10/4/2016. Similarities between the ACC/AHA Guidelines and the NLA Recommendations

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1 Lipid Management CoxHealth Heart and Vascular Summit Oct 15, 2016 DISCLOSURES I have no potential conflicts of interest and nothing relevant to this lecture to disclose Learning Objectives Develop an evidence-based and patientcenteredapproach in managing lipids, utilizing both primary and secondary cardiovascular disease prevention strategies. Describe an evidence-based approach to the patient concerned about statin intolerance. Discuss the appropriate use of both statin and non-statin therapies. 1

2 Blood Cholesterol Trends in the US : Analysis of 105 Million Patient Records Similarities between the ACC/AHA Guidelines and the NLA Recommendations Lipid screening for the primary prevention is recommended at 5-year intervals Lifestyle management advocated as the first step in all treatment algorithms ASCVD risk reduction overall goal Mod-or high-intensity statin therapy is the central focus of pharmacotherapy Patient/provider discussion of risk/benefit ratio precedes all drug management decisions lipid f/u on a regular basis is warranted to assess for adherence 2

3 The Differences Evidence Base ACC/AHA RCT with ASCVD outcomes Meta-analyses of RCTs NLA RCT with ASCVD outcomes Meta-analyses of RCTs Selected post-hoc analyses of RCT Observational epidemiologic studies Genetic studies Metabolic studies Mechanistic studies Central Focus ACC/AHA Defines the statin benefit groups Risk/Benefit discussion Use mod-or high-intensity statin therapy on a background of lifestyle modification Avoid non-statin therapy because it is less favorable net benefit No lipid goals/targets NLA Identifies an individual persons ASCVD risk based on clinical parameters and RF s Risk vs. Benefit discussion Emphasize the healthy lifestyle and may use modor high-intensity statin therapy +/-adjunctive nonstatins, if necessary, to achieve non-hdl-c targets 3

4 The Decision is Yours 2013 ACC/AHA Cholesterol Treatment Guide 4 Statin Benefit Groups: 1. With clinical ASCVD 2. With primary elevations in LDL-C >190 mg/dl yrswith DM and LDL-C yrswithout DM or clinical ASCVD or DM, LDL- C , andan estimated 10-year ASCVD risk of 7.5% or higher 2013 ACC/AHA Cholesterol Treatment Guide In select individuals who are not in 1 of the 4 statin benefit groups, additional factors may be considered, including: LDL > 160 or other evidence of genetic hyperlipidemia FH premature ASCVD (male < 55, female < 65) hs-crp >2 mg/dl CAC score >300 Agatston units or >75th percentile Ankle brachial index (ABI) < 0.9 Elevated lifetime risk of ASCVD 4

5 2013 ACC/AHA Cholesterol Treatment Guide No recommendation was made to support (or refute) the initiation or continuation of statin therapy in 2 specific groups: 1. NYHA Class II-IV heart failure 2. ESRD on maintenance HD Statin Intensity vs. Statin Benefit Group 1. Individuals with clinical ASCVD Age < 75: High-intensity Age > 75: Moderate-intensity 2. With primary elevations of LDL C > 190 mg/dl High-intensity yrs with diabetes and LDL C Estimated 10-y ASCVD risk > 7.5%: High-intensity Estimated 10-y ASCVD risk < 7.5%: Moderate-intensity 4. Without clinical ASCVD or diabetes, age 40 75, LDL C andestimated 10 year ASCVD risk of > 7.5% Moderate to high-intensity Statin Intensity vs. Statin Benefit Group 1. Individual with clinical ASCVD Age < 75: High intensity Age > 75: Moderate-intensity 2. With primary elevation of LDL C > 190 mg/dl High intensity yrs with diabetes and LDL C Estimated 10-y ASCVD risk > 7.5%: High intensity Estimated 10-y ASCVD risk < 7.5%: Moderate-intensity 4. Without clinical ASCVD or diabetes, age 40 75, LDL C andestimated 10 year ASCVD risk of > 7.5% Moderate to high intensity 5

6 Statin Intensity vs. Statin Benefit Group 1. Individual with clinical ASCVD Age < 75: High-intensity Age > 75: Moderate intensity 2. With primary elevation of LDL C > 190 mg/dl High-intensity yrs with diabetes and LDL C Estimated 10-y ASCVD risk > 7.5%: High-intensity Estimated 10-y ASCVD risk < 7.5%: Moderate intensity 4. Without clinical ASCVD or diabetes, age 40 75, LDL C andestimated 10 year ASCVD risk of > 7.5% Moderate to high-intensity Statin Intensity High Intensity (Lowers LDL C > 50%) Atorvastatin 40-(80) mg Rosuvastatin 20 mg Moderate Intensity (Decreases LDL C 30 to 50%) Atorvastatin mg Rosuvastatin 5-10 mg Simvastatin mg Pravastatin mg Lovastatin 40 mg Fluvastatin 40 mg bid ASCVD Risk Calculator Non Modifiable Risk Factors Age Sex Race Modifiable Risk Factors Total Cholesterol HDL Cholesterol Systolic BP Anti-hypertensive medication use Diabetes status Smoking status 6

7 Key Disclaimer of the ACC/AHA ASCVD Pooled Cohort Risk Calculator It doesn t definitively recommend statin therapy for individual with 10-year risk > 7.5% It advises that for such individual before initiating statin therapy it is reasonable for clinicians and patients to engage in a discussion which considers the potential for ASCVD risk reduction benefits and for adverse effects, for drug-drug interactions and patient preferences for treatment. Pooled Risk Cohort Equations Criticism and Response Criticisms Lack of long-term prospective validation Possible overestimation of risk in some observational epidemiologic studies > 96% of men age >65 are statin candidates Responses Validation better than previous risk equations Over-representation of healthy individuals in certain observational epidemiologic studies does not invalidate application to general population Older patients are at higher risk and are thus usually good candidates for statins Case of Mr. J My cholesterol is high! 59-year-old white male with a 15 year history of hypertension controlled with lisinopril40 mg daily and amlodipine 5 mg daily. Also takes ASA, 81 mg/d PMHx: HTN and Prediabetes; A1C 6.4%, FBS 110 mg/dl SHx: Smokes 1ppd VS: T 98.9, BP 150/88, P 80, RR 20 Labs: CMP benign; Cr 1.14; TC 240; HDL 35; TG 178 7

8 Case of Mr. J My cholesterol is high! 59-year-old whitemalewith a 15 year history of hypertension controlled with Hydrochlorothiazide 25mg daily and Amlodipine 10 mg daily. Also takes ASA, 81 mg/d PMHx: HTN and Prediabetes; A1C 6.4%, FBS 110 mg/dl SHx: Smokes 1/2ppd VS: T 98.9, BP 150/88, P 80, RR 20 Labs: CMP benign; Cr 1.14; TC 240; HDL 35; TG 178 Estimated 10-year CVD risk: 29.0%! Est 10-year CVD risk if he quit smoking: 18.4% Statin Intensity vs. Statin Benefit Group 1. Individual with clinical ASCVD Age < 75: High-intensity Age > 75: Moderate-intensity 2. With primary elevation of LDL C > 190 mg/dl High-intensity yrs with diabetes and LDL C Estimated 10-y ASCVD risk > 7.5%: High-intensity Estimated 10-y ASCVD risk < 7.5%: Moderate-intensity 4. Without clinical ASCVD or diabetes, age 40 75, LDL C andestimated 10 year ASCVD risk of > 7.5% Moderate to high-intensity Mr. J: Oh, by the way I stopped that cholesterol medicine Within one month after starting Atorvastatin 40mg daily, Mr. J develops generalized fatigue, muscle soreness, and bilateral muscle aching. 8

9 Mr. J: I can t take this medicine! The American College of Cardiology recommends the following strategy to assess, treat, and manage those with possible statin intolerance: 1. Evaluate 2. Follow-up 3. Drug compare Statin Intolerance: Evaluate Check total CK If > 5x ULN, suggests rhabdomyolysis Symptoms suggesting statin intolerance: Muscle ache, Weakness, Soreness, Stiffness, Cramping, Tenderness, General Fatigue, Bilateral Symptoms unlikely to be statin intolerance: Tingling, Twitching, Shooting Pain, Nocturnal Cramps, Joint Pain, Unilateral Statin Intolerance: Evaluate Muscle Enzyme CK level Rhabdomyolysis Creatinine UA (particularly myoglobin) Risk Factor/Secondary Cause TSH VitD 25-OH Hepatic panel (ALT) Electrolyte panel Renal panel ESR (erythrocyte sedimentation rate) 9

10 Statin Intolerance: Evaluate Patient characteristics that increase risk of statin intolerance: Low BMI Frailty Excessive grapefuit juice consumption (>1.2L/d) Alcoholism Drug Abuse (amphetamine, cocaine, heroin) Heavy physical exertion/exercise Recent Trauma Dehydration or decrease in daily fluid intake Personal of FH of statin intolerance Drug Interactions (Niacin, Fibrates, Strong CYP3A4 inhibitors) Medication types that increase risk for statin adverse effects include: Fibrates (e.g., gemfibrozil, fenofibrate) Niacin 1 gram Strong CYP3A4 inhibitors Immunosuppressants(e.g., cyclosporine A, azathioprine) Hepatitis C protease inhibitors Anti-retrovirals Glucocorticoids Medication types that predispose individuals to non statin related muscle symptoms include: Anti-retrovirals Glucocorticoids Atypical anti-psychotics Neuroleptics and psychotropic agents (e.g., haloperidol, risperidone) Anti-viral agents (e.g., zidovudine, ritonavir, didaosine) Analgesics and antiinflammatorydrugs (e.g., salicylates, nonsteroidal antiinflammatory drugs, glucocorticoids) Anesthetics and neuromuscular blocking agents (e.g., propofol, ketamine, succinylcholine) 10

11 Statin Intolerance: Follow up Take patient off original potentially offending statin until symptoms resolve. Consider a re-challenge with lower dose or same dose of original statin Consider an alternate statin Consider statin characteristics(i.e., metabolism, lipophilicity, etc) Evaluate potential drug interactions Statin Intolerance: Drug Compare Statin characteristics considered when evaluating for statin intolerance: Dose intensity Half-life (Shorter acting better tolerated) Lipophilic? (Consider switching to Pravastatin, Rosuvastatin not lipophilic) better tolerated P-glycoprotein substrate? (Atorvastatin, Lovastatin, Simvastatin) less tolerated Pregnancy category 11

12 Available for ios and Android Web version also available at: What about non-statin lipid-lowering therapy? Niacin 12

13 AIM-HIGH Trial Does Niacin in patients with low HDL Cholesterol levels receiving intensive statin therapy improve outcomes? RCT of 3414 pts with known CAD given Niacin ER mg/d vs placebo All pts given Simvastatin 40-80mg/d +/-Ezetimibe 10mg/d to achieve LDL mg/dl Outcomes: CHD death; non-fatal MI; ischemic stroke; hospitalization for ACS; or revascularization.. AIM-HIGH Trial At 2 years of Niacin therapy: HDL from 35 to 42 mg/dl TGs from 164 to 122 mg/dl LDL from 74 to 62 mg/dl At 3 years trial was stopped because there was no difference in outcomes (16.4% in Niacin group vs 16.2% in Placebo group; HR, 1.02; 95%CI, ; P=0.79) AIM-HIGH Trial Conclusion: Niacin, when it is added to intensive statin therapy, does not improve any cardiovascular outcomes among patients with ASCVD and LDL levels less than 70 mg/dl, despite significant improvements in HDL and TG levels. There was actually a trend toward a higher risk for ischemic stroke among patients taking Niacin, which is not inconsistent with the increase in Afib seen the Coronary Drug Project Study. 13

14 HPS2-THRIVE Trial Niacin + Laropiprant Does it improve CVD outcomes or reduce mortality in pts with CVD? RCT of 25,673 pts ages yrsw/ known CVD, treated at baseline w/ Simvastatin 40mg; Ezetimibe 10mg was added if TC remained > 135 mg/dl Randomized to Niacin ER 1g/d + Laropiprant20mg/d (in order to reduce flushing) x 4wks then titrated up to 2g/40mg/day vs Placebo HPS2-THRIVE Trial During median f/u of 3.9 yrs of Niacin/Laropiprant: HDL by 6 mg/dl LDL by 10 mg/dl However, there was no significant difference in major vascular events, and: Absolute in disturbances in diabetes control 3.6% Absolute in diabetes diagnosis of 1.4% in all-cause mortality w/ active drug of 0.5% (P = 0.08) Omega-3 Fatty Acids 14

15 Omega-3 Fatty Acids Omega-3 fats contribute to the production of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA): Inhibit inflammatory immune response Inhibit platelet aggregation Mild vasodilators Possible antiarrhythmic properties Omega-3 Fatty Acids Prior to AHA guidelines suggested use for patients with: Preexisting disease High risk of disease High Triglycerides GISSI-P Trial (1999) showed n-3 PUFA given after MI decreased (12.3% vs 14.6%, NNT=44): Mortality and sudden death (all causes) Nonfatal MI Nonfatal Stroke Omega-3 Fatty Acids RCTs subsequent to GISSI-P, particularly those in the treatment guideline era,have (largely) failed to replicate that study s findings Omega-3 FA supplements added to the current standard of CVD care (e.g., statin, ACEI, BB, Anti-platelets) offer no statistically significant benefit 15

16 Omega-3 Fatty Acids Clinical Question: What about using n-3 FA s with high-risk pts? RCT of 12,505 with known CVD or at least 4 RF s but no previous h/o MI: Age >65, male, HTN, HLD, Tobacco use, Obesity, FHxof premature CVD DM + at least 1 of the above RF s also included 1 g n-3 FA vs Placebo Primary combined outcomes of death, nonfatal MI, stroke after 5 yrsof f/u: 11.7% of the n-3 FA s group 11.9% of the placebo control group Omega-3 Fatty Acids The only differences seen were a in hospitalizations for heart failure(1.5% vs 2.3%; P=0.002; NNT = 125 for 5 yrs) and a very slight prevention benefit in women, but not men. Conclusion: There is no evidence that n-3 FA s prevent CV events or death in older adults who have CVD(or who are at risk for it but have not had a MI). Fibrates 16

17 Fibrates-ACCORD Lipid Clinical Question:Is the addition of a fibrate plus a statin more effective than a statin alone in pts w/ T2DM? RCT: Simvastatin + Fenofibrate vs Simvastatin + placebo Primary Outcome was a major CV event defined as nonfatal MI, stroke, or CV death At 4.7 yrsf/u: No clinically or statistically important difference was seen between groups regarding the primary outcomes or all cause mortality (HR 0.92; 95% CI ; p=0.32) 2.2% in the fibrate + statin groupvs 2.4% per year in statin only group Fibrates-ACCORD Lipid Found just one subgroup with numeric (but not statistically or clinically significant) difference: Overall means TG level at start = 162 Most dyslipidemic(mean TG 204, HDL 29.5 mg/dl) Rate of primary outcome 12.4% with fenofibratevs. 17.3% with placebo Fibrates-ACCORD Lipid Conclusion:There is no benefit to adding a fibrate to a statin for pts with T2DM plus known CVD or at least 2 CV RF s Except perhaps in our most dyslipidemic high risk T2DM patients there still may be some value to fenofibrate 17

18 Ezetimibe Ezetimibe-ENHANCE ENHANCE published in 2008 showed that although ezetimibe reduces LDL, it does NOT halt the progression of CAIMTin pts with familial hypercholesterolemia when added to statin therapy. Ezetimibe-IMPROVE-IT RCT>18K pts ages >50 yrsof age (mean age 64 yrs) from 39 countries who had been hospitalized for ACS < 10 days Simvastatin 40mg daily vs Simvastatin 40mg + ezetimibe 10mg daily Primary endpoint: composite of CV death, MI, unstable angina requiring hospitalization, coronary revascularization, or stroke Overall, after 7 years f/u (2% ARR; NNT = 50) Most improvement came from a reduction in nonfatal MI (13.1% vs 14.8%; P = 0.002; NNT = 58) Small reduction also in risk of stroke (4.2% vs 4.8%; P = 0.05; NNT = 167) N EnglJ Med. 2015;372:

19 N EnglJ Med. 2015;372: Ezetimibe- Bottom Line is: Ezetimibe plus simvastatin had a marginally better outcome: 1 fewer nonfatal MI for every 58 patients who added ezetimibe for 7 yrsafter an ACS. $300 per month = $1.26 Million per event saved!! 19

20 Non-Statin Lipid Lowering Therapy Niacin: No benefit when added to statin. Omega-3 Fatty Acids: May be better than nothing, but no benefit when added to statin. Fibrates: No benefit when added to statin, except (perhaps) in the most dyslipidemichigh-risk diabetic patient. Ezetimibe: (very modest) benefit in high-risk patients, but may be costly to get that benefit. References Circulation. 2014;129(suppl 2):S1-S45 DOI: /01.cir a N Engl J Med. 2011;365: Lancet Aug 7;354(9177): N Engl J Med 2013;368(19): N Engl J Med. 2010;362: N EnglJ Med. 2015;372: