Introduction. Objective. Critical Questions Addressed

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3 Introduction Objective To provide a strong evidence-based foundation for the treatment of cholesterol for the primary and secondary prevention of ASCVD in women and men Critical Questions Addressed CQ1: What is the evidence for LDL C and non-hdl C goals for the secondary prevention of ASCVD? CQ2: LDL C and Non-HDL C Goals in Primary Prevention CQ3: For primary and secondary prevention, what is the impact on lipid levels, effectiveness, and safety of specific cholesterol-modifying drugs used for lipid management in general and in selected subgroups?

4 Key Findings RCTs indicated a consistent reduction in ASCVD events from statin therapy in both secondary and primary prevention Relative reduction in ASCVD risk is consistent for primary and secondary prevention and for various patient subgroups Absolute reduction in ASCVD events is proportional to baseline absolute ASCVD risk Statin therapy reduces ASCVD events across the spectrum of baseline LDL C levels >70 mg/dl Extent of relative-risk reductions for ASCVD is proportional to the degree of LDL C lowering observed on statin therapy. Therefore, more intensive statin therapy could reduce risk more than moderate-or lower-intensity statin therapy No ASCVD event reduction in those with New York Heart Association (NYHA) class II-IV heart failure Receiving maintenance hemodialysis

5 Key Findings NO RCT evidence to support titrating cholesterol-lowering drug therapy to achieve target LDL C or non-hdl-c levels As per the ATP III guidelines: Clinicians use targets such as LDL C <70 mg/dl and LDL C <100 mg/dl for secondary and primary ASCVD prevention (non-hdl C targets are 30 mg/dl higher) without hard evidence No evidence to support addition of non-statin hypolipidemics for CV risk reduction Available RCT evidence indicates a clear net absolute benefit of initiation of moderate-to-intensive statin therapy at a baseline estimated 10-year ASCVD risk of 7.5%. When baseline ASCVD risk is 5.0% to <7.5%, there is still net absolute benefit with moderate-intensity statin therapy. A risk-benefit discussion is even more important for individuals with this range of ASCVD risk The net benefit of high-intensity statin therapy appears to be marginal in such individuals.

6 Key Findings In adults with and without CHD/CVD who received more intensive compared to less intensive statin therapy or placebo, relative risk reductions per 1 mmol/l (38.7 mg/dl) LDL C reduction were: For major coronary events: 24% For nonfatal myocardial infarction: 27% Total mortality: 10% per 1 mmol/l Risk for CVD mortality: 14% For coronary revascularization: 24% 23% to 28% relative reductions in CVD risk per 39 mg/dl (1 mmol/l) reduction in LDL C were observed after 1 year to beyond 5 years of statin treatment

7 Recommendations High-intensity statin therapy Lowers LDL C by approximately 50% Indications: Secondary prevention in patients <75 years age LDL-C 190 mg/dl at baseline Diabetics y with LDL C 70 to189 mg/dl and without clinical ASCVD but with estimated 10- year ASCVD risk of 7.5% Non-diabetics y with estimated 10-year ASCVD risk of 7.5% Moderate-intensity statin therapy Lowers LDL C by approximately 30% to <50% Indication: Secondary prevention in patients <75 years age or those not tolerating high doses of statins LDL-C 190 mg/dl at baseline in those not tolerating high doses of statins All diabetics y with LDL C 70 to189 mg/dl and without clinical ASCVD Non-diabetics y with estimated 10 year ASCVD risk of 7.5%

8 Intensity of Statin Therapy High-Intensity Statin Therapy Daily dose lowers LDL-C on average, by approximately 50% Atorvastatin (40 ) 80 mg Rosuvastatin 20 (40) mg Moderate-Intensity Statin Therapy Daily dose lowers LDL-C on average, by approximately 30% to <50% Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin mg Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2-4 mg Low-Intensity Statin Therapy Daily dose lowers LDL-C on average, by <30% Simvastatin 10 mg Pravastatin mg Lovastatin 20 mg Fluvastatin mg Pitavastatin 1 mg Specific statins and doses are noted in bold that were evaluated in Statins and doses that are approved by the U.S. FDA but were not tested in the RCTs reviewed are listed in italics. Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.

9 What s New in the Guideline Focus on ASCVD Risk Reduction: 4 statin benefit groups A New Perspective on LDL C and/or Non-HDL C Treatment Goals Global Risk Assessment for Primary Prevention Safety Recommendations

10 4 Statin Benefit Groups 1. Patients with clinical ASCVD 2. Primary elevations of LDL C >190 mg/dl 3. Diabetics aged 40 to 75 years with LDL C 70 to189 mg/dl and without clinical ASCVD, or 4. Without clinical ASCVD or diabetes with LDL C 70 to189 mg/dl and estimated 10-year ASCVD risk >7.5% Treatment decisions in selected individuals who are not included in the 4 statin benefit groups may be informed by other factors as recommended by the Risk Assessment Work Group guideline.

11 Patients with Clinical ASCVD Clinical ASCVD: Acute coronary syndromes, History of MI, Stable or unstable angina, Coronary or other arterial revascularization, Stroke or TIA, Peripheral arterial disease presumed to be of atherosclerotic origin Recommendations: In women and men 75 years of age High-intensity statin therapy as first-line therapy, unless contraindicated In individuals with clinical ASCVD >75 years of age Evaluate the potential for ASCVD risk-reduction benefits and for adverse effects, drug-drug interactions and consider patient preferences, when initiating a moderateor high-intensity statin. It is reasonable to continue statin therapy in those who are tolerating it When either high-intensity statin therapy is contraindicated or when characteristics predisposing to statin-associated adverse effects are present, moderate-intensity statin should be used as the second option, if tolerated

12 Primary Prevention in Adult 21 Years with LDL C 190 mg/dl 10-year ASCVD risk estimation is not required Observational data has shown significant reductions in ASCVD events without achieving specific LDL C targets Recommendations Use high-intensity statin therapy unless contraindicated For individuals unable to tolerate high-intensity statin therapy, use the maximum tolerated statin intensity After the maximum intensity of statin therapy has been achieved, addition of a non-statin drug may be considered to further lower LDL C Evaluate the potential for ASCVD risk reduction benefits, adverse effects, drug-drug interactions, and consider patient preferences

13 Diabetics aged 40 to 75 years with LDL C 70 to 189 mg/dl and without clinical ASCVD In adults with diabetes without CVD, moderate-dose statin therapy, compared with placebo/control, reduced the RR for CVD events by 27% per 38.7 mg/dl LDL C reduction In adults aged 40 to 75 years with diabetes and >1 risk factor, fixed moderate-dose statin therapy that achieved a mean LDL C 72 mg/dl reduced the RR for CVD by 37% Diabetics often have lower LDL C levels than those without diabetes "Goal" directed therapy often encourages use of a lower statin dose than is supported by the RCTs Non-statin drugs may be added to address low HDL C or high triglycerides, for which RCT evidence of an ASCVD event reduction is lacking

14 Diabetics aged 40 to 75 years with LDL C 70 to 189 mg/dl and without clinical ASCVD Recommendations Giving a maximally-tolerated statin intensity should receive primary emphasis Moderate-intensity statin therapy should be initiated or continued for adults 40 to 75 years of age with diabetes mellitus High-intensity statin therapy is reasonable for adults 40 to 75 years of age with diabetes mellitus with a 7.5% estimated 10- year ASCVD risk unless contraindicated. In adults with diabetes mellitus, who are <40 or >75 years of age Evaluate the potential for ASCVD benefits and for adverse effects, for drugdrug interactions, and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy

15 Primary Prevention in Individuals without Diabetes Mellitus & With LDL C 70 to 189 mg/dl In men and postmenopausal women aged 40 to 75 years without CHD/CVD, moderate-dose statin therapy reduces the RR for CVD by 24 25% compared with placebo For those with a 5% to <7.5% estimated 10-year ASCVD risk Potential for adverse effects may outweigh the potential for ASCVD risk reduction benefit when high-intensity statin therapy is used in this risk group With moderate-intensity statin therapy the ASCVD risk reduction clearly exceeds the potential for adverse effects. In individuals 40 to 75 years of age with <5% estimated 10-year ASCVD risk, the net benefit from statin therapy over a 10-year period may be small. Additional factors may also be considered to inform treatment decision No primary prevention RCT data available for individuals 21 to 39 years of age and few data were available for individuals >75 years of age.

16 Primary Prevention in Individuals without Diabetes Mellitus & With LDL C 70 to 189 mg/dl Recommendations: Pooled Cohort Equations should be used to estimate 10-year ASCVD risk If estimated 10-year ASCVD risk 7.5% treat with moderate- to high-intensity statin therapy It is reasonable to offer treatment with a moderate-intensity statin if estimated 10-year ASCVD risk is 5% to <7.5% In adults with LDL C <190 mg/dl who are not otherwise identified in a statin benefit group, or for whom after quantitative risk assessment a risk- based treatment decision is uncertain, additional factors may be considered to inform treatment decision making. These factors may include primary LDL C >160 mg/dl or other evidence of genetic hyperlipidemias, family history of premature ASCVD with onset <55 years in a first degree male relative or <65 years in a first degree female relative, high sensitivity-creactive protein >2 mg/l, CAC score 300 Agatston units or 75 percentile for age, sex, and ethnicity, ABI <0.9, or lifetime risk of ASCVD.

17 Individuals >75 Years of Age A larger amount of data supports the use of moderateintensity statin therapy for secondary prevention in individuals with clinical ASCVD >75 years of age. Initiation of statins for primary prevention of ASCVD in individuals >75 years of age requires consideration of additional factors, including increasing comorbidities, safety considerations, and priorities of care A discussion of the potential ASCVD risk reduction benefits, risk of adverse effects, drug-drug interaction, and patient preferences precede the initiation of statin therapy for primary prevention in older individuals.

18 New LDL C and/or Non-HDL C Treatment Goals LDL-C lowering provides benefit irrespective of baseline levels Lack of RCT evidence to support continued use of specific LDL C and/or non- HDL C treatment targets RCTs either compared fixed doses of statins with placebo or untreated controls, or compared fixed doses of higher-intensity statins with moderateintensity statins Benefit : Risk ratio not in favor of prescribing non-statin therapy to achieve treatment gaols Non-statin therapies do not provide acceptable ASCVD risk reduction benefits AIM-HIGH demonstrated the futility of adding niacin in individuals with low HDL C and high triglycerides, and ACCORD demonstrated the futility of adding fenofibrate in persons with diabetes

19 New LDL C and/or Non-HDL C Treatment Goals Use of LDL C targets may result in under-treatment with evidencebased statin therapy or overtreatment with nonstatin drugs that have not been shown to reduce ASCVD events in RCTs (even though the drug may additionally lower LDL C and/or non-hdl C) Implications of treating to an LDL C goal may mean that a suboptimal dose of statin is used because the goal has been achieved, or that adding a non-statin therapy to achieve a specific target results in down-titration of the evidence-based dose of statin for safety reasons Appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit

20 Global Risk Assessment for Primary Prevention Estimated absolute 10-year risk of ASCVD (defined as nonfatal MI, CHD death, nonfatal and fatal stroke) should be used to guide the initiation of statin therapy Pooled Cohort Equations to be used for estimating 10-year ASCVD risk Applicable to African-American and non-hispanic white men and women 40 through 79 years of age with or without diabetes who have LDL C levels 70 to 189 mg/dl May underestimate the risk for persons from some race/ethnic groups, especially American Indians, some Asian Americans (e.g., of south Asian ancestry), and some Hispanics (e.g., Puerto Ricans) May overestimate the risk for others, including some Asian Americans (e.g., of east Asian ancestry) and some Hispanics (e.g., Mexican Americans). For those with clinical ASCVD or with LDL C 190 mg/dl who are already in a statin benefit group, it is not appropriate to estimate 10-year ASCVD risk

21 Benefit: Risk Analysis Potential ASCVD risk reduction benefits Relative risk reduction of ~30% for moderate-intensity statin or ~45% for high-intensity statin therapy. Potential adverse effects. Excess risk of diabetes 1 year incidence of new onset diabetes: ~0.1 excess case per 100 individuals with moderate-intensity statin ~0.3 excess cases per 100 individuals with high-intensity statin Long-term adverse effects of statin-associated cases of diabetes over a 10-year period are unclear and are unlikely to be equivalent to an MI, stroke, or ASCVD death Myopathy (~0.01 excess case per 100) and hemorrhagic stroke (~0.01 excess case per 100) make minimal contributions to excess risk from statin therapy

22 Important Considerations Asian ancestry may also influence the initial choice of statin intensity Decreasing the statin dose may be considered when 2 consecutive values of LDL C are <40 mg/dl. However, no data was identified that suggests an excess of adverse events occurred when LDL C levels were below this level. Those who develop diabetes during statin therapy should be encouraged to adhere to a heart healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce their risk of ASCVD events. Do an initial fasting lipid panel (total cholesterol, triglycerides, HDL C, and calculated LDL C), followed by a second lipid panel 4 to 12 weeks after initiation of statin therapy and then every 3 to 12 months as clinically indicated. Statins used in combination with other cholesterol-lowering drug therapies might require more intensive monitoring.

23 Grey Areas Pooled Cohort Equations not validated for Indians May underestimate the ASCVD risk Recommendations may not apply to non-diabetic Indians with LDL-C between mg/dl Lack of clarity on younger adults (<40 years of age) who have a low estimated 10-year ASCVD risk, but a high lifetime ASCVD risk based on single strong factors or multiple risk factors

24 Statin use in Heart Failure & Hemodialysis

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26 Intensive Statin Therapy

27 % reduction in MACE Reduction in MACE with Statins S LIPID CARE HPS WOSCOPS AFCAPS ASCOT-LA JUPITER Enas EA. How to beat the heart disease epidemic among South Asians. Downers Grove, 2005

28 Benefits Intensive Statin Therapy Trials using Atorvastatin 80 mg/d in Randomized Placebo Controlled Study # of subjects Treatment (mg/d) Decrease in LDL-C AVERT (2000) 314 x 18M Atorvastatin 80 * >115 mg/dl 36% Decrease in MACE MIRACLE (2001) 3,086 X 4M Atorvastatin 80* mg/dl 26% ALLIANCE (2004) 2,442 x 53M Atorvastatin 80* mg/dl 17% PROVE-IT (2004) 4,162 x 24M Atorvastatin 80* mg/dl 16% REVERSAL (2005) 654 x18m Atorvastatin 80* mg/dl IDEAL (2005) 8,888 x 56 M TNT (2005) 10,001 x 53 Atorvastatin 80 vs. simvastatin 20 Atorvastatin 80 vs. 10 mg mg/dl 13% < mg/dl Halted progression of atherosclerosis 22% SPARCLE (2006) 4,071 x 57M Atorvastatin 80* mg/dl SAGE (2007) 893 Atorvastatin 80* NA 26% Stroke 16-31% 29; 67% in death * Placebo controlled Enas EA, CSI Cochin, Cardiology Update 2009

29 Meta-analysis trials comparing intensive versus moderate statin therapy LDL changes Baseline Standard therapy Intensive therapy TNT PROVE IT-TIMI IDEAL A-to-Z Pooled Cannon CP. J Am Coll Cardiol 2006;48:438-45

30 Risk reduction vs. Atorvastatin 10 mg (%) TNT: Atorvastatin 80 mg vs.10 mg Reduces Cardiovascular Risk 0 Nonfatal MI Fatal and nonfatal stroke Revasc Hospitalization for CHF Angina % P= % P= % P=.02 28% P< % P=.01 Incremental risk reductions vs. Atorvastatin 10 mg Previously, in ASCOT-LLA, Atorvastatin 10 mg significantly reduced risk of MI, stroke, revascularization, and angina in primary prevention patients 1 1. Sever PS, et al. Lancet. 2003;361: LaRosa JC, et al. N Engl J Med. 2005;352:

31 Meta-analysis trials comparing intensive versus moderate statin therapy Risk of ALT and or AST >10 x ULN* Trial Standard dose ALT and or AST >10 x ULN High dose TNT 0.18% 1.2% PROVE IT-TIMI % 3.3% IDEAL 0.16% 1.37% A-to-Z 0.36% 0.84% *Cannon CP. J Am Coll Cardiol 2006;48:438-45

32 Efficacy and Safety of Statin Treatment: A Prospective Meta-analysis of Data from 90,056 Participants in 14 Randomised Trials A 40 mg/dl increase in LDL-C or non-hdl-c confer a 40% increase in CVD risk beginning with an LDL of 40 mg/dl A 40 mg/dl reduction in LDL-C statin therapy safely reduces the 5-year incidence of MACE ( major adverse CVD events such as MI stroke, CVD deaths ) and CARP (coronary artery revascularization procedures) by 20%, irrespective of the initial lipid profile. The reduction in MACE will be higher with greater LDL-C reduction (see next slide) The absolute benefit relates chiefly to an individual's absolute risk of such events and to the absolute reduction in LDL-C achieved. Baigent C. Lancet 2005;366:

33 Reduction in MACE from Lowering LDL-C with Statins for 5 years in 1000 Patients Major Cardiovascular Events* Secondary prevention Primary prevention LDL-C reduction RRR ARR RRR ARR 40 mg/dl 20% 48/ % 25/ mg/dl 40% 96/ % 50/ mg/dl 60% 144/ % 75/ mg/dl 80% 192/ % 100/1000 * Includes coronary artery revascularization procedures Baigent C. Lancet 2005;366:

34 % of patients TNT Study Post Hoc Analysis: Rates of MACE According to the Achieved LDL Quintiles P=< Q1(54) Q2((70) Q3 (83) Q4 (97) Q5 (122) (Mean LDL-C in mg/dl) MACE = Major Acute Cardiovascular Events Larosa JC. Am J Cardiol 2007;100:

35 TNT Study Post Hoc Analysis No. patients Quintiles Range Mean +SD Atorva 10 mg Atorva 80 mg Total 1 < , < ,403 1, < , , < , ,030 5 > , ,984 Larosa JC. Am J Cardiol 2007;100:

36 Can LDL-C be too low? Benefits of Aggressive versus Modest LDL-C Reduction in the PROVE-IT Study Achieved LDL (mg/dl) Risk reduction CI (Referent) 1 > % > % <40 39% Viviott SD. J Am J cardiol 2005;46:1411

37 Statin Safety: Muscle Toxicity Myopathy is a general term for all potential muscle problems Symptomatic myopathy- refers to all complaints referable to skeletal muscle and include cramps, pain, or weakness Asymptomatic myopathy- refers to CK elevation without complaints referable to skeletal muscle Clinically important rhabdomyolysis refers to muscle symptoms with CK elevation with change in renal function Mild CK elevation- <10 times ULN Moderate CK elevation- >10 times but <50 times ULN Severe CK elevation- >50 times ULN Thompson PD. Am J Cardiol 2006;97:69C-76C.

38 Not All Statins Are Created Equal Atorvastatin has been studied most extensively at doses ranging from 10 mg to 80 mg, for safety, efficacy and outcome Greater benefits at higher doses (80 mg/dl) clearly demonstrated with atorvastatatin Atorvastatin studies led to changes in NCEP guidelines Atorvastatin has received approval from US FDA for primary and secondary prevention

39 Side Effects of Intensive Statin Therapy Trials using Atorvastatin 80 mg/d Trial # of subjects and follow-up ALT/AST >3 x ULN CK>3 x ULN Newman et al 2000) 4,798 (variable) 26 (0.6%) 2 (0.06%) PROVE-IT (2004) 2,099 for 2 years 20 (0.6%) NA TNT (2005) 4,995 x 4.9 years 60 (1.2%) 0 IDEAL (2005) 4,439 x (1.38%) 0 SPARCLE (2006) 2,365 x 4.9 years 51 (2.2%) 2 (0.08%) Total atorvastatin 18, (1.43%) 4 (0.024%) Enas EA, CSI Cochin, Cardiology Update 2009

40 How safe is Intensive statin Therapy? 100 times safer than diabetic medications! 100 times safer than low-dose Aspirin!!

41 When Does the Benefit Outweigh the Risk of Aspirin in Primary Prevention? MEN WOMEN Age group 10- year risk of MI is 10- year risk of Stroke is years 4% 3% years 9% 8% years 12% 11% USPSTF. Ann Intern Med 2009;150:

42 Key Points (1) Efficacy The optimum LDL-C is currently standardized at 40 mg/dl For every 1 mg/dl increase from 40 mg/dl, confers a 1% higher risk for CVD; those with 70 mg/dl have a 30% higher risk compared to people with optimum LDL-C Regression of atherosclerosis requires an LDL-C <70 mg/dl, non-hdl-c <100 mg/dl and a systolic blood pressure <115 mm Hg The LDL-C target is <100 mg/dl for Asian Indians and <70 mg/dl for those with CVD, diabetes, metabolic syndrome and chronic kidney disease Intensive statin therapy may be often required to achieve these goals Intensive LDL-C lowering yields superior benefits than moderate lowering The CVD risk reduction is directly proportional to the absolute reduction in LDL- C and not the statin dose; A 50 mg/dl reduction in LDL-C and/or non-hdl-c confers a 50% reduction in CVD after 5 years of treatment.

43 Key Points (2) Remarkable Safety Asymptomatic transaminase elevations are not associated with an increased risk of liver disease or hepatotoxicity The risk of significant transaminase elevation with atorvastatin 80mg is 1.4% compared to 5.3% for fenofibrate The risk of liver failure with statin therapy is one in a million essentially same as the general population The risk of muscle toxicity is low 3 fatal and 30 non-fatal rhabdomyolysis cases per million person-years Statin toxicity is not related to the LDL-lowering efficacy Statin toxicity is driven by the blood concentrations of the statin, which in turn may be related to the dose of the specific statin used, drug interactions and or genetic susceptibility More than 80% of statin associated myopathy is attributable to concomitant use of fibrates or CPY3A4 inhibitors

44 Key Points (3) Comparison of High-dose Statins Toxicity varies among high doses of different statins The risks outweighs the benefits for simvastatin 80 mg; compared with 40 mg/d simvastatin 80 mg is associated with 700% increase in myopathy only a 7% additional LDL-C reduction. The JUPITER Trial has demonstrated the benefits and safety of lowering LDL-C rosuvastatin 20 mg/d to <55 mg/dl in nearly 5,000 patients and <40 mg/dl in 2,500 patients. Atorvastatin 80 mg /d reduces the risk of MI stroke, heart failure, and CARPs by about 25%, compared with atorvastatin 10 mg/d, with minimal risk AST/ALT >3x ULN - 1.4%; CK >10x ULN % Intensive statin therapy with Atorvastatin 80 mg/day or Rosuvastatin 20mg/day appears be 100 times safer than 81 mg /d of aspirin, which has a significant risk of GI bleeding requiring transfusion (1-3%) and hemorrhagic stroke (0.01%).

45 Key Points (4) Statins for High TG and Diabetes Non-HDL-C is a better predictor of CVD risk than LDL-C in patients with high TG, which spuriously lowers LDL-C The non-hdl-c targets is set at 30 mg/dl higher than the LDL-C target Intensive statin therapy can lower non-hdl-c by >50% (the same magnitude as LDL-C reduction) in patents with high TG. Intensive statin therapy is more effective than fibrates in lowering non- HDL-C Reducing non-hdl-c by 50% reduces the CVD risk by 50 % but lowering TG has not been shown to reduce CVD risk to-date Among patients with diabetics, statin therapy would prevent 9,250 MACE per million person-years of therapy in primary prevention, with minimal risk.

46 Key Points (5) Use of Statin Ahead of Aspirin in Primary Prevention In primary prevention, the benefits outweighs the risk for statins but for aspirin, the risks and benefits balances each other or may be even harmful. The benefit of aspirin in primary prevention of CVD in patients with diabetes is very small and risk high For every CVD event prevented with aspirin, one major GI bleeding is produced The risk benefit analysis supports the use of statin far ahead of aspirin in primary prevention of CVD Physicians should recognize and communicate to their patients that treatment of chronic conditions like high cholesterol and high blood pressure is lifelong.

47 High-Dose Atorvastatin Safety and benefits established for 80 mg/dl dose in more than 15,000 subjects High-dose atorvastatin therapy is more effective than usual dose therapy in lowering LDL-C and MACE In a person with an LDL-C 220 mg/dl, an 80 mg dose can decrease LDL-C by 120 mg/dl (55%) with a resultant 60% reduction in CVD risk in 5 years No increase in muscle toxicity with higher doses

48 Efficacy and Safety of Statin Treatment: Prospective Meta-analysis of Data from 90,056 Participants in 14 Randomised Trials Efficacy and Safety of Statin Treatment: Prospective Meta-analysis of Data from 90,056 Participants in 14 Randomised Trials The risk reduction achieved is only half in the first 2 years and may be double (40% reduction in MACE for 40 mg/dl decrease in LDL-C) These findings reinforce the need to consider prolonged statin treatment with substantial LDL-C reductions in all patients at high risk for any type of major vascular event Benefits of statins outweigh the risk in all but a very small group who are at high risk of complications There is no evidence that statins increases the incidence of cancer or hemorrhagic stroke Baigent C. Lancet 2005;366:

49 Indications for Atorvastatin Prevention of CVD Angina, MI, CARP, stroke To improve lipid profile in familial and nonfamilial dyslipidemia Fredrickson Types IIa, IIb, III & IV Pediatric dyslipidemia (in Asian Indians) LDL-C >160 mg/dl LDL-C >130 mg/dl with Positive family history or >2 risk factors Atorvastatin PI

50 Summary Statins Extensively studied for efficacy, safety, and clinical outcome Consistently reduce, LDL-C, non-hdl-c, and TG Significantly reduce fatal and nonfatal MACE in patients with and without CAD or CVD Significantly reduce first and subsequent MACE and CARP when used alone or in combination with other agents Benefits documented in children, adults, elderly, men, and women A 80 mg/dl decrease in LDL results in at least 40% reduction in MACE High dose statin therapy is more effective than usual dose therapy in lowering LDL-C and MACE Baigent C. Lancet 2005;366: