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“ Coronary Artery Disease Risk Reduction and Dyslipidemia ”

“ Coronary Artery Disease Risk Reduction and Dyslipidemia ”. John G. McGinnity M.S., P.A.-C. Clinical Associate Professor Wayne State University. Trends in Cardiovascular Risk Factors in the U.S. Population Aged 20-74 NHES: 1960-62, NHANES:1971-75 to 1999-2000. JAMA 2005. 293: 1868-74.

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“ Coronary Artery Disease Risk Reduction and Dyslipidemia ”

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  1. “Coronary Artery Disease Risk Reduction and Dyslipidemia” John G. McGinnity M.S., P.A.-C. Clinical Associate Professor Wayne State University

  2. Trends in Cardiovascular Risk Factors in the U.S. Population Aged 20-74 NHES: 1960-62, NHANES:1971-75 to 1999-2000 JAMA 2005. 293: 1868-74. AHA 2006 Heart and Stroke update

  3. The New Evolution: “Trends in Cardiac Risk Factors” Illustration: The Economist, Dec. 13, 2003.

  4. Obesity Trends* Among U.S. AdultsBRFSS, 1990, 1998, 2006 (*BMI 30, or about 30 lbs. overweight for 5’4” person) 1998 1990 2006 No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

  5. Modifiable Cigarette smoking Dyslipidemia Hypertension Obesity Physical inactivity Diabetes *Risk Equivalent Risk Factors for CHD: JNC 7 and NCEP ATP III Nonmodifiable • Age • JNC 7: >55 (men)>65 (women) • ATP III: ≥45 (men)≥55 (women) • Family history of CHD • <55 years in first-degree male relative • <65 years in first-degree female relative • Male gender *ATP III considers diabetes a CHD risk equivalent because it substantially increases the 10-year risk of CHD. NCEP ATP III. 2002. NIH Publication No. 02-5215; NHBPEPCC. 2003. NIH Publication No. 03-5233.

  6. CHD Risk “Equivalents” Point to ≥ 20% 10-year Risk for a CHD Event • Diabetes • Other Clinical Atherosclerotic Disease • Peripheral arterial disease • Abdominal aortic aneurysm • Carotid artery disease • ≥2 risk factors with 10-year risk for hard CHD ≥20% Grundy SM et al. Circulation. 2004;110:227-239; NCEP ATP III. 2002. NIH Publication No. 02-5215. Available at:http://www.nhlbi.nih.gov/guidelines/cholesterol/.

  7. National Guidelines on Hypertension and Dyslipidemia • JNC 7: assess a patient’s lipid profiles when setting appropriate BP treatment goals • NCEP ATP III: recognize hypertension as a major risk factor that modifies lipid goals When hypertension or dyslipidemia is diagnosed,test for the other condition Chobanian AV et al. JAMA. 2003;289:2560-2572. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

  8. 64% lower risk 91% lower risk Impact of Elevated SBP and Total Cholesterol on CHD Mortality: MRFIT 33.7 n = 202,620 Age-Adjusted CHD Death Rates Per 10,000 Person-years 21 22.6 17.1 12.7 12.2 17.7 12.3 9.6 8.3 245 16.7 5.9 10.9 8.5 221–244 6.3 5.5 13.7 7.9 7.9 203–220 Cholesterol Quintile (mg/dL) 6 4.3 182–202 5.6 5 3.4 3.1 <182 59% lower risk 142 <118 132–141 125–131 118–124 SBP Quintile (mm Hg) MRFIT= Multiple Risk Factor Intervention Trial;SBP = systolic blood pressure. Adapted from Neaton JD, et al. Arch Intern Med. 1992;152:56-64.

  9. COURAGE: Study Design Patients with stable CAD; 1, 2, or 3 vessel disease (>70% visual stenosis of proximal segment); Class I or II indication for PCI and objective evidence of ischemia Randomized (n=2287) Percutaneous Intervention (PCI) + OMT N = 1149 Optimal Medical Therapy (OMT) N = 1138 Follow-up Period 2.5 - 7.0 Years 212 Primary Events 202 Primary Events Primary Endpoint: Composite of all cause death and nonfatal MI Boden WE, et al. N Engl J Med 2007:356

  10. COURAGEComposite Endpoint p=0.62 Boden WE, et al. N Engl J Med 2007:356

  11. COURAGE: Conclusions • PCI added to optimal medical therapy did not reduce the primary composite end point of death and nonfatal myocardial infarction or reduce major cardiovascular events, as compared with optimal medical therapy alone, during follow-up of 2.5 to 7.0 years • The degree of angina relief was significant in both the PCI group and the medical-therapy group, though higher in the PCI group Boden WE, et al. N Engl J Med 2007:356

  12. 100 100 14% 80 80 18% 60 60 MI Patients (%) 68% 40 40 20 20 0 0 Ambrose1988 Little1988 Nobuyoshi1991 Giroud1992 All 4Studies <50% 50%–70% >70% Are The Majority of MIs Are Caused by Lesions With <50% Stenosis? Coronary Stenosis Severity Prior to Myocardial Infarction (MI) Falk et al. Circulation. 1995;92:657-671.

  13. Concurrent Hypertension, Dyslipidemia, and Smoking Increase CVD Risk 9 Dyslipidemia 4 Hypertension 3 16 6 4.5 Smoking 1.6 Poulter N. Am J Hypertens. 1999;12:92S-95S.

  14. Risk of CHD in Mild Hypertension by Intensity of Associated Risk Factors 40 42 36 30 21 10-Year Probability of Event (%) 24 18 14 10 12 6 4 6 0 Risk Factors SBP 150-160 mm Hg + + + + + + TC 240-262 mg/dL − + + + + + HDL-C 33-35 mg/dL − − + + + + Diabetes − − − + + + Cigarette smoking − − − − + + ECG-LVH − − − − − + Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S.

  15. Atherosclerosis Timeline Adapted from: Pepine CJ. Am J Cardiol. 1998;82:21H-24H.

  16. Can You Tell a Patient Their Risk of Acute Myocardial Infarction, Stoke or Cardiac Death in the Next 10 Years? ?

  17. Framingham • Quick Facts: Study started in 1948 with 5,000 patients between 30-62 years of age… • Approximately 55% of first cohort were women • Population was homogenous withlittle racial diversity Take a Trip to Framingham… BOSTON

  18. Calculating the Risk JAMA 2001; 285(19):2486-97

  19. Dyslipidemia

  20. Dyslipidemia Prevalence, Mean Total Cholesterol in U.S. Adults 33% 222 220 30% 215 = % adult population with TC > 240 mg/dL 210 20% 17% = Mean total chol. in adult population (mg/dL) 205 203 10% 200 195 1960-62 1971-74 1976-80 1988-94 1999-2002 National Center for Health Statistics, 2004.

  21. Adults > 20 yr old: Has your cholesterol been checked in prior 5 years? Yes: 72.8% CDC: National Center for Chronic Disease Prevention, 2005. Behavioral Risk Factor Surveillance System, 2003.

  22. Dyslipidemias Are Risk Factors for CVD Hypertriglyceridemia Elevated LDL Small, dense LDL Atherosclerosis Low HDL Diabetes Hypertension Insulin resistance EndothelialDysfunction Hyperinsulinemia Hypercoagulability Visceral adiposity HDL = high-density lipoprotein; LDL = low-density lipoprotein. Deedwania PC. Am J Med. 1998;105:1S-3S.

  23. Three Sources of Cholesterol Intestinal cholesterol absorption Peripheral cholesterol synthesis Hepatic cholesterol synthesis Modifying factors Genetic predisposition Diet/Lifestyle Drug therapies Enzymatic regulation Overweight Smoking Physical activity Different actions of lipid-altering drugs may have complementary actions in lowering LDL-C Determinants of Cholesterol Levels

  24. Differentiating Particles Chylomicron • Non-HDL-C = • total cholesterol – HDL • 2. Non-HDL-C is the sum of all the atherogenic particles VLDL IDL LDL HDL

  25. Net Cholesterol Balance in Humans

  26. Apolipoproteins • Apolipoprotein B • Potential marker for all atherogenic lipoproteins • Insufficient evidence to justify replacing LDL-C • Non-HDL-C correlates with apolipoprotein B; can serve as a “surrogate” • Apolipoprotein A-1 • Carried in HDL-C and usually low when HDL-C is reduced • Associated with increased CHD risk, but not independently of low HDL-C • Apolipoprotein E • Typical of dysbetalipoproteinemia • Apolipoprotein C-III • A form of VLDLr that appears to be atherogenic ATP III. JAMA. 2001 May 16;285(19):2486-2497.

  27. Comparison of LDL & Non-HDL Goals for Risk Categories NCEP ATP III. Circulation. 2002;106:3145-3421.

  28. Reviewing ATP III-R Targets • LDL-C primary target • Optimal LDL-C below 100 mg/dL and may be BELOW 70 mg/dL* • Non-HDL-C goals for patients with TGs >200 mg/dL • Total Cholesterol – HDL = Non-HDL • Introduction of CHD risk equivalents *Grundy SM et al. Circulation. 2004;110:227-239. NCEP ATP III. Circulation. 2002;106:3145-3421.

  29. ADA/ACC 2008 Consensus Statement:Treatment Goals in Patients With Cardiometabolic Risk and Lipoprotein Abnormalities Goals LDL-C Non–HDL-C Apo B • Highest-Risk Patient • Known CVD • Diabetes plus ≥1 additional major CVD risk factora <70 mg/dL <100 mg/dL <80 mg/dL <130 mg/dL <90 mg/dL • High-Risk Patients • No diabetes or known CVD but ≥2 major CVD risk factorsa • Diabetes but no other major CVD risk factorsa <100 mg/dL “In individuals on statin therapy who continue to have low HDL-C or elevated non–HDL-C, especially if Apo B levels remain elevated, combination therapy is recommended. The preferred agent to use in combination with a statin is nicotinic acid…” aMajor risk factors beyond dyslipidemia include smoking, hypertension, and family history of premature CHD. Brunzell JD, et al. Diabetes Care. 2008;31:811-822.

  30. Diabetes Mellitus: A CV Risk Equivalent • Diabetics are 2-4 x more likely to develop heart disease* • More than 65% of pt’s with DM die from heart disease or stroke* • Booth et al. retrospective study of 151,872 pt’s from 1992-99 in Ontario, Canada. demonstrated DM pt’s are: • 3x more likely to be admitted w/ AMI or stroke • 1.6x more likely to die from an AMI/Stroke • Good news is mortality is decreasing even though # of events increased • Noted 65% increase in # of DM pt’s during the time period *American Diabetes Association Booth et al. Diabetes Care 2006;29:32-37.

  31. Reviewing ATP III-R Targets • Patients warranting aggressive lipid lowering include those with established CVD plus any of the following: • Multiple risk factors • Severe/poorly controlled risk factors • Multiple risk factors of the metabolic syndrome patients with acute coronary syndromes • These patients have option LDL-C lowered below 70 mg/dL* *Grundy SM et al. Circulation. 2004;110:227-239. NCEP ATP III. Circulation. 2002;106:3145-3421.

  32. ATP III Changes HDL Classification • Low HDL-C now a risk factor & treatment target • Modest increases in HDL-C = CHD risk reduction • Low HDL-C strongly associated with CHD • High HDL-C reduces risk 1% decreasein LDL-C reduces CHD risk by 1% 1%increasein HDL-C reduces CHD risk by 3% NCEP ATP III. Circulation. 2002;106:3145-3421. Gray et al. Ann Intern Med. 1994;121:252-258.

  33. Therapy should target both HDL and LDL Goals:HDL vs. LDL Risk Reduction LDL 280mg/dl HDL 50mg/dl = 75% Decrease 25% Increase HDL 40mg/dl LDL 70mg/dl 1% decrease in LDL-C reduces CHD risk by 1% 1% increase in HDL-C reduces CHD risk by 3%

  34. Reaching Dyslipidemia Target Goals: Statins Fibrates Cholesterol Absorption Inhibitors Bile-acid Sequestrants Niacin

  35. Effects of Drug Classes on Serum Lipids TC LDL HDL TG Resins 20% 10%–20% 3%–5% Variable Ezetimibe 20% 10%–20% 3%–5% Variable Nicotinic acid 25% 10%–15% 15%–35% 20%–50% Fibrates 15% Variable 6%–15% 20%–50% Statins 15%–60% 20%–60% 3%–15% 10%–40% Fish Oil (PUFA) None None ??  3% 25%–35% Adapted from Gotto AM Jr. Management of lipid and lipoprotein disorders. In: Gotto AM Jr, Pownall HJ, eds. Manual of lipid disorders. Baltimore: Williams & Wilkins; 1992; Rubins HB, et al. N Engl J Med. 1999;341:410–418.

  36. Controversies regarding safety of dyslipidemia drug therapies

  37. Traditional Treatment Options • Statins • Block production of enzymes used to make cholesterol • Effective at lowering LDL, decreasing triglycerides, reducing C-reactive protein • First-line treatment in most patients • Side effects include increased liver enzymes and myopathy • Contraindicated in active/chronic liver disease, drug interactions ATP III, 2002

  38. Statins:What Do We Know About the Side Effects • Elevation of hepatic enzymes—dose dependent • Dose dependent • Range from 0.1–3% • Myopathy/Rhabdomyolysis -CK levels > 10-fold (Range 0.1% – 0.5%1) rhabdomyolysis incidence 1 in 10,000 pt’s • More than 474,458,000 Rx written for statins thru 2001 (excluding cerivastatin) • 42 cases of fatal rhabdomyolysis reported2 • Possible Drug interactions • Erythromycin, Biaxin, Cyclosporin, anti-fungal agents Verapamil, Amiodarone (Simvastatin)1 1. Graham et al. JAMA 2004;294(21):2585-2590 2. Staffa NEJM 2002;346:539-540.

  39. Evaluation of LFT’s with Statin Use Because the rate of liver failure in a population not receiving statin therapy is about the same, as statin patients, it may support a conclusion that there is no relation between liver failure and statin therapy NLA Statin Safety Assessment Task Force can find no evidence to support the continued monitoring of liver function tests in statin patient. However because of medical-legal issues we also believe that cessation of LFT testing is not advisable. McKenney JM et al. Am J Cardiol 2006;97[suppl]:89c-94c.

  40. Statin Risk Factors for Myopathy Adapted from Toth et al. Expert Rev Cardiovasc Ther 2008, 6:955-969.

  41. Statin-Associated Rhabdomyolysis: Adverse Event Reports* 120 † 100 Cerivastatin Fluvastatin Atorvastatin Lovastatin Pravastatin Simvastatin Ezetimibe Rosuvastatin‡ * U.S. data (FDA Adverse Events Reporting System) shown for all statins. † Cerivastatin withdrawn from U.S. market August 2001. ‡ U.S. plus other global data (on file at Astra Zeneca) shown for rosuvastatin only. Data points correspond to reports received 4/03 – 9/03, 10/03 – 3/04, 4/04 – 9/04, and 10/04 – 3/05. Adapted from “AstraZeneca rosuvastatin Clinical Information” web site, Figure 3. Available at http://www.rosuvastatininformation.com/gUserFiles/adverse_event19julv2.pdf. Accessed August 5, 2005. 80 60 Reported cases per 1 million prescriptions 40 20 0 3/99 – 8/99 9/99 – 2/00 3/00 – 8/00 9/00 – 2/01 3/01 – 8/01 9/01 – 2/02 3/02 – 8/02 9/02 – 2/03 3/03 – 8/03 8/03 – 2/04 3/04 – 8/04 10/04 – 3/05

  42. Statin-Associated Rhabdomyolysis: Fatal Event Reports* Cerivastatin Fluvastatin Atorvastatin Lovastatin Pravastatin Simvastatin Ezetimibe Rosuvastatin‡ * U.S. data (FDA Adverse Events Reporting System) shown for all statins. † Cerivastatin withdrawn from U.S. market August 2001. ‡ U.S. plus other global data (on file at Astra Zeneca) shown for rosuvastatin only. Data points correspond to reports received 4/03 – 9/03, 10/03 – 3/04, 4/04 – 9/04, and 10/04 – 3/05. Adapted from “AstraZeneca rosuvastatin Clinical Information” web site, Figure 4. Available at http://www.rosuvastatininformation.com/gUserFiles/adverse_event19julv2.pdf. Accessed August 5, 2005. 25 † 20 Reported cases per 1 million prescriptions 15 10 5 0 3/99 – 8/99 9/99 – 2/00 3/00 – 8/00 9/00 – 2/01 3/01 – 8/01 9/01 – 2/02 3/02 – 8/02 9/02 – 2/03 3/03 – 8/03 8/03 – 2/04 3/04 – 8/04 10/04 – 3/05

  43. Stopping StatinsIs it safe in….Stable CAD vs. ACS

  44. FDA News ReleaseMarch 19, 2010 • Warned patient and healthcare providers about the potential risk of muscle injury from simvastatin 80mg. • “Myopathy is a known side effect of all statins, today's warning highlights the greater risk of developing muscle injury, including Rhabdomylosis for patient prescribed the higher doses…..” http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm205215.htm

  45. Statin Drug InteractionsFDA Drug Safety Communication • Antifungal Agents – Itraconazole / Ketoconazole • Erythromycin / Clarithromycin / Telithromycin • HIV protease inhibitors • Nefazodone • Gemfibrozil • Cyclosporine • Danazol • Amiodarone (do not use more than 20mg of simvastatin) • Verapamil (do not use more than 20mg of simvastatin) • Diltiazem (do not use more than 40mg of simvastatin) FDA Drug safety Communication 3/19/10 http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm

  46. Traditional Treatment Options • Bile-acid resins • Prevent the recycling of bile acids in the intestines → liver removes cholesterol from the blood • Effective at lowering LDL-C and slight increases in HDL-C • May raise triglycerides • Side effects include GI distress • Cannot be given concomitantly with other medications • TG > 400 mg/dL ATP III, 2002

  47. Drug Therapy Bile Acid Sequestrants • Major actions • Reduce LDL-C 15–30% • Raise HDL-C 3–5% • May increase TG • Side effects • GI distress/constipation • Decreased absorption of other drugs • Contraindications • Raised TG (especially >400 mg/dL)

  48. Traditional Treatment Options • Nicotinic acids • Effective in lowering triglycerides and raising HDL • Less effective at lowering LDL • Many patients experience intense side effects, including flushing and palpitations — 10% to 40% discontinue therapy • Dosage should be increased gradually • Other side effects include hyperglycemia, upper GI distress, hepatotoxicity, and peptic ulcer disease • Contraindicated in chronic liver disease and severe gout ATP III, 2002.

  49. Drug Therapy Nicotinic Acid • Major actions • Lowers LDL-C 5–25% • Lowers TG 20–50% • Raises HDL-C 15–35% • Side effects: flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity • Contraindications: liver disease, severe gout, peptic ulcer

  50. Traditional Treatment Options • Fibrates • Reduce production of triglycerides and increase the removal of triglycerides from the blood stream • Used more commonly in patients with elevated triglycerides • Raise HDL-C • Less and variably effective at lowering LDL-C • Side effects include dyspepsia, gallstones, and myopathy • Contraindicated in severe renal disease and severe hepatic disease ATP III, 2002.

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