Statins in the Primary and Secondary Prevention of CAD Prof. M. Ishaq Karachi Institute of Heart Diseases

Elevated Serum Cholesterol Levels are Linked to Increased Risk of CHD CHD death rate (per 1000 men in 6 years) Serum cholesterol (mg/dL) References Martin et al. Lancet 1986;2:933–6 Coronary heart disease risk increases progressively as serum cholesterol levels rise above 181 mg/dL (4.68 mmol/L)

Total Cholesterol Distribution: CHD vs Non-CHD Population Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9. 1996 Reprinted with permission from Elsevier Science. 35% of CHD Occurs in People with TC<200 mg/dL Total Cholesterol (mg/dL) No CHD CHD Framingham Heart Study—26-Year Follow-up

Normal Fatty streak Lipid rich plaque Complex plaque Thrombus Lipid core Fibrous cap Foam cells Development of Atherosclerotic Plaques

LDL cholesterol (mg/dL) <100Optimal Near optimal/above optimal Borderline high High  190Very high HDL cholesterol (mg/dL) <40Low  60High NCEP ATP III Lipid and Lipoprotein Classification NCEP ATP III guidelines. JAMA. 2001;285: NCEP ATP III classification

Diabetes: CHD risk equivalent Framingham projections of 10-year CHD risk SALIENT Features of NCEP ATP III NCEP ATP III guidelines. JAMA. 2001;285: Focus on Multiple Risk Factors Optimal LDL cholesterol <100 mg/dL: changed from  100 mg/dL Categorical low HDL cholesterol <40 mg/dL: raised from <35 mg/dL Modification of Lipid and Lipoprotein Classification Complete lipoprotein profile preferred (TC, LDL, HDL, TG) Secondary option: fasting TC and HDL; proceed to lipoprotein profile if TC >200 mg/dL or HDL <40 mg/dL New Recommendations for Screening/Detection

CHD or CHD 100 to  130 risk equivalent † 2+ risk factors 130 to  risk factor 160 to  190 NCEP ATP III LDL Cholesterol Goals and Therapy Recommendations *Authorities disagree on when to initiate drug therapy. † This category refers to patients without clinically evident CHD, but who have a similar risk for CHD events (eg, patients with diabetes, multiple risk factors, or other forms of atherosclerotic disease, such as peripheral artery disease). NCEP ATP III guidelines. JAMA. 2001;285: Initiate therapeutic lifestyle changes Goal Initiate drug therapy* LDL cholesterol level (mg/dL)

ATP III Treatment Recommendations for CHD and CHD Risk Equivalents Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285: No treatment recommended because “no evidence” LDL-C <100 mg/dL Options:TLC alone Fibrate Statin LDL-C 100–129 mg/dL Lifestyle and statin LDL-C 130 mg/dL

NCEP-ATP III Metabolic Syndrome Some patients have a variety of risk factors that constitute a condition named metabolic syndrome The ATP III guidelines recognise metabolic syndrome as a secondary target of risk-reduction therapy after LDL-C lowering *on treatment References 1. NCEP Expert Panel. JAMA 2001;285:2486–97 Risk factor of metabolic syndromeDefining level Abdominal obesity (waist circumference) Men Women >102 cm (> 40 in) > 88 cm (> 35 in) TGs  1.7 mmol/L ( 150 mg/dL) HDL-C Men Women < 1.1 mmol/L (< 40 mg/dL) < 1.3 mmol/L (< 50 mg/dL) Blood pressure  130/85 mmHg* Fasting glucose  6.1 mmol/L ( 110 mg/dL)

First-line agents HMG CoA reductase inhibitor HMG CoA reductase inhibitor Fibric acid derivative Fibric acid derivative Second-line agents Bile acid binding resins Bile acid binding resins Nicotinic acid Nicotinic acid Pharmacologic Agents for Treatment of Dyslipidemia American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60. In diabetic patients, nicotinic acid should be restricted to <2g/day. Short-acting nicotinic acid is preferred. Effect on lipoprotein LDLHDLTriglyceride

Mechanism of Action of Statins Cholesterol Synthesis Pathway acetyl CoA HMG-CoA mevalonic acid mevalonate pyrophosphate isopentenyl pyrophosphate geranyl pyrophosphate farnesyl pyrophosphate squalene cholesterol dolicholsubiquinones HMG-CoA synthase HMG-CoA reductase Squalene synthase X Statins

Clinical Pharmacokinetics of Statins References 1. Adapted from Corsini et al. Pharmacol Ther 1999;84:413–428. ParameterAtorvas tatin Fluvast atin Lovastati n Pravasta tin Simvasta tin Fraction absorbed (%) –80 C max (ng/mL) 27– –2045–5510–34 Hepatic extraction (%) > 70> 68> 7046–6678–87 Metabolism CYP3A4CYP2C9CYP3A4SulfationCYP3A4 Systemic metabolites ActiveInactiveActiveInactiveActive Clearance (L/hr/kg) – Based on 40 mg oral dose

Major coronary events Coronary deaths Cardiovascular deaths All-cause deaths Proportional risk reduction (%) References 1. LaRosa et al. JAMA 1999;282:2340–6 6 –31% –29% –27% –21% –35 –30 –25 –20 –15 –10 –5 0 Proven Mortality Benefits Of Lowering LDL-C A 28% reduction in LDL-C significantly reduces cardiovascular events in hypercholesterolaemic patients

Change in LDL-C and Non-HDL-C by Statins after 54 Weeks of Therapy Ballantyne CM et al. Am J Cardiol 2001;88: Mean Dose Average baseline LDL-C: 178 mg/dL Average baseline non-HDL-C: 216 mg/dL 24 mg 42 mg 52 mg 23 mg Atorvastatin (n=1,888) Fluvastatin (n=474) Pravastatin (n=461) Simvastatin (n=462) –42 –38 –35 –29 –32 –26 –36 –32 LDL-CNon-HDL-C Percent Change

Elevated TG Levels Increase the Risk Of CHD Percentage increase in relative risk associated with 1 mmol/L (equivalent to 88 mg/dL) increase of TG when adjusted for HDL-C and other risk factors References Hokanson et al. J Cardiovascular Risk 1996;3:213–9 An increase in TG levels significantly increases the risk of cardiovascular disease Increase in risk (%) MenWomen

Combination of Risk Factors Increases The Risk of Cardiovascular Events Men: smoking, SBP > 160 mmHg Men: No risk factors Women: smoking, SBP > 160 mmHg Women: No risk factors References 1. Pyorala et al. Eur Heart J 1994; 15:1300–31 Risk factors in addition to LDL-C levels include cigarette smoking, hypertension, age and low HDL-C level A combination of risk factors increases the risk of cardiovascular events Plasma total cholesterol (mg/dL) year risk of CHD events (%)

Major Statin Trials.Primary prevention trials: —AFCAPS/TexCAPS (lovastatin) - 36% reduction in first coronary events —WOSCOPS (paravastatin) - 31 % reduction in fatal and non- fatal MI.Secondary prevention trials: —4S (simvastatin) - relative risk of death reduced by 30%, 42% reduction in coronary death —CARE (paravastatin) - CHD death and non-fatal MI reduced by 24% —LIPS: The latest trial in PCI presented at the ACC meting

Major Statin Trials (contd.).Angiographic trial: —LCAS (fluvastatin) - Significantly less lesion progression and fewer new lesions in treated patients with improvement in myocardial blood flow by PET.Post-CABG/PTCA trial: —FLARE (fluvastatin) - 63% reduction in death and MI with fluvastatin.Severe atherosclerosis trial: —LiSA (fluvastatin) - 71% reduction in major adverse cardiac events (MACE) —lower incidence of angina pectoris attacks —decreased use of antianginal drug in fluvastatin group

Key Statin Trials and Spectrum of Risk 4S 1 LIPID 2 CARE 3 WOSCOPS 4 AFCAPS/TexCAPS 5 CHD/high cholesterol CHD/average to high cholesterol CHD/average cholesterol No MI/high cholesterol No CHD/average cholesterol Secondary prevention Primary prevention Increasing risk

TC, total cholesterol, CD, cardiac death; MI, myocardial infarction; NA, not available *including silent MI + resuscitated cardiac arrest; **including unstable angina; # including fatal MI Statins Reduce the Risk of Cardiac Death and Myocardial Infarction References 1. Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383–9 2. Heart Protection Study Collaborative Group. Lancet 2002;6:7–22 3. Shepherd et al. NEJM 1995;333:1301–7 4. Sacks et al. NEJM 1996;335:1001–9 5. LIPID study group. NEJM 1998;339:1349–57 6. Shepherd et al. Lancet 2002;360:1623–30 7. ALLHAT Collaborative Research Group J Am Med Assoc 2002;288:2998– Sever et al. Lancet 2003;361:1149–58 9. Downs et al. JAMA 1998;279:1615– Serruys et al. JAMA 2002;287:3215– Holdaas. Lancet 2003;361:2024–31 TrialSample size LDL-CCD + MI annual rate CD + MI % of reductio n CD % of reductio n mmol/L baseline mmol/L change % change 4 S *3442 HPS WOSCOPS CARE LIPID PROSPER ALL-HAT ASCOT-LLA NA AFCAPS/Tex CAPS **3233 LIPS ALERT √

Statin Evidence: Expanding Benefits Acute coronary event 4S CARE/LIPID 4 mo No history of CADUnstable CAD 3 mo t = 0 6 mo Stable CAD Secondary preventionPrimary prevention AFCAPS / TexCAPS/ WOSCOPS MIRACL Hypertension ASCOT-LLA HPS S6

Statins Lower LDL-C Levels and Cardiovascular Event Rate in Secondary Prevention of CHD LIPS, Lescol ® Intervention Prevention Study (Lescol ® ) 1 CARE, Cholesterol And Recurrent Events study (pravastatin) 2 4S, Scandinavian Simvastatin Survival Study (simvastatin) 3 LIPID, Long-term Intervention with Pravastatin in Ischaemic Disease study (pravastatin) 4 Statin LDL-C achieved (mg/dL) Placebo CARE LIPID 4S Event rate (%) LIPS References 1. Serruys et al. JAMA 2002;287:3215–22 2. Sacks et al. N Eng J Med 1996;335:1001–9 3. Scandinavian Simvastatin Survival Group. Lancet 1994;344:1383–9 4. LIPID Study Group. N Eng J Med 1998;339:1349–57 √

heart protection study 08-JUN-2008-ZCR-2007-MEA-(PK)-1193-SS

High-Risk Patient Groups in Which Statin Therapy Was Not Prospectively Tested Prior to the Heart Protection Study Patients with diabetes –With coronary heart disease (CHD) –Without CHD Patients with previous stroke Patients with peripheral vascular disease Patients with low cholesterol Elderly Women Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; MRC/BHF Heart Protection Study Collaborative Group Eur Heart J 1999;20:

Increased 5-year risk of CHD death because of –Diabetes mellitus or treated hypertension –Cerebrovascular or peripheral vascular disease –MI or other CHD Age 40–80 years Men and women Total cholesterol 3.5 mmol/L (135 mg/dl) Statin not considered clearly indicated or contraindicated by patients’ primary physicians Heart Protection Study Patient Inclusion Criteria Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; MRC/BHF Heart Protection Study Collaborative Group Eur Heart J 1999;20:

20,536 high-risk patients Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; MRC/BHF Heart Protection Study Collaborative Group Eur Heart J 1999;20: ; HPS Group communication. Heart Protection Study High-Risk Patient Groups CHD 7414 Diabetes 2912 Other vascular diseases

*Patients could be in more than one vascular event category. **Includes coronary and noncoronary revascularizations. Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22. Impact of Simvastatin in Heart Protection Study Major Vascular Events Vascular event* Major coronary event Nonfatal MI Coronary death Stroke Revascularization** ANY MAJOR VASCULAR EVENT 27% risk reduction p< % risk reduction p< % risk reduction p< % risk reduction p< Simvastatin Placebo betterbetter Risk ratio and 95% CI

Adapted from Heart Protection Study Collaborative Group Lancet 2002;860:7-22. % of patients Placebo (n=10,267) 25.2% Simvastatin (n=10,269) 19.8% 2585 Patients with Events 2033 Patients with Events RR=24% p< Impact of Simvastatin in Heart Protection Study Major Vascular Events

*Includes coronary and noncoronary revascularizations Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22. % of patients Placebo (n=10,267) Simvastatin (n=10,269) RR=27% p< Major coronary event 11.8% 8.7% Stroke 5.7% 4.3% Revascularization* 11.7% 9.1% RR=25% p< RR=24% p< Impact of Simvastatin in Heart Protection Study Major Vascular Events Number of patients with event

*Patients could be in more than one disease category. Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22. Impact of Simvastatin on Major Vascular Events By Prior CHD Status 24% risk reduction p< % risk reduction p< % risk reduction p< Prior CHD With prior MI No prior MI, with other CHD No prior CHD* Cerebrovascular disease Peripheral vascular disease Diabetes ALL PATIENTS Baseline feature Simvastatin Placebo betterbetter Risk ratio and 95% CI

Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22; HPS Group communication. Impact of Simvastatin on Major Vascular Events Patients with Diabetes—Five-Year Risk % of patients All patients with diabetes n=2985n=2978 With diabetes, with prior CHD n=1009n=972 With diabetes, without prior CHD n=1976n= % 20.2% 37.8% 33.4% 18.6% 13.8% RR=23% p< Placebo Simvastatin

In more than 20,000 patients at high risk for CHD –Simvastatin significantly reduced the risk of major vascular events in high-risk patients With or without prior CHD Regardless of baseline cholesterol levels –Simvastatin significantly reduced the risk of major vascular events in patients with diabetes with or without prior CHD –Simvastatin 40 mg had a long-term tolerability profile comparable to placebo Adapted from Heart Protection Study Collaborative Group Lancet 2002;360:7-22. Heart Protection Study Major Medical Conclusions

Safety of Statin Therapy Statin monotherapy is generally well tolerated over the long term and has a low incidence of adverse events 1 Statin treatment is associated with a small risk of muscular adverse effects, or myopathies –In rare cases, myopathy may proceed to muscle cell breakdown, or rhabdomyolysis, a potentially fatal condition –The risk of muscular toxicity with statin therapy is very low, but is increased in high-risk groups (e.g. the elderly, patients with CHD, diabetic patients) –These patients typically take multiple medications and are therefore at risk of drug interactions with statins Elevations in liver enzymes >3 times upper limit of normal range are experienced by 1–2% of patients. Such elevations have been reported in all lipid-lowering drugs References 1. Corsini. Cardiovasc Drug Therapy 2003;17:265–85 2. Friday. Exp Biol Med 2003;228:769–78 √

CONCLUSION Total cholesterol levels are linearly related to CHD mortality HDL and triglycerides are also independent risk factors for CHD ATP III suggests aggressive treatment of dylipidemia. Reduction in LDL- and increase in HDL-levels significantly reduce morbidity/mortality Only one-third of treated patients reach LDL-target Cholesterol lowering is beneficial for both Primary and Secondary Prevention of CHD Recent data suggest that statin benefit independent of baseline LDL Levels. 2

“ Safety and efficacy of statins have revolutionized the treatment of dyslipidaemia and statins have therefore become an essential step in the management of all subsets of CHD, Strokes & peripheral vascular disease”

Thank you for your attention