Disclosures. Choosing a Statin/New Therapies. Case. How else would you do to treat him? LDL-C Reduction with Different Statin Strategies

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1 Disclosures I have no disclosures relevant to this talk Choosing a Statin/New Therapies Aryan Aiyer, MD Assistant Professor of Medicine University of Pittsburgh School of Medicine UPMC Heart and Vascular Institute Case 78 year old admitted with STEMI and treated with PCI to RCA No prior history of CAD Very active physically. Still works as an attorney Only risk factor was treated hypertension with lisinopril Started on aspirin, clopidogrel, metoprolol Referral for cardiac rehab How else would you do to treat him? A. Start high intensity statin with atorvastatin 80 po qd B. Start rosuvastatin po qd C. Start simvastatin 80 po qd D. Start pravastatin 40 po qd E. Don t start a statin. Not proven in the elderly F. Start a PCSK9 inhibitor Log-Linear Relationship Between LDL-C Levels and Relative Risk for CHD LDL-C Reduction with Different Statin Strategies Relative Risk for CHD, Log Scale This relationship is consistent with a large body of epidemiologic data and data available from clinical trials of LDL-C lowering therapy. These data suggest that for every 30-/dL change in LDL-C, the relative risk for CHD is changed in proportion by about 30%. The relative risk is set at 1.0 for LDL-C = 40 /dl. Change in LDL-C from Baseline (%) Rosuvastatin Atorvastatin Simvastatin LDL-C, /dl 40 Pravastatin Reprinted with permission from Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 04;1: ; LDL-C, low-density lipoprotein cholesterol. Adapted from Jones PH et al. Am J Cardiol. P < vs rosuvastatin P < vs rosuvastatin P < vs rosuvastatin 40

2 Proportion with Event (%) CHD Events, % 30% 25% % 15% % 5% Statins Really Reduce CHD Events CHD + Revasc + Stroke (HPS = CHD Only) Solid Shapes = Drug therapy Outline Shapes = Placebo 2 Prevention 4S WOSCOPS CARE HPS LIPID 1 Prevention AFCAPS WOSCOPS 0% Mean On-Treatment LDL-C Level at Follow-Up (/dl) Adapted from Ballantyne CM. Am J Cardiol. 1998;82:3Q-12Q. Heart Protection Study (HPS) Collaborative Group. Lancet. 02;360:7-22. Trial Are the elderly well-represented in landmark trials? 4S (1994) 23 CARE (1996) 31 LIPID (1998) 39 WOSCOPS (1995) 0 AFCAPS/TexCAPS (1998) 21 Heart Protection Study (03) 46 PROVE IT TIMI 22 (04) 30 TNT (05) 38 JUPITER (08) 52 Percentage of Patients > 65 years Observed Data in Clinical Trials Elderly are at high risk of cardiovascular events Age is a predominant risk factor Perhaps other risk factors cluster, in part, as a consequence of age (e.g. diabetes, hypertension, inflammation). Observed benefit of statins in the elderly appear similar to younger cohorts Trials of Statins in the Elderly PROSPER SAGE Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) 5804 patients aged years with a history of vascular disease or with cardiovascular risk factors Randomized to pravastatin 40 /d or placebo Baseline TC /dl Follow-up 3.2 years (mean) Primary endpoint (composite): coronary death, nonfatal MI, fatal or nonfatal stroke Shepherd J et al. Lancet 02;360: Kaplan Meier Analysis of Time to Primary Endpoint: PROSPER 15 5 p=0.014 Placebo Follow-up (years) Shepherd J et al. Lancet 02;360: Pravastatin

3 Major Endpoints: PROSPER Mortality by Cause: PROSPER Endpoint Primary endpoint: Pravastatin (%) Placebo (%) Hazard ratio CHD death/mi/stroke Secondary endpoints: CHD death/mi Fatal or nonfatal stroke Other outcomes: Nonfatal MI Nonfatal stroke Transient ischemic attack All CV events p Cause of death Pravastatin (%) Placebo (%) Hazard ratio CHD Stroke Vascular Nonvascular Cancer Trauma/suicide NA NA All causes p Shepherd J et al. Lancet 02;360: Shepherd J et al. Lancet 02;360: Study Assessing Goals in the Elderly (SAGE) 893 ambulatory patients aged years with stable coronary artery disease Randomized to pravastatin 40 /d (moderate intensity) or atorvastatin 80 /d (high intensity) Baseline LDL levels between /dl Baseline Characteristics: SAGE Mean age 72.5 years 30% female 97% white Mean LDL 145 7% current smoking 46% had prior MI 23% diabetic Follow-up 12 months Primary endpoint : Percent change in duration of myocardial ischemia on holter monitoring High risk cohort Deedwania P. Circulation 07;115: Changes in Lipid Values: SAGE Primary Endpoint of Mean Duration of Myocardial Ischemia: SAGE Deedwania P. Circulation 07;115: Deedwania P. Circulation 07;115:700-07

4 Major Adverse Cardiac Events: SAGE All Cause Mortality: SAGE Deedwania P. Circulation 07;115: Deedwania P. Circulation 07;115: ACC/AHA Guideline On The Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults Statin Benefit Groups Four Statin Benefit Groups New ASCVD Risk Estimator/Calculator Lifestyle Modification is a critical component to ASCVD risk reduction No strong evidence for continued use of LDL or non-hdl target levels Statins are first line therapy Following lipid levels may be useful to track adherence and response of therapy Established ASCVD (Secondary Prevention) Adults aged years with diabetes and LDL-C /dl without clinical ASCVD LDL-C > 190 /dl Adults aged years without diabetes or ASCVD and with a -year calculated ASCVD risk > 7.5% ASCVD Risk Estimator Enables providers to estimate -year risk and lifetime risk of CV events Coronary death Nonfatal MI Fatal or nonfatal stroke Quantitative assessment of risk based on representative populations (pooled cohorts) While applied to individuals, the estimates are based on group averages ASCVD Risk Estimator Gender Age (-79) Race Total Cholesterol HDL SBP Treatment for Hypertension Diabetes Smoker

5 ASCVD Risk Estimator How can I access this tool? Web-based version available through ACC website Excel spreadsheet version Downloadable app Provides automated treatment recommendations reflective of the 13 guidelines after input of data Some concern that it may overestimate risk Summary of Statin Initiation Recommendations to Reduce ASCVD Risk Age >21 y and a candidate for statin therapy Definitions of High- and Moderate-Intensity Statin Therapy High Daily dose lowers LDL-C by approx. 50% (See Table 5) Heart-healthy lifestyle habits are the foundation of ASCVD prevention (See 13 AHA/ACC Lifestyle Management Guideline) Moderate Daily dose lowers LDL-C by approx. 30% to <50% Regularly monitor adherence to lifestyle and drug therapy with lipid and safety assessments (See Fig 5) Clinical ASCVD No LDL-C 190 /dl No Diabetes Type 1 or 2 Age y Age 75 y High-intensity statin (Moderate-intensity statin if not candidate for high-intensity statin) Age >75 y OR if not candidate for high-intensity statin Moderate-intensity statin High-intensity statin (Moderate-intensity statin if not candidate for high-intensity statin) Moderate-intensity statin Estimated -y ASCVD risk 7.5%* High-intensity statin No Summary of Statin Initiation Recommendations to Reduce ASCVD Risk No Intensity of Statin Therapy DM age <40 or >75 y Primary prevention (No diabetes, LDL-C /dl, and not receiving statin therapy) Estimate -y ASCVD Risk every 4-6 years Pooled Cohort Equations* <5% -y ASCVD risk Age <40 or >75 y and LDL-C <190 /dl 7.5% -y ASCVD risk (Moderate- or highintensity statin) 5%-<7.5% -y ASCVD risk (Moderate-intensity statin) In selected individuals, additional factors may be considered to inform treatment decision making Clinician-Patient Discussion Prior to initiating statin therapy, discuss: 1. Potential for ASCVD risk reduction benefit 2. If decision is unclear, consider primary LDL-C >160 /dl, family history of premature ASCVD, lifetime ASCVD risk, abnormal CAC score or ABI, or hs-crp >2 /L 3. Potential for adverse effects and drug drug interactions 4. Healthy lifestyle 5. Management of other risk factors 6. Patient preferences Emphasize adherence to lifestyle Manage other risk factors Monitor adherence No to statin to statin Encourage adherence to lifestyle Initiate statin at appropriate intensity Manage other risk factors Monitor adherence (See Fig 5) *Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biologic basis for a less-than-average response. Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 in IDEAL (Pedersen et al). Although simvastatin 80 was evaluated in RCTs, initiation of simvastatin 80 or titration to 80 is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis. Individuals Not in a Statin Benefit Group In those for whom a risk decision is uncertain, these factors may inform clinical decision making: Family history of premature ASCVD Elevated lifetime risk of ASCVD LDL-C 160 /dl hs-crp 2.0 /L CAC score 300 Agatston units ABI <0.9 Statin use still requires discussion between clinician and patient So how do we apply these guidelines and clinical trial data to our elderly patient who just had an MI?

6 Clinical ASCVD: Initiating Statin Therapy Clinical ASCVD Not currently on statin therapy Initial evaluation prior to statin initiation Fasting lipid panel* ALT CK (if indicated) Consider evaluation for other secondary causes (Table 6) or conditions that may influence statin safety (Table 8, Rec 1). Aged <75 y without contraindications, conditions or drug-drug interactions influencing statin safety, or a history of statin intolerance Initiate high-intensity statin therapy Counsel on healthy lifestyle habits Monitor statin therapy (Figure 5) Aged >75 y OR with conditions or drug-drug interactions influencing statin safety, or a history of statin intolerance Initiate moderate-intensity statin therapy Counsel on healthy lifestyle habits Evaluate and Treat Laboratory Abnormalities 1. Triglycerides 500 /dl 2. LDL C 190 /dl Secondary causes (Table 6) If primary, screen family for FH 3. Unexplained ALT >3X ULN *Fasting lipid panel preferred. In a nonfasting individual, a nonfasting non-hdl C >2 /dl may indicate genetic hypercholesterolemia that requires further evaluation or a secondary etiology. If nonfasting triglycerides are >500 /dl, a fasting lipid panel is required. It is reasonable to evaluate the potential for ASCVD benefits and for adverse effects, and to consider patient preferences, in initiating or continuing a moderate- or high-intensity statin, in individuals with ASCVD >75 years of age. Case (cont d) Placed on atorvastatin 80 po qd by residents at discharge Continues with cardiac rehab and is doing great Returned to work 2 months later he visits with his PCP with his wife. Noticing more myalgias Wife tells PCP that they have done internet research about medication side effects They are very concerned about taking statins. Case (cont d) What should we do? A. Stop the statin B. Reduce dose of statin C. Check CPK level D. Start Co-Enzyme Q- E. Tell patient to tough it out. Statins are good for you. F. Tell patient and wife to stop believing everything on the internet Statin Safety Muscle-related adverse events Liver-related adverse events New onset diabetes Cognitive Effects Definition of Muscle Findings Myalgia Muscle ache or weakness without creatinine kinase (CK) elevation Myopathy Myalgia, plus elevation in serum CK > x ULN Rhabdomyolysis CK 000 > IU/L or CK > x ULN plus an elevation in serum creatinine or medical intervention with IV hydration National Lipid Association Statin Safety Task Force. McKenney JM, et.al. Am J Cardiol 06:97(8A):89C-94C

7 Incidence of Muscle AE Factors Increasing the Risk of Statin-Induced Myopathy Muscle AE Incidence Myalgia 1.5-3% Myopathy 5/0,000 Rhabdomyolysis 1.6/0,000 Patient Characteristics Increasing age Female gender Renal insufficiency Hepatic dysfunction Hypothyroidism Diet (e.g. grapefruit juice with statins metabolized by 3A4) Polypharmacy and multiple chronic diseases Statin Properties High systemic exposure (higher doses, high bioavailability, limited protein binding) Potential for drug-drug interactions metabolized by CYP pathways Law M et.al. Am J Cardiol 06;97 (suppl 8A) 52C-61C. Statin Pharmacokinetics Percent of CK elevation > x ULN by statin dose Recommendations from the NLA Statin Safety Task Force for Muscle Issues Patient monitoring Rule out other etiologies of muscle symptoms or asymptomatic CK elevation (e.g. hypothyroidism, trauma Routine CK levels is not recommended Symptom monitoring with CK measurement only in symptomatic patients Exacerbating factors should be considered (e.g. sepsis, alcohol abuse, infection) Recommendations from the NLA Statin Safety Task Force for Muscle Issues Management of Muscle Symptoms Intolerable muscle symptoms Discontinue statin regardless of CK levels and rechallenge only after patient becomes symptom-free Tolerable Muscle symptoms Mild CK elevation: Continue statin and use symptoms as guide to stop or continue treatment Moderate to severe CK elevation: Stop statin and weigh risks and benefits CK elevation with renal dysfunction or need for iv fluids: Discontinue statin therapy

8 Management of Patients with Intolerable Muscle Symptoms on Statin Therapy Statin Safety Statin Therapies Non-statin drugs Diet Alternate day statin dosing Lower dose or intensity Hydrophilic statins (e.g pravastatin, rosuvastatin) Ezetimibe Bile Acid Resins Fibrates/Niacin Plant Sterols Soluble Viscous Fiber Muscle-related adverse events Liver-related adverse events New onset diabetes Cognitive Effects Supplements Red Yeast Rice Vit D CoEnzyme Q Statin adverse drug reactions Nonspecific elevation in transaminases Guidelines recommend testing only when initiating Rx Neurologic Very mild cognitive dysfunction, rarely impairment Rare peripheral neuropathy Statin adverse drug reactions (continued) Diabetogenic Meta-analysis of placebo-controlled trials, statin Rx for 4y increased new cases of DM by 9% (1 per 255 patients) (Lancet ;375:735) Meta-analysis of intensive vs moderate dose trials for 5y found 12% increase (JAMA 11;305:2556) Largest primary prevention trial found 27% more new DM (Jupiter) Among 154,000 post-menopausal women (WHI; observational) statin Rx associated with nearly 50% increased new-onset DM (Arch Int Med 12;172:144) Case (cont d) You stop the statin Symptoms resolve You call back and want to put him back on atorvastatin but at a lower dose (e.g. po qd) He s somewhat averse to restarting statins Wondering if PCSK9 inhibitor treatment is right for him? PCSK9 Inhibitors New class of lipid-lowering drugs Proprotein convertase subtilisin/kexin type 9 inhibitor Monoclonal antibody to the PCSK9 protein Approved by FDA in 15 Indications Familial Hypercholesterolemia Established CVD who are on maximally tolerated statin and require additional LDL lowering

9 LDL-C Mean (SE) % Change from Baseline LDL Receptor Function and Life Cycle The Role of PCSK9 in the Regulation of LDL Receptor Expression For illustration purposes only For illustration purposes only Impact of an PCSK9 mab on LDL Receptor Expression Change in Calculated LDL-C at 2 Weekly Intervals from Baseline to Week 12 For illustration purposes only 0 - BASELINE WEEK 2 WEEK 4 WEEK 6 WEEK 8 WEEK WEEK % - 5.1% % % % % % % -80 Placebo SAR Q2W SAR Q2W SAR Q2W 2 Mean percentage change in calculated LDL-C from baseline to weeks 2, 4, 6, 8,, and 12 in the modified intent-to-treat (mitt) population, by treatment group. Week 12 estimation using LOCF method. Case (Final Plan) Patient agrees to rechallenge with statin Settle on rosuvastatin po qd Agree to follow closely for symptoms He wants to take Co-Q supplementation