoidance of tobacco products Maintenance of a healthy weight Eckel RH et al., Circulation 2013, DOI: 10.1161/01.cir.0000437740.48606.d1

Dietary Recommendations for LDL Lowering Consume a dietary pattern that emphasizes intake of vegetables, fruits, whole grains; includes low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, nuts; and limits intake of sweets, sugar-sweetened beverages, and red meats Strong recommendation (I, LOE A) Eckel RH et al., Circulation 2013, DOI: 10.1161/01.cir.0000437740.48606.d1

Dietary Recommendations for LDL Lowering Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions (including diabetes). Achieve this pattern by following plans such as the DASH dietary pattern, the USDA Food Pattern, or the AHA Diet. Eckel RH et al., Circulation 2013, DOI: 10.1161/01.cir.0000437740.48606.d1

Dietary Recommendations for LDL Lowering Aim for a dietary pattern that achieves 5 to 6% of calories from saturated fat. Reduce per cent of calories from saturated fat. Reduce per cent of calories from trans fat. All strong recommendations (I, LOE A) Eckel RH et al., Circulation 2013, DOI: 10.1161/01.cir.0000437740.48606.d1

Physical Activity Recommendations for Lipid Management Advise adults to engage in aerobic physical activity to reduce LDL-C and non-hdl-c: 3 to 4 sessions a week, lasting on average 40 minutes per session, and involving moderate-to-vigorous intensity physical activity Moderate recommendation (IIa, LOE A) Eckel RH et al., Circulation 2013, DOI: 10.1161/01.cir.0000437740.48606.d1

PCNA Materials

PCNA Materials

Non-Statin Agents for Additional Risk Reduction Clinician-Patient Discussion When treatment goal is not met on statin. 1. Potential for additional ASCVD risk reduction from addition of non-statin therapy to lower LDL-C. 2. Potential for adverse events or drug-drug interactions from addition of non-statin therapy 3. Patient preference Consider adding ezetimibe and continue to monitor adherence to meds, lifestyle and LDL-C response to therapy. Consider adding or replacing statin with PCSK 9 inhibitor and continue to monitor adherence to meds, lifestyle and LDL-C response to therapy. Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519

Shared Decision-Making Engage in a clinician patient discussion before initiating treatment When deciding on statin therapy for primary prevention When deciding on option for a statin intolerant patient Treatment plan informed by: clinical judgment statin safety issues consideration of patient preferences The more empowered patients feel, the more likely they will be motivated to manage their condition and adhere to medications. Lin GA, Fagerlin F. Circ Cardiovasc Qual Outcomes 2014 DOI: 10.1161/CIRCOUTCOMES.113.000322

Options for Non-Statin Therapies

Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519 Non-Statin Strategies for Management of LDL-Related ASCVD Risk Strategy/Agent Mechanism of Action Mean % LDL Reduction Consider referral to lipid specialist Ezetimibe PCSK9 inhibitors Reduces cholesterol absorption in small intestine Human monoclonal antibody to PCSK9. Binds to PCSK9 and increases number of LDL receptors available to clear circulating LDL. Monotherapy 18%; Combined with statin 25% Added to statin: Alirocumab 43-47% Evolocumab 58-64%

Non-Statin Strategies for Management of LDL- Related ASCVD Risk Strategy/Agent Mechanism of Action Mean % LDL Reduction Bile acid sequestrants Phytosterols Soluble/viscous fiber Bind bile acids in intestine and impede their absorption. More cholesterol is converted to bile acids increasing demand for cholesterol and increasing HMG-CoA reductase. Hepatic LDL receptors increase which increases LDL-C clearance from the blood. Decrease cholesterol transport toward the intestinal brush border; may also interfere with transporter-mediated cholesterol uptake. Traps cholesterol and bile acids in small intestine; results in decreased absorption. Colesevelam monotherapy 15%, added to statin 10-16%; Cholestyramine monotherapy 10.4%; Colestipol 16-27% 5-15% 10-12% Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519

Non-Statin Strategies for Management of LDL-Related ASCVD Risk Strategy/Agent Mechanism of Action Mean % LDL Reduction Mipomerson Antisense oligonucleotide targeted to human mrna for apob-100; inhibits translation of the apob-100 protein. For HoFH: addition to maximally tolerated lipid lowering therapy 25% Lomitapide LDL apheresis Inhibits MTP, preventing the assembly of apob-containing lipoproteins; inhibits the synthesis of VLDL and thus LDL. Selectively removes apob-containing lipoproteins, producing an acute reduction in LDL-C. For HoFH: 40-50% when added to other lipid lowering therapy Weekly or biweekly treatment: 50-60% Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519

Ezetimibe Inhibitor of intestinal cholesterol absorption Reduces elevated LDL-C either alone or in combination with a statin or other lipid-lowering medication Dose is 10 mg once daily, with or without food Outcome data was shown by the IMPROVE-IT trial when given in combination with simvastatin

Improve-It Trial Evaluated the clinical efficacy of combination Ez/simva vs simvastatin alone in ACS patients 50 years of age LDL-C 50-125 mg/dl (or 50-100 mg/dl if prior lipidlowering treatment) Primary endpoint: CV death, MI, hospital admission for UA, coronary revascularization, or stroke Absolute RR over 7 years was 2% 32.7% in the Ez/simva arm experiencing a primary endpoint vs 34.7% in the simvastatin arm Cannon CP et al., N Engl J Med, 2015: DOI: 10.1056/NEJMoa1410489 41

IMPROVE-IT: Kaplan Meier Curves for Primary Efficacy Endpoint Cannon CP et al., N Engl J Med 2015;372:2387-2397

PCSK9 INHIBITORS PCSK9 is a protein secreted by the hepatocyte Loss of function mutations in PCSK9 decrease LDL-C and CV risk Clinical trials with monoclonal antibodies to PCSK9 demonstrate 60%-70% reductions in LDL-C Injectable cholesterol-lowering drugs Clinical outcomes studies not yet complete

Novel Lipid-Regulating Drug Targets. Marina Cuchel et al. Eur Heart J 2014;eurheartj.ehu274 The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology

Alirocumab (Praluent) Indications -- diet + maximally tolerated statin: Adults with heterozygous FH Clinical ASCVD who require additional LDL lowering Most common adverse effects: Nasopharyngitis, injection site reactions, influenza Neurocognitive effects 0.8% vs. 0.7% (placebo) Abnormalities in liver enzymes 2.5% vs. 1.8% (placebo) D=Discontinuation of treatment 0.3% vs <0.1% (placebo) Allergic reactions leading to discontinuation of treatment 0.6% vs 0.2% (placebo) Source: Praluent product information

ODYSSEY LONG TERM Study Design: Alirocumab. ClinicalTrials.gov identifier: NCT01507831 Hefh or high cv-risk patients on maximally tolerated satin Other lipid-lowering therapy LDL-C 70 mg/dl R N = 1553 N = 788 Double-blind treatment (18 months) Alirocumab 150 mg Q2W SC (single 1 ml injection using prefilled syringe for self-administration) Placebo Q2W SC Followup (8 weeks) Assessments W0 W4 W8 W12 W16 W24 W36 W52 W64 W78 Primary Efficacy Endpoint Pre-specified Analysis Efficacy: all patients up to W52 (ITT) Safety: all patients randomized and treated 85.8% (2009/2341) completed 52 weeks (both treatment arms) 26.1% (405/1553 alirocumab) and 25.6% (202/788 placebo) had completed 78 weeks by time of this analysis Mean treatment duration: 65 weeks (both treatment arms)

Odyssey Trial: LDL Cholesterol Levels Over Time LDL Cholesterol Levels Over Time

Evolocumab (Repatha) Indications diet + maximally-tolerated statin: HeFH Clinical ASCVD who require additional LDL lowering HOFH who require additional LDL lowering Common adverse effects: Nasopharyngitis, upper respiratory tract infection, flu, back pain, and reactions such as redness, pain, or bruising at injection site Neurocognitive effects 0.2% vs. 0.7% (placebo) Abnormalities in liver enzymes 0.8% vs. 1% (placebo) Adverse effects leading to discontinuation 2.2% vs. 1% (placebo) Source: Praluent product information

Osler 1 and 2 Trials: Evolocumab 4465 patients who completed 1 of 12 phase 2 or 3 studies (parent trials) Randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone Followed for median of 11.1 months Assessed for lipid levels, safety, and CV events (death, MI, unstable angina, coronary revascularization, stroke TIA, and HF) as a prespecified exploratory analysis Sabatine MS et al., N Engl J Med 2015;372:1500-1509.

Osler Trials: LDL-C Levels Sabatine MS et al., N Engl J Med 2015;372:1500-1509.

Osler Trials: Cumulative Incidence of Cardiovascular Events Sabatine MS et al., N Engl J Med 2015;372:1500-1509.

Patients with Clinical ASCVD with Comorbidities Consider BAS as alternative to ezetimibe if TG < 300 mg/dl. Patient with ASCVD and baseline LDL-C 190 mg/dl with < 50% reduction in LDL-C (may consider LDL-C 70 mg/dl): Reasonable to consider a PCSK9 inhibitor as a first add-on medication (rather than ezetimibe or BAS) If < 50% reduction in LDL-C (may consider LDL-C 70 mg/dl) with triple therapy, refer to lipid specialist and RDN. Specialized therapies (mipomersen, lomitapide, LDL apheresis) may be needed for patients with baseline LDL-C 190 mg/dl and inadequate response to statins, ezetimibe, and PCSK9 inhibitors. Lloyd-Jones DM et al, JACC 2016, DOI: 10.1016/j.jacc.2016.03.519

Lessons Learned: Obtaining Approval for PCSK9 Inhibitors Given high cost of drugs, oversight by insurers and pharmacy programs is intense. Work closely with reps. Learn if one agent is preferred by a particular insurance/pharmacy plan. Clearly identify the indication on enrollment form. Clearly describe any statin failures (drug, dose, LDL-C, adverse effect). Include most recent labs. Enlist the help of specialty pharmacist if available. Other tips?

Summary Clinicians should thoroughly assess muscle symptoms in patients taking statins. Statins are the class of medications with proven outcomes. In a patient with clinical ASCVD, several attempts should be made to find a medication regimen that is tolerated. Strategies for reducing residual risk in patients with ASCVD on maximally-tolerated statin therapy include: Evaluate and introduce strategies to improve statin adherence Intensify lifestyle Control other risk factors Consider the addition of non-statin agents

Summary The IMPROVE-IT trial showed a modest outcome benefit for ACS patients who received simvastatin plus ezetimibe versus simvastatin alone. PCSK9 inhibitors are generally well-tolerated and show a profound reduction in LDL-C. However, outcome data is not yet available. Patients should be engaged in a discussion before initiating treatment and when making decisions about treatment options.

Discussion Questions 1. Is statin intolerance something you commonly manage in your practice? How do you evaluate someone with complaints of intolerance? 2. Have you used the PCSK9 s in your practice? What was your experience? Ease of getting the medication covered by insurance? Patients response to an injectable medicine? Patient results/outcomes? 3. What other non-statin medications do you use when patients can t/refuse to take statins.