1. 1 Οδηγίες AHA/ACC για δευτερογενή πρόληψη για ασθενείς με καρδιαγγειακή αθηροσκληρωτική νόσο: Αναθεώρηση 2006

2. 2 Το πλήρες κείμενο των οδηγιών μπορείτε να το βρείτε στο δικτυακό τόπο της AHA (www.americanheart.org) και του ACC (www.acc.org) Circulation 2006;113:2363-2372 and J Am Coll Cardiol 2006;47:2130-2139

3. 3 Introduction Since the 2001 update of the AHA/ACC consensus statement on secondary prevention, important evidence from clinical trials has emerged that further supports and broadens the merits of aggressive risk reduction therapies This growing body of evidence confirms that aggressive comprehensive risk factor management improves survival, reduces recurrent events and the need for interventional procedures, and improves the quality of life The secondary prevention patient population includes those with established coronary and other atherosclerotic vascular disease, including peripheral arterial disease, atherosclerotic aortic disease and carotid artery disease.

4. 4 AHA/ACC Secondary Prevention for Patients with Coronary Artery and Other Atherosclerotic Vascular Disease *Dr. Pasternak withdrew from the Writing Group on June 22nd, 2004, when he accepted an offer of employment as Vice President, Clinical Research, Cardiovascular and Atherosclerosis at Merck Research Laboratories. Circulation 2006;113:2363-2372 and J Am Coll Cardiol 2006;47:2130-2139

5. 5 Class I Benefit >>> Risk Procedure or treatment SHOULD be performed or administered Class IIa Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure or administer treatment Class IIb Benefit ≥ Risk Additional studies with broad objectives needed; Additional registry data would be helpful Procedure or treatment MAY BE CONSIDERED Class III Risk ≥ Benefit No additional studies needed Procedure or treatment should NOT be performed or administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL Applying Classification of Recommendations and Level of Evidence

6. 6 Level A Multiple (3-5) population risk strata evaluated General consistency of direction and magnitude of effect Class I Recommendation that procedure or treatment is useful/ effective Sufficient evidence from multiple randomized trials or meta- analyses Class IIa Recommendation in favor of treatment or procedure being useful/ effective Some conflicting evidence from multiple randomized trials or meta- analyses Class IIb Recommendation’ s usefulness/ efficacy less well established Greater conflicting evidence from multiple randomized trials or meta- analyses Class III Recommendation that procedure or treatment not useful/ effective and may be harmful Sufficient evidence from multiple randomized trials or meta- analyses Applying Classification of Recommendations and Level of Evidence

7. 7 Level B Limited (2-3) population risk strata evaluated Class I Recommen- dation that procedure or treatment is useful/ effective Limited evidence from single randomized trial or non- randomized studies Class IIa Recommen-dation in favor of treatment or procedure being useful/ effective Some conflicting evidence from single randomized trial or non- randomized studies Class IIb Recommen- dation’s usefulness/ efficacy less well established Greater conflicting evidence from single randomized trial or non- randomized studies Class III Recommen-dation that procedure or treatment not useful/effective and may be harmful Limited evidence from single randomized trial or non- randomized studies Applying Classification of Recommendations and Level of Evidence

8. 8 Level C Very limited (1-2) population risk strata evaluated Class I Recommen- dation that procedure or treatment is useful/ effective Only expert opinion, case studies, or standard-of- care Class IIa Recommendation in favor of treatment or procedure being useful/effective Only diverging expert opinion, case studies, or standard-of-care Class IIb Recommen- dation’s usefulness/ efficacy less well established Only diverging expert opinion, case studies, or standard-of-care Class III Recommendation that procedure or treatment not useful/effective and may be harmful Only expert opinion, case studies, or standard-of-care

9. 9 Secondary Prevention Definition Therapy to reduce recurrent cardiovascular events and decrease cardiovascular mortality in patients with established atherosclerotic vascular disease Patients covered include those with established coronary and other atherosclerotic vascular disease, including peripheral arterial disease, atherosclerotic aortic disease and carotid artery disease Individuals with sub-clinical atherosclerosis and patients whose only manifestation is diabetes are covered in other guidelines

10. 10 Components of Secondary Prevention Cigarette smoking cessation Blood pressure control Lipid management to goal Physical activity Weight management to goal Diabetes management to goal Antiplatelet agents / anticoagulants Renin angiotensin aldosterone system blockers Beta blockers Influenza vaccination

11. 11 Evidence Based Therapies The writing group emphasizes the importance of giving consideration to the use of cardiovascular medications that have been proven to be of benefit in randomized clinical trials. This approach strengthens the evidence-based foundation for therapeutic application of these guidelines. The committee acknowledges that in many trials there is under-representation of ethnic minorities, women, and the elderly.

12. 12 Goal: Complete Cessation and No Exposure to Environmental Tobacco Smoke Cigarette Smoking Recommendations Ask about tobacco use status at every visit. Advise every tobacco user to quit. Assess the tobacco user’s willingness to quit. Assist by counseling and developing a plan for quitting. Arrange follow-up, referral to special programs, or pharmacotherapy (including nicotine replacement and bupropion. Urge avoidance of exposure to environmental tobacco smoke at work and home.

13. 13 0.11.0 10 Ceased smokingContinued smoking RR (95% Cl) Study Aberg, et al. 19830.67(0.53-0.84) Herlitz, et al. 19950.99(0.42-2.33) Johansson, et al. 19850.79 (0.46-1.37) Perkins, et al. 19853.87(0.81-18.37) Sato, et al. 19920.10(0.00-1.95) Sparrow, et al. 19780.76(0.37-1.58) Vlietstra, et al. 19860.63(0.51-0.78) Voors, et al. 19960.54(0.29-1.01) Cigarette Smoking Cessation: Risk of Non-fatal MI* Critchley JA et al. JAMA. 2003;290:86-97. *Includes those with known coronary heart disease CI=Confidence interval, RR=Relative risk

14. 14 Ask and document pt’s tobacco use status Advise: Provide a strong, personalized message to quit using tobacco Assess* readiness to quit in next 30 days Prevent Relapse Congratulate successes Encourage to remain tobacco-free Discuss benefits experienced by patient Address weight gain, negative mood, and lack of support Increase Motivation Relevance to patients personal situation Risks: short and long term, environmental Rewards: potential benefits of quitting Roadblocks: identify barriers and potential solutions Repetition: repeat motivational intervention Reassess readiness to quit Assist Negotiate a plan STAR** Discuss pharmacotherapy Social support Provide educational materials Arrange follow-up to check plan or adjust meds Call right before and after quit date Weekly follow-up x 2 weeks, then monthly x 6 months Ask about difficulties (withdrawal, depressed mood) Build upon successes Seek commitment to stay tobacco-free **STAR Set quit date Tell family, friends, and coworkers about it Anticipate challenges: withdrawal, breaks Remove tobacco from the house, car, and social life Recent Quitter (<6 months) Current User Not Ready Ready Smoking Cessation Algorithm Treating Tobacco Use and Dependence: A Clinical Practice Guideline, U.S. Department of Health and Human Services, June 2000

15. 15 Smoking Cessation Pharmacotherapy* AgentCautionSide Effects DosageDurationInstructions Bupropion SR (Zyban®) Seizure disorder Eating disorder Taking MAO inhibitor Pregnancy Insomnia Dry mouth 150 mg QAM then 150 mg BID 3 days Maintenance (8 weeks, but may be used up to 6 months) Start 1-2 weeks before quit date. Take second dose in early afternoon or decrease to 150 mg QAM for insomnia. Transdermal Nicotine Patch** Within 2 weeks of a MI Unstable angina Arrhythmias Decompensated heart failure Skin reaction Insomnia 21 mg QAM 14 mg QAM 7 mg QAM or 15 mg QAM 4 weeks 2 weeks 8 weeks Apply to different hairless site daily. Remove before bed for insomnia. Start at <15 mg for <10 cigs/day *Pharmacotherapy combined with behavioral support provides the best success rate **Other nicotine replacement therapy options include: nicotine gum, lozenge, inhaler, nasal spray

16. 16 Goal: <140/90 mm Hg or <130/80 if diabetes or chronic kidney disease Blood Pressure Control Recommendations Blood pressure 120/80 mm Hg or greater:  Initiate or maintain lifestyle modification: weight control, increased physical activity, alcohol moderation, sodium reduction, and increased consumption of fresh fruits vegetables and low fat dairy products Blood pressure 140/90 mm Hg or greater (or 130/80 or greater for chronic kidney disease or diabetes)  As tolerated, add blood pressure medication, treating initially with beta blockers and/or ACE inhibitors with addition of other drugs such as thiazides as needed to achieve goal blood pressure

17. 17 Prospective Studies Collaboration. Lancet. 2002;360:1903-1913 Usual Diastolic BP (mm Hg)Usual Systolic BP (mm Hg) Ischemic Heart Disease Mortality 50-59 60-69 70-79 80-89 Age at Risk (Y) 40-49 256 128 64 32 16 8 4 2 1 0 120140160180 50-59 60-69 70-79 80-89 Age at Risk (Y) 40-49 256 128 64 32 16 8 4 2 1 0 809010011070 Blood Pressure: Lower is Better Ischemic Heart Disease Mortality BP=Blood pressure

18. 18 Veterans Administration, 1967 Veterans Administration, 1970 Hypertension Stroke Study, 1974 USPHS Study, 1977 EWPHE Study, 1985 Coope and Warrender, 1986 SHEP Study, 1991 STOP-Hypertension Study, 1991 MRC Study, 1992 Syst-Eur Study, 1997 Total 0 0.5 1.0 1.5 2.0 0.79 (0.69 to 0.90) He J et al. Am Heart J 1999; 138:211-219 Better than placebo Worse than placebo Blood Pressure: Risk of CHD with Active Treatment CHD=Coronary heart disease

19. 19 Yes>100 >160Stage 2 Hypertension Yes90–99140–159Stage 1 Hypertension Yes80–89120–139Pre- hypertension Encourage<80<120Normal With compelling indications Initial drug therapy Lifestyle modification DBP* mmHg SBP* mmHg BP classification JNC VII Guidelines for Management and Treatment ACEI=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor blocker, BB=  -blocker, BP=Blood pressure, CCB=Calcium channel blocker, DBP=Diastolic blood pressure, SBP=Systolic blood pressure Chobanian AV et al. JAMA. 2003;289:2560-2572 *Treatment determined by highest blood pressure category. † Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. ‡Treat patients with chronic kidney disease or diabetes mellitus to blood pressure goal of <130/80 mmHg. Drug(s) for the compelling indications. ‡ Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Drug(s) for compelling indications. ‡

20. 20 ModificationRecommendationApproximate SBP Reduction Range Weight reductionMaintain normal body weight (BMI=18.5-24.9) 5-20 mmHg/10 kg weight lost Adopt DASH eating plan Diet rich in fruits, vegetables, low fat dairy and reduced in fat 8-14 mmHg Restrict sodium intake <2.4 grams of sodium per day2-8 mmHg Physical activityRegular aerobic exercise for at least 30 minutes on most days of the week 4-9 mmHg Moderate alcohol consumption <2 drinks/day for men and <1 drink/day for women 2-4 mmHg JNC VII Lifestyle Modifications for BP Control Chobanian AV et al. JAMA. 2003;289:2560-2572 BMI=Body mass index, SBP=Systolic blood pressure

21. 21 Clinical-Trial BasisCompelling Indication ALLHAT, HOPE, ANBP2, LIFE, CONVINCE High CAD Risk ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS Post-MI MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, Val-HeFT, RALES Initial Therapy Options Diuretic, BB, ACEI, CCB BB, ACEI, Aldo Ant Diuretic, BB, ACEI, ARB, Aldo Ant Heart Failure JNC VII Compelling Indications for Drug Classes ACEI=Angiotensin converting enzyme inhibitor, Aldo Ant=Aldosterone antagonist, ARB=Angiotensin receptor blocker, BB=b-blocker, CAD=Coronary artery disease, CCB=Calcium channel blocker, MI=Myocardial Infarction Chobanian AV et al. JAMA. 2003;289:2560-2572 Recurrent Stroke PreventionPROGRESSDiuretic, ACEI NKF-ADA Guideline, UKPDS, ALLHAT NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK Diuretic, BB, ACEI, ARB, CCB ACEI, ARB Diabetes Mellitus Chronic Kidney Disease

22. 22 Lipid Management Goal LDL-C should be less than 100 mg/dL Further reduction to LDL-C to < 70 mg/dL is reasonable *Non-HDL-C = total cholesterol minus HDL-C If TG >200 mg/dL, non-HDL-C should be < 130 mg/dL*

23. 23 Risk CategoryLDL-C and non-HDL- C Goal Initiate TLC Consider Drug Therapy High risk: CHD or CHD risk equivalents (10-year risk >20%) and <100 mg/dL if TG > 200 mg/dL, non-HDL-C should be < 130 mg/dL  100 mg/dL >100 mg/dL (<100 mg/dL: consider drug options) Very high risk: ACS or established CHD plus: multiple major risk factors (especially diabetes) or severe and poorly controlled risk factors <70 mg/dL, non-HDL-C < 100 mg/dL All patients>100 mg/dL (<100 mg/dL: consider drug options) Grundy, S. et al. Circulation 2004;110:227-39. Lipid Management Goals: NCEP ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes

24. 24 Lipid Management Recommendations Start dietary therapy (<7% of total calories as saturated fat and <200 mg/d cholesterol) Adding plant stanol/sterols (2 gm/day) and viscous fiber (>10 mg/day) will further lower LDL Promote daily physical activity and weight management. Encourage increased consumption of omega-3 fatty acids in fish or 1 g/day omega-3 fatty acids in capsule form for risk reduction. For all patients

25. 25 *Trans fatty acids also raise LDL-C and should be kept at a low intake. Note: Regarding total calories, balance energy intake and expenditure to maintain desirable body weight. <200 mg/dCholesterol ~15% of total caloriesProtein 20–30 g/dFiber 50%–60% of total caloriesCarbohydrate (esp. complex carbs) 25%–35% of total caloriesTotal fat Up to 20% of total caloriesMonounsaturated fat Up to 10% of total caloriesPolyunsaturated fat <7% of total caloriesSaturated fat* Recommended IntakeNutrient Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. ATP III Dietary Recommendations ATP=Adult Treatment Panel

26. 26 Lipid Management Recommendations If baseline LDL-C > 100 mg/dL, initiate LDL-lowering drug therapy If on-treatment LDL-C > 100 mg/dL, intensify LDL- lowering drug therapy (may require LDL lowering drug combination) If baseline is LDL-C 70 to 100 mg/dL, it is reasonable to treat to LDL < 70 mg/dL Assess fasting lipid profile in all patients, and within 24 hours of hospitalization for those with an acute event. For patients hospitalized, initiate lipid-lowering medication as recommended below prior to discharge according to the following schedule: When LDL lowering medications are used, obtain at least a 30-40% reduction in LDL-C levels.

27. 27 Lipid Management Recommendations If TG are 200-499 mg/dL, non-HDL-C should be < 130 mg/dL Further reduction of non-HDL to < 100 mg/dL is reasonable Therapeutic options to reduce non-HDL-C: More intense LDL-C lowering therapy I (B) or Niacin (after LDL-C lowering therapy) IIa (B) or Fibrate (after LDL-C lowering therapy) IIa (B) If TG are > 500 mg/dL, therapeutic options to prevent pancreatitis are fibrate or niacin before LDL lowering therapy; and treat LDL-C to goal after TG-lowering therapy. Achieve non-HDL-C < 130 mg/dL, if possible

28. 28 Baseline LDL-C (mg/dL) Statin (n = 10,269) Placebo (n = 10,267) <100 282 (16.4%) 358 (21.0%) 100–129 668 (18.9%) 871 (24.7%)  130 1083 (21.6%) 1356 (26.9%) All patients 2033 (19.8%) 2585 (25.2%) Event Rate Ratio (95% CI) Statin BetterStatin Worse 0.40.60.81.01.21.4 0.76 (0.72–0.81) P<0.0001 Heart Protection Study (HPS) HMG-CoA Reductase Inhibitor: Secondary Prevention 20,536 patients with CAD, other occlusive arterial disease, or DM randomized to simvastatin (40 mg) or placebo for 5.5 years CAD=Coronary artery disease, CI=Confidence interval, DM=Diabetes mellitus, HPS Collaborative Group. Lancet 2002;360:7-22

29. 29 Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study 3 6 9 1215 182124 27 30 Follow-up (months) 30 25 20 15 10 5 0 P =0.005 Recurrent MI or Cardiac Death 16% RRR Atorvastatin Pravastatin ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Cannon CP et al. NEJM 2004;350:1495-1504 HMG-CoA Reductase Inhibitor: Secondary Prevention 4,162 patients with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months

30. 30 LaRosa JC et al. NEJM. 2005;352:1425-1435 LDL-C=Low density lipoprotein cholesterol; 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. 30 25 20 15 10 5 0 07090110130150170190210 LDL-C (mg/dL) TNT (atorvastatin 80 mg/d) TNT (atorvastatin 10 mg/d) HPS CARE LIPID CARE HPS Event (%) 4S Statin Placebo Relationship between LDL Levels and Event Rates in Secondary Prevention Trials of Patients with Stable CHD HMG-CoA Reductase Inhibitor: Secondary Prevention

31. 31 HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol, TC=Total cholesterol, TG=Triglycerides *Daily dose of 40mg of each drug, excluding rosuvastatin. TherapyTCLDLHDLTG 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%  14-35%  30-70% Reasonable to Poor Fibrates  19%  4-21%  11-13%  30% Good Lipid Management Pharmacotherapy

32. 32 Physical Activity Recommendations Assess risk with a physical activity history and/or an exercise test, to guide prescription Encourage 30 to 60 minutes of moderate intensity aerobic activity such as brisk walking, on most, preferably all, days of the week, supplemented by an increase in daily lifestyle activities Advise medically supervised programs for high-risk patients (e.g. recent acute coronary syndrome or revascularization, HF) Goal: 30 minutes 7 days/week, minimum 5 days/week

33. 33 Observational study of self-reported physical activity in 772 men with established coronary heart disease Light or moderate exercise is associated with lower risk Wannamethee SG et al. Circulation 2000;102:1358-1363 Exercise Evidence: Mortality Risk

34. 34 Weight Management Recommendations Goal: BMI 18.5 to 24.9 kg/m2 Waist Circumference: Men: < 40 inches Women: < 35 inches Assess BMI and/or waist circumference on each visit and consistently encourage weight maintenance/ reduction through an appropriate balance of physical activity, caloric intake, and formal behavioral programs when indicated. If waist circumference (measured at the iliac crest) >35 inches in women and >40 inches in men initiate lifestyle changes and consider treatment strategies for metabolic syndrome as indicated. The initial goal of weight loss therapy should be to reduce body weight by approximately 10 percent from baseline. With success, further weight loss can be attempted if indicated. *BMI is calculated as the weight in kilograms divided by the body surface area in meters 2. Overweight state is defined by BMI=25-30 kg/m2. Obesity is defined by a BMI >30 kg/m2.

35. 35 Mhurchu N et al. Int J Epidemiol 2004;33:751-758 0.5 1.0 2.0 4.0 162024283236 Body Mass Index (kg/m 2 )* Hazard Ratio 0.5 1.0 2.0 4.0 162024283236 0.5 1.0 2.0 4.0 162024283236 Hemorrhagic Stroke Ischemic Stroke Ischemic Heart Disease CV Risk Increases with Body Mass Index CV=Cardiovascular Body mass index is calculated as the weight in kilograms divided by the body surface area in meters 2.

36. 36 Grundy, et al. Diagnosis and management of the metabolic syndrome: an AHA/NHLBI Scientific Statement. Circulation 2005;112:2735-2752. Risk FactorDefining Level Waist circumference (abdominal obesity)>40 in (>102 cm) in men >35 in (>88 cm) in women Triglyceride level>150 mg/dl HDL-C level<40 mg/dl in men <50 mg/dl in women Blood pressure>130/>85 mmHg Fasting glucose>100 mg/dl Definition of the Metabolic Syndrome Defined by presence of >3 risk factors HDL-C=High-density lipoprotein cholesterol

37. 37 3,234 patients with elevated fasting and post-load glucose levels randomized to placebo, metformin (850 mg twice daily), or lifestyle modification* for 2.8 years Lifestyle modification reduces the risk of developing DM Metabolic Syndrome: Risk of Developing DM Diabetes Prevention Program (DPP) Knowler WC et al. NEJM 2002;346:393-403 *Includes 7% weight loss and at least 150 minutes of physical activity per week Placebo Metformin Lifestyle modification Incidence of DM (%) 20 40 0 1423

38. 38 Diabetes Mellitus Recommendations Goal: Hb A1c < 7% Lifestyle and pharmacotherapy to achieve near normal HbA1C (<7%). Vigorous modification of other risk factors (e.g., physical activity, weight management, blood pressure control, and cholesterol management as recommended). Coordinate diabetic care with patient’s primary care physician or endocrinologist. ) HbA1c = Glycosylated hemoglobin

39. 39 Antiplatelet Agents / Anticoagulation Recommendations

40. 40 Aspirin Recommendations Start and continue indefinitely aspirin 75 to 162 mg/d in all patients unless contraindicated For patients undergoing CABG, aspirin (100 to 325 mg/d) should be started within 48 hours after surgery to reduce saphenous vein graft closure Post-PCI-stented patients should receive 325 mg per day of aspirin for 1 month for bare metal stent, 3 months for sirolimus-eluting stent and 6 months for paclitaxel-eluting stent

41. 41 Start and continue clopidogrel 75 mg/d in combination with aspirin for post ACS or post PCI with stent placement patients for up to 12 months for post PCI-stented patients >1 month for bare metal stent, >3 months for sirolimus-eluting stent >6 months for paclitaxel-eluting stent * Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile Clopidogrel Recommendations

42. 42 Anticoagulation Recommendations Manage warfarin to international normalized ratio 2.0 to 3.0 for paroxysmal or chronic atrial fibrillation or flutter, and in post-MI patients when clinically indicated (e.g., atrial fibrillation, LV thrombus.) Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with increased risk of bleeding and should be monitored closely

43. 43 Aspirin Evidence: Secondary Prevention Antithrombotic Trialist Collaboration. BMJ 2002;324:71–86. Category % Odds Reduction Acute myocardial infarction Acute stroke Prior myocardial infarction Prior stroke/transient ischemic attack Other high risk Coronary artery disease (e.g. unstable angina, heart failure) Peripheral arterial disease (e.g. intermittent claudication) High risk of embolism (e.g. atrial fibrillation) Other (e.g. diabetes mellitus) All trials 1.00.50.01.52.0 Control better Antiplatelet better Effect of antiplatelet therapy* on vascular events** *Aspirin was the predominant antiplatelet agent studied **Vascular events include MI, stroke, or death

44. 44 Aspirin Evidence: Dose and Efficacy 0.51.01.52.0 500-1500 mg34 19 160-325 mg19 26 75-150 mg12 32 <75 mg 3 13 Any aspirin65 23 Antiplatelet Better Antiplatelet Worse Aspirin Dose No. of Trials (%) Odds Ratio for Vascular Events 0 P<.0001 Indirect Comparisons of Aspirin Doses on Vascular Events in High-Risk Patients Antithrombotic Trialists Collaboration. BMJ. 2002;324:71-86

45. 45 Clopidogrel Evidence: ACS (Non-STEMI and UA) Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial The CURE Trial Investigators. NEJM. 2001;345:494-502 NSTEMI-ACS=Non ST-segment elevation acute coronary syndrome 369012 Rate of death, myocardial infarction, or stroke P<0.001 Months of Follow Up Aspirin + Clopidogrel Aspirin + Placebo 12,562 patients with a NSTEMI-ACS randomized to daily aspirin (75-325 mg) or clopidogrel (300 mg load, 75 mg thereafter) plus aspirin (75-325 mg) for 3-12 months (average 9 months)

46. 46 Steinhubl S et al. JAMA 2002; 288:2411-20 Clopidogrel for the Reduction of Events during Observation (CREDO) Trial Clopidogrel Evidence: Post PCI DAP=Dual antiplatelet therapy, PCI=Percutaneous coronary intervention, RRR=Relative risk reduction *Dual antiplatelet therapy=Aspirin (75-325 mg daily) plus Clopidogrel (300 mg load followed by 75 mg daily). 0 123690 Risk of MI, Stroke, or Death (%) 27% RRR, P=0.02 10 5 15 4 weeks of DAP 1 year of DAP Months from Randomization 2 2,116 patients undergoing PCI randomized to 4 weeks of DAP* followed by aspirin (75-325 mg) monotherapy vs persistent DAP* for 1 year

47. 47 Renin-Angiotensin-Aldosterone System Blockers Recommendations

48. 48 ACE Inhibitor Recommendations Use in all patients with LVEF < 40%, and those with diabetes or chronic kidney disease indefinitely, unless contraindicated Consider for all other patients Among lower risk patients with normal LVEF where cardiovascular risk factors are well controlled and where revascularization has been performed, their use may be considered optional ACE=Angiotensin converting enzyme, LVEF= left ventricular ejection fraction

49. 49 Angiotensin Receptor Blocker Recommendations Use in patients who are intolerant of ACE inhibitors with HF or post MI with LVEF less than or equal to 40%. Consider in other patients who are ACE inhibitor intolerant. Consider use in combination with ACE inhibitors in systolic dysfunction HF. ACE=Angiotensin converting enzyme inhibitor, LVEF=Left Ventricular Ejection fraction, HF=Heart failure, MI=Myocardial infarction

50. 50 Aldosterone Antagonist Recommendations Use in post MI patients, without significant renal dysfunction or hyperkalemia, who are already receiving therapeutic doses of an ACE inhibitor and beta blocker, have an LVEF < 40% and either diabetes or heart failure ACE=Angiotensin converting enzyme inhibitor, LVEF=Left Ventricular Ejection fraction, MI=Myocardial infarction *Contraindications include abnormal renal function (creatinine >2.5 mg/dL in men or >2.0 mg/dL in women) and hyperkalemia (K+ >5.0 meq/L)

51. 51 Years Probability of Event 0 0.05 0.15 0.2 0.25 0.3 0123 0.35 0.4 4 ACE-I Placebo OR: 0.74 (0.66–0.83) 0.1 Flather MD, et al. Lancet. 2000;355:1575–1581 SAVE Radionuclide EF  40% AIRE Clinical and/or radiographic signs of HF TRACE Echocardiogram EF  35% ACE Inhibitor Evidence: Post MI with LVD or HF ACE-I=Angiotensin converting enzyme inhibitors, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction, OR=Odds ratio

52. 52 ACE Inhibitor Evidence: CAD, CVD, PVD or DM Days of Follow-Up CV death, MI, or stroke (%) 22% RRR, P<0.001 0.00 0.05 0.10 0.15 0.20 050010001500 Placebo Ramipril HOPE Investigators. NEJM 2000;342:145-153 Heart Outcomes Prevention and Evaluation (HOPE) Study ACE-I=Angiotensin converting enzyme inhibitors, DM=Diabetes mellitus, CV=Cardiovascular, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction 9, 9,297 patients with DM or vascular disease plus one additional CV risk factor, but without HF or known LVSD randomized to ramipril (10 mg) or placebo for 5 years

53. 53 00.511.5 2 Cardiovascular death (0.86; 0.72-1.03) Non-fatal MI (0.78; 0.20-0.90) Cardiac arrest (0.54; 0.20-1.47) Combined endpoint (0.80; 0.71-0.91) ACE Inhibitor Evidence: CAD European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) Favors PerindoprilFavors Placebo EUROPA Investigators. Lancet 2003;362:782-788 13,655 patients with CAD and presumed normal left ventricular function randomized to perindopril (8 mg) or placebo for 4.2 years ACE-I=Angiotensin converting enzyme inhibitors, CAD=Coronary artery disease, CV=Cardiovascular, MI=Myocardial infarction

54. 54 ACE Inhibitor Evidence: CAD Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial Primary End Point (%)* 30 25 20 15 10 5 0 0 1 2 3 4 5 6 Years After Randomization Placebo Trandolapril PEACE Trial Investigators. NEJM 2004;351:2058-2068 *Includes death from cardiovascular causes, myocardial infarction, or coronary revascularization 8,290 patients with stable coronary artery disease and normal left ventricular function randomized to trandolapril (4 mg) or placebo for 4.8 years

55. 55 ACE Inhibitor Evidence: Secondary Prevention Comparison between the HOPE and PEACE trials Braunwald, E. et al., NEJM 2004;351:2058-68. CHD=Coronary heart disease, MI=Myocardial infarction *Reflects greater blood pressure control, revascularization, and use of other risk-reducing medications (i.e., antiplatelet therapy,  -blocker, lipid-lowering medication) MI, Cardiac death, or Stroke (%) Years

56. 56 ARB Evidence: Post MI with LVD or HF Pfeffer M et al. NEJM 2003;349:1893-1906. Valsartan in Acute Myocardial Infarction Trial (VALIANT) 0.0 0.1 0.2 0.3 0.4 0 612 18243036 Valsartan Valsartan and Captopril Captopril All Cause Mortality Months Valsartan vs. Captopril: HR = 1.00; P = 0.982 Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726 EF=Ejection fraction, HR=Hazard ratio, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction, RAS=Renin angiotensin system 14,703 patients with post-MI HF or LVSD (EF <0.40) randomized to captopril (50 mg three times daily), valsartan (160 mg twice daily), or captopril (50 mg three times daily) plus valsartan (80 mg twice daily) over 2 years

57. 57 ARB Evidence: Heart Failure Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) Alternative Trial Granger CB et al. Lancet. 2003;362:772-777 ACE-I=Angiotensin converting enzyme inhibitors, ARB=Angiotensin receptor blockers, EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction 012 3 Years 50 HR 0.77 p=0.0004 0 40 30 20 10 Candesartan Placebo CV Death of Hospitalization for HF 2,028 patients with symptomatic HF, LVSD (EF <40%), and intolerance to ACE-I randomized to candesartan (32 mg) or placebo over 34 months

58. 58 ARB Evidence: Heart Failure 0123 0 10 20 30 40 50 3.5 HR 0.85, p=0.011 Candesartan Placebo CV Death of Hospitalization for HF Years Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) Added Trial ACE-I=Angiotensin converting enzyme inhibitors, ARB=Angiotensin receptor blockers, EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, RAS=Renin angiotensin system McMurray JJ et al. Lancet. 2003;362:767-71 2,548 patients with symptomatic HF and LVSD (EF <40%) randomized to candesartan (32 mg) or placebo in addition to an ACE-I over 34 months

59. 59 Pitt B et al. NEJM 1999;341:709-717 Aldosterone Antagonist: Heart Failure Randomized Aldactone Evaluation Study (RALES) EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, NYHA=New York Heart Association RR = 0.70, P<0.001 Months Survival (%) 3633302724211815129630 1.00.90.80.70.60.50 0 Spironolactone Placebo 1,663 patients with NYHA Class III or IV HF and LVSD (EF <0.35) randomized to spironolactone (25 mg) or placebo (50 mg) for 24 months

60. 60 Aldosterone Antagonist: Post MI HF and LVSD Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) RR = 0.85, P=0.008 61218243036 0 5 10 15 20 25 0 All Cause Mortality (%) Month Eplerenone Placebo 6,644 patients with evidence of heart failure and LVSD (EF <0.40) after a MI randomized to eplerenone (50 mg) or placebo for 16 months Pitt B et al. NEJM 2003;348:1309-21 EF=Ejection fraction, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction

61. 61  -blocker Recommendations

62. 62 Start and continue indefinitely in all post MI, ACS, LV dysfunction with or without HF symptoms, unless contraindicated. Consider chronic therapy for all other patients with coronary or other vascular disease or diabetes unless contraindicated. *Precautions but still indicated include mild to moderate asthma or chronic obstructive pulmonary disease, insulin dependent diabetes mellitus, severe peripheral arterial disease, and a PR interval >0.24 seconds. MI=Myocardial infarction, HF=Heart Failure  -blocker Recommendations

63. 63 Phase of Treatment Acute treatment Secondary prevention Overall Total # Patients 28,970 24,298 53,268 0.51.02.0 RR of death  -blocker better RR (95% CI) Placebo better 0.87 (0.77-0.98) 0.77 (0.70-0.84) 0.81 (0.75-0.87)  -blocker Evidence Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A textbook of Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, 1168. Summary of Secondary Prevention Trials of  -blocker Therapy CI=Confidence interval, RR=Relative risk

64. 64 6,644 patients with LVEF <0.40 after a MI with or without HF randomized to carvedilol or placebo for 24 months The CAPRICORN Investigators. Lancet. 2001;357:1385–1390. RR 0.77 P=.03 0.7 0.75 0.8 0.85 0.9 0.95 1 00.511.522.5 Carvedilol Placebo Years Proportion Event-free n=975 n=984  -blocker Evidence: Post MI with Left Ventricular Dysfunction Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN)

65. 65 StudyDrug HF Severity Patients (n) Follow-up (years) Mean Dosage Effects on Outcomes CIBISBisoprolol*Moderate- Severe 6411.93.8 mg/day All cause mortality  22% (p=NS) CIBIS-IIBisoprolol*Moderate- Severe 2,6471.37.5 mg/day All cause mortality  34% (P<0.0001) BESTBucindolol*Moderate- Severe 2,7082.0152 mg/day All cause mortality  10% (p=NS) MERIT-HFMetoprolol succinate # Mild- Moderate 3,9911.0159 mg/day All cause mortality  34% (P=0.0062) MDCMetprolol tartrate* Mild- Moderate 3831.0108 mg/day Death or Need for Tx  30% (P=NS) CAPRICORNCarvedilolMild1,9891.340 mg/day All cause mortality  23% (P =0.03) US CarvedilolCarvedilolMild- Moderate 1,0940.545 mg/day All-cause mortality†  65% (P=.0001) COPERNICUSCarvedilolSevere2,2890.937 mg/day All-cause mortality  35% (P =0.0014)  -blocker Evidence: Benefit in HF and LVSD *Not an approved indication † Not a planned end point. # Not approved for severe HF or mortality reduction alone

66. 66 Influenza Vaccination Patients with cardiovascular disease should have influenza vaccination

67. 67 Influenza Vaccination Evidence Community cohort of 140,055 subjects in the 1998–1999 season of which 55.5 % were immunized. Nichol et al. N Engl J Med 2003;348:1322-32. Hospitalization Vaccinated Subjects (N=77,738) Unvaccinated Subjects (N=62,317) Adjusted Odds Ratio P value Pneumonia or influenza495 (0.6)581 (0.9) 0.68 (0.60–0.78) <0.001 Cardiac disease888 (1.1)1026 (1.6) 0.81 (0.73–0.89) <0.001 Ischemic heart disease457 (0.6)535 (0.9) 0.80 (0.70–0.91) 0.001 Heart failure466 (0.6)538 (0.9) 0.81 (0.70–0.92) 0.002 Cerebrovascular disease398 (0.5)427 (0.7) 0.84 (0.72–0.97) 0.018 Death943 (1.2)1361 (2.2) 0.52 (0.47–0.57) <0.001 Hospitalization or death2387 (3.1)2910 (4.7) 0.65 (0.62–0.70) <0.001 Effectiveness of Influenza Vaccination during the Influenza Seasons

68. 68 The Need to Implement Secondary Prevention Multiple studies of the use of these recommended therapies in appropriate patients continue to show that many patients in whom therapies are indicated are not receiving them in actual clinical practice. The AHA and ACC urge that in all medical care settings where these patients are managed that programs to provide practitioners with useful reminder clues based on the guidelines, and continuously assess the success achieved in providing these therapies to the patients who can benefit from them be implemented. Encourage that the AHA’s Get With the Guidelines and/or ACC’s Guidelines Applied to Practice Programs be instituted to identify appropriate patients for therapy

69. 69 AHA GWTG Program GWTG is a national initiative of the AHA to improve guidelines adherence in patients hospitalized with cardiovascular disease. GWTG uses collaborative learning sessions, conference calls, e-mail and staff support to assist hospital teams improve acute and secondary prevention care systems. A web-based Patient Management Tool is used for point of care data collection and decision support, on-demand reporting, communication and patient education.

70. 70 Demographics 6 clicks Clinical/Lab 8 clicks Dischargemeds and interventions 7 clicks Interactively checks patient’s data with the AHA guidelines SIMPLE, ONE PAGE, ON-LINE FORM ©2001 Outcome Sciences, Inc.

71. 71 Impact of AHA Get With The Guidelines-CAD Program on Quality of Care * ** * * p< 0.05 compared to baseline * * * * * * * * GWTG-CAD: 123 US Hospitals n=27,825 Labresh, Fonarow et al. Circulation 2003;108:IV-722 * *

72. 72 AHA/ACC Secondary Prevention for Patients with Coronary Artery and Other Atherosclerotic Vascular Disease Circulation 2006;113:2363-2372 and J Am Coll Cardiol 2006;47:2130-2139

73. 73 Evidence confirms that aggressive comprehensive risk factor management improves survival, reduces recurrent events and the need for interventional procedures, and improves the quality of life for these patients. Every effort should be made to ensure that patients are treated with evidence-based, guideline recommended, life-prolonging therapies in the absence of contraindications or intolerance. Secondary Prevention Conclusions