Dyslipedemia New Guidelines New ACC/AHA Prevention Guidelines on Blood Cholesterol November 12, 2013 Mohammed M Abd El Ghany Professor of Cardiology Cairo Universlty 1
1 0 Cholesterol Management Pharmacotherapy Therapy TC LDL-C HDL-C TG Patient tolerability Statins* 19 37% 25 50% 4 12% 14 29% Good Ezetimibe 13% 18% 1% 9% Good Bile acid sequestrants 7 10% 10 18% 3% Neutral or Poor Nicotinic acid 10 20% 10 20% 14 35% 30 70% Reasonable to poor Fibrates 19% 4 8% 11 13% 30% Good TC = Total cholesterol, LDL-C = Low-density lipoprotein cholesterol, HDL-C = Highdensity lipoprotein cholesterol, TG = Triglycerides *Daily dose of 40 mg of each drug, excluding rosuvastatin Yeshurun D et al. South Med J 1995;88:379 391. NCEP. Circulation 1994;89:1333 1445. Knopp RH. N Engl J Med 1999;341:498 511. Gupta EK et al. Heart Dis 2002;4:399 409. A log-linear relationship exists between LDL levels and relative risk for CHD suggesting that for every 30 mg/dl change in LDL- C, the relative risk for CHD is changed in proportion by about 30%. 3.7 Relative Risk for CHD (Log Scale) 2.9 2.2 1.7 1.3 1.0 40 70 100 130 160 190 LDL-C (mg/dl) Grundy SM et al. Circulation 2004;110:227 239. 2
Event (%) Impact of Statins: Secondary Prevention Relationship between LDL-C Levels and Event Rates in Secondary Prevention Trials of Patients with Stable CHD 30 25 20 Statin Placebo 4S 4S 15 10 5 LIPID LIPID CARE CARE HPS HPS TNT (atorvastatin 10 mg/d) TNT (atorvastatin 80 mg/d) 0 3 70 90 110 130 150 170 190 LDL-C (mg/dl) LDL-C=low-density lipoprotein cholesterol; CHD=coronary heart disease; TNT=Treating to New Targets; HPS=Heart Protection Study; CARE=Cholesterol and Recurrent Events Trial; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study. LaRosa et al. N Engl J Med 2005;352:1425 1435. 210 3
Multivariate hazard ratio for predictors of mortality in post MI patients Statin treatment initiated early in the postinfarction period for patients with acute myocardial infarction. Early statin treatment following acute myocardial infarction and 1-year survival. JAMA 2001;285:430 436 4
Intensive LDL-C Goals for High Risk Patients ATP III Update 2004 1 Recommended LDL-C treatment goals <100 mg/dl: Patients with CHD or CHD risk equivalents (10 year risk >20%) 1 <70 mg/dl: Therapeutic option for very high risk patients 1 <100 mg/dl <70 mg/dl AHA/ACC guidelines for patients with CHD *,2 <100 mg/dl: Goal for all patients with CHD,2 <70 mg/dl: A reasonable goal for all patients with CHD 2 2006 Update If it is not possible to attain LDL-C <70 mg/dl because of a high baseline LDL-C, it generally is possible to achieve LDL-C reductions of >50% with more intensive LDL-C lowering therapy, including drug combinations. *And other forms of atherosclerotic disease. 2 Factors that place a patient at very high risk: established cardiovascular disease plus: multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (e.g., cigarette smoking); metabolic syndrome (triglycerides 200 mg/dl + non HDL-C 130 mg/dl with HDL-C <40 mg/dl); and acute coronary syndromes. 1 1. Grundy SM et al. Circulation 2004;110:227 239. 2. Smith SC Jr et al. Circulation 2006; 113:2363 2372. Stone NJ, et al. Ann Intern Med. 2014 Jan 28. [Epub ahead of print] 5
Encourage adherence to a healthy lifestyle. A healthy lifestyle is the foundation for cardiovascular health. for a diet that is low in saturated fat, trans fat and sodium; a) Emphasizes vegetables,fruits, whole grains, low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts. b) Limits sweets, sugar-sweetened beverages, and red meats. c) Engage in regular aerobic physical activity. Maintain a healthy body weight. Avoid smoking. Control hypertension and diabetes when present. Stone NJ, et al. Ann Intern Med. 2014 Jan 28. [Epub ahead of print] 6
Statin therapy is recommended for adults in groups demonstrated to benefits Strong RCT evidence shows that reduction in ASCVD events from statin therapy exceeds adverse events for 4 patient groups: I. those with clinical ASCVD (acute coronary syndromes, myocardial infarction, stable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease of atherosclerotic origin) when statins are used for secondary prevention. II. III. IV. those with LDL-C levels of 190 mg/dl or greater. those aged 40 to 75 years with diabetes and LDL-C levels of 70 to 189 mg/dl. those aged 40 to 75 years without diabetes and with a 10-year ASCVD risk of 7.5% or greater when statins are used for primary prevention. ASCVD: Atherosclerotic Cardiovascular Disease Stone NJ, et al. Ann Intern Med. 2014 Jan 28. [Epub ahead of print] Statins have an acceptable margin of safety when used in properly selected individuals and appropriately monitored (1/2) Strong RCT evidence supports safety of statins when they are used as directed in conjunction with regular follow-up assessments in properly selected patients. Adjustment of statin intensity is recommended in: a) Individuals older than 75 years with a history of statin intolerance or other characteristics b) Individuals receiving drug therapy that may increase statin adverse events. Routine monitoring of hepatic enzymes level or creatine kinase level is not recommended unless clinically indicated by symptoms suggesting hepatotoxicity or myopathy. RCT: Randomized Controlled Trials Stone NJ, et al. Ann Intern Med. 2014 Jan 28. [Epub ahead of print] 7
Use the Newly Developed Pooled Cohort Equations for Estimating 10-Year ASCVD Risk The Pooled Cohort Equations are currently the best available method for estimating 10-year ASCVD risk to guide statin initiation. Application of the inclusion and exclusion criteria from RCTs is cumbersome and results in under-identifying high-risk and over-identifying low-risk individuals for statin treatment. Stone NJ, et al. Ann Intern Med. 2014 Jan 28. [Epub ahead of print] URL: http://clincalc.com/cardiology/ascvd/pooledcohort.aspx 8
Initiate the Appropriate Intensity of Statin Therapy Statin Therapy High-, Moderate-, and Low-Intensity Statin Therapy High-Intensity Daily Dose Moderate- Intensity Atorvastatin 40 80 mg 10 (20) mg Rosuvastatin 20 (40) mg (5) 10 mg Low-Intensity Simvastatin 20 40 mg 10 mg Pravastatin 40 (80) mg 10 20 mg Lovastatin 40 mg 20 mg Fluvastatin Fluvastatin 80 mg (Fluvastatin XL) 40 mg 20 40 mg Pitavastatin 2 4 mg 1 mg Stone NJ, et al. Ann Intern Med. 2014 Jan 28. [Epub ahead of print] Initiate the Appropriate Intensity of Statin Therapy (2/2) The appropriate intensity of statin therapy should be used to reduce ASCVD risk and minimize adverse effects. High intensity statins (LDL-C level decreased by 50%) are recommended for: a) Adults aged 75 years or younger who have clinical ASCVD and no safety concerns. b) Individuals with LDL-C levels of 190 mg/dl or greater. c) Individuals with or without diabetes who have a 10-year ASCVD risk of 7.5% or greater. Moderate-intensity statins (LDL-C level decreased by 30% to 50%) are recommended for: a) Adults aged 75 years or younger who have clinical ASCVD and safety concerns. b) Individuals older than 75 years with clinical ASCVD. c) Primary prevention in patients with LDL-C levels less than 190 mg/dl. Low intensity statin therapy may be used when high- or moderateintensity statins are not tolerated. ASCVD: Atherosclerotic Cardiovascular Disease Stone NJ, et al. Ann Intern Med. 2014 Jan 28. [Epub ahead of print] 9
Evidence is Inadequate to Support Treatment to Specific LDL-C or Non HDL-C Goals RCT trials did not compare titration to different LDL-C goals. Treating to goal may result in treatment with less-thanoptimum statin intensity or adding non-statin therapy in the absence of RCT evidence that combination therapy improves outcomes. RCT: Randomized Controlled Trials Stone NJ, et al. Ann Intern Med. 2014 Jan 28. [Epub ahead of print] Regularly Monitor Patients for Adherence to Lifestyle and Statin Therapy A fasting lipid panel is needed after initiation of or changes in statin or other drug therapy. Percentage reductions in LDL-C level should not be used as treatment goals or performance measures but should be used to assess and provide feedback to promote adherence to healthy lifestyle behaviors and statin therapy. Safety measurements should be assessed as clinically indicated. Stone NJ, et al. Ann Intern Med. 2014 Jan 28. [Epub ahead of print] 10
In persons unable to tolerate the recommended intensity of statin therapy, use the maximally tolerated intensity of statin. If there are muscle or other symptoms, establish their relationship to statin therapy (class IIa, level B) Obtain a history of muscle symptoms before initiating statin therapy. If muscle or other symptoms develop during statin therapy, discontinue the statin. Once mild to moderate muscle or other symptoms resolve, rechallenge with the same dose of statin or lower; if muscle symptoms recur, discontinue statin and rechallenge with progressively lower doses of the same or a different statin. If muscle symptoms persist 2 mo after statin discontinuation, consider other conditions that may increase the risk for muscle symptoms Stone NJ, et al. Ann Intern Med. 2014 Jan 28. [Epub ahead of print] 11
Statins Beyond Lipid Lowering Endothelial normalization Anti-inflammatory effects Depletion & stability of lipid core Strengthening of fibrous cap Inhibition of platelet thrombus formation Reduction of thrombogenic response 12
STATINS PREVENTION OF ACUTE CORONARY SYNDROMES Prevention of plaque rupture Prevention of thrombosis Statins :Change in Plaque Character Plasma LDL-C LDL-C entry Esterification Smaller lipid core More solid plaque 13
Cardiology Department Cairo University Intravascular Ultrasound Statins Initial study Six months STATINS Anti-inflammatory Effects Inflammatory cells in active plaque Monocyte adhesion to Endothelial cells 14
EFFECTS OF STATIN THERAPY ON HS-CRP LEVELS. Aggressive Lipid Lowering Jilal et al. Circulation April 2001 15
STATINS ANTITHROMBOTIC EFFECTS Tissue factor Expression Platelet aggregration PAI-1 16
Statins therapy reduces CVD risk more than BP lowering therapy Ebrahim S, et al. BMJ. 2014 Jan 27;348:g280 Statins, What is behind the pleiotropic effects??? Unique ability to reduce oxidative stress in various tissue and cell types in the cardiovascular system, and this is believed to be a key mechanism by which they reduce cardiovascular risk. Individual sources of reactive oxygen species in the human vascular endothelium (such as NADPH-oxidase and uncoupled endothelial nitric oxide synthase (enos)). Statins appear to modify both. Antoniades C, et al. Antioxid Redox Signal. 2014 Jan 11. [Epub ahead of print] 17
Statins, What is behind the pleiotropic effects. Indeed, LDL supresses NO bioavailability in the vascular endothelium by affecting enos gene expression and enzymatic activity, partly via caveoline-1-dependent mechanisms. Antoniades C, et al. Antioxid Redox Signal. 2014 Jan 11. [Epub ahead of print] 18
atorvastatin 80 mg or rosuvastatin 20 mg Tentzeris I, et al. Am J Cardiol. 2014 Jan 14. pii: S0002-9149(14)00038-1. [Epub ahead of print] High Dose Statins Significantly Reduce Mortality vs. Low Dose or No Statins Tentzeris I, et al. Am J Cardiol. 2014 Jan 14. pii: S0002-9149(14)00038-1. [Epub ahead of print] 19
High Dose Statins Significantly Reduce Mortality vs. Low Dose or No Statins in Diabetics Tentzeris I, et al. Am J Cardiol. 2014 Jan 14. pii: S0002-9149(14)00038-1. [Epub ahead of print] JUPITER Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin 20
JUPITER - Objective The primary objective was to investigate whether long-term treatment with rosuvastatin 20 mg decreases the rate of first major cardiovascular events compared with placebo in patients with low to normal LDL-C but at increased cardiovascular risk as identified by elevated CRP levels Ridker PM. Circulation 2003; 108: 2292 2297 For complete therapeutic and safety information please consult the CRESTOR Product Monograph. JUPITER - Patient Flow 89,890 subjects screened 17,802 randomized Rosuvastatin 20mg n=8,901 Placebo n=8,901 Lost to follow up n=44 Lost to follow up n=37 Completed study n=8,857 Completed study n=8,864 Ridker P et al. N Eng J Med 2008;359: 2195-2207 For complete therapeutic and safety information please consult the CRESTOR Product Monograph. 21
Percent total mortality Percent of patients with primary endpoint JUPITER - Primary Endpoint Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or arterial revascularization 9 8 7 6 5 4 3 2 1 0 Hazard Ratio 0.56 (95% CI 0.46-0.69) P<0.00001 Placebo 0 1 2 3 4 5 Years Number at risk RSV 8901 8412 3893 1353 538 157 Placebo 8901 8353 3872 1333 531 174 *Extrapolated figure based on Altman and Andersen method Rosuvastatin 20 mg NNT for 2y = 95 5y* = 25 Ridker P et al. N Eng J Med 2008;359: 2195-2207 JUPITER - Total Mortality Death from any cause 7 6 Hazard Ratio 0.80 (95% CI 0.67-0.97) p=0.02 Placebo 5 Rosuvastatin 20mg 4 3 2 1 0 0 1 2 3 4 5 Number at risk Years RSV 8901 8787 4312 1602 676 227 Placebo 8901 8775 4319 1614 681 246 Ridker P et al. N Eng J Med 2008;359: 2195-2207 For complete therapeutic and safety information please consult the CRESTOR Product Monograph. 22
JUPITER summary and perspectives A 44% reduction in the primary endpoint of major cardiovascular events (composite of: CV death, MI, stroke, unstable angina, arterial revascularisation) was observed in patients who received rosuvastatin 20 mg compared with placebo (p< 0.00001) A 20% reduction in total mortality was observed in patients who received rosuvastatin 20 mg compared with placebo (p=0.02), a unique finding for statins in a population without established CHD Ridker P et al. N Eng J Med 2008;359: 2195-2207 23
Recommendations 1. Encourage adherence to a healthy lifestyle. 2. Statin therapy is recommended for adults in groups demonstrated to benefits. 3. Statins have an acceptable margin of safety when used in properly selected individuals and appropriately monitored. 4. Engage in a clinician patient discussion before initiating statin therapy, especially for primary prevention in patients with lower ASCVD risk. ASCVD: Atherosclerotic Cardiovascular Disease Stone NJ, et al. Ann Intern Med. 2014 Jan 28. [Epub ahead of print] Recommendations (cont.) 5. Use the newly developed pooled cohort equations for estimating 10-year ASCVD risk. 6. Initiate the appropriate intensity of statin therapy. 7. Evidence is inadequate to support treatment to specific LDL-C or non HDL-C goals. 8. Regularly monitor patients for adherence to lifestyle and statin therapy. ASCVD: Atherosclerotic Cardiovascular Disease Stone NJ, et al. Ann Intern Med. 2014 Jan 28. [Epub ahead of print] 24
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