1. presented by Paul St. Laurent, MSN, RN, ACNP, CCRN Acute Care Nurse Practitioner Baylor Heart and Vascular Hospital

2. What Do We Already Know?  Aspirin reduces the risk of myocardial infarction  Antiplatelet therapy reduces stent thrombosis  Beta blockers reduce post MI mortality  ACE inhibitors and angiotensin receptor blockers inhibit LV remodeling  Statins reduce major coronary events 2 TRUE OR FALSE?

3. Evidence Based Medicine (EBM) “The conscientious, explicit and judicious use of current best evidence in making decisions about the care of the individual patient. It means integrating individual clinical expertise with the best available external clinical evidence from systematic research." 3 Sackett DL, BMJ, 1996:312 (7023): 71-72

4. Steps in EBM Process THE PATIENT 1: THE PATIENT Clinical problem arises from care of patient THE QUESTION 2: THE QUESTION Construct question derived from case THE RESOURCE 3: THE RESOURCE Select resource, conduct search THE EVALUATION 4: THE EVALUATION Appraise evidence for validity and applicability THE PATIENT 5: THE PATIENT Integrate evidence with clinical expertise, patient preferences and apply it to practice SELF-EVALUATION 6: SELF-EVALUATION Evaluate your performance with this patient 4 http://www.hsl.unc.edu/services/tutorials/ebm/index.htm

5. Case Scenario  STEP 1: The patient Mrs. Jones BP is 160/80  STEP 2: The question What BP medication should she take? PMH: DM and chronic kidney disease Thiazide, BB, ACEI, ARB, CCB, other?  STEP 3: The resources National hypertension guidelines National Heart, Lung, and Blood Institute (JNC 7), National Kidney Foundation, European Society of Hypertension 5

6. JNC 7  Published in 2003  Coalition of 39 major professional, public, and voluntary organizations, and seven federal agencies  Incorporates results of many large-scale clinical trials 6

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8. Case Scenario  STEP 4: The evaluation Which ACEI or ARB is best? Review literature for validity and applicability  STEP 5: The patient Prefers once a day dosing Prefers generic $4 list You prescribe lisinopril 20 mg daily  STEP 6: Self-evaluation Mrs. Jones returns for follow up in 4 weeks BP 140/72 8

9. Coronary Artery Disease 9

10. Antiplatelet Medications 10

11. Aspirin: Mechanism of Action  Most widely studied antiplatelet drug  Some of strongest evidence available about long term effects pertain to patients with coronary disease  Irreversibly inhibits COX-1 within platelets, prevents formation of thromboxane A2, diminishes platelet aggregation  Platelet inhibition mechanism for clinical benefit 11

12. Antiplatelet Effect of Aspirin 12

13. Aspirin: The Evidence  Antithrombotic Trialists’ Collaboration (2002)  Collaborative meta-analysis of randomized trials  287 studies, 135,000 patients  25% REDUCTION in combined outcome of any serious vascular event Non-fatal MI, non-fatal stroke, death from any vascular cause 13 Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2001;324:71-86.

14. Aspirin Dosing  No trial has compared different doses of ASA in patients who present with UA/NSTEMI  Indirect comparisons of doses ranging from less than 75 mg to up to 1500 mg Similar reductions in the odds of vascular events  Less than 75 mg daily Benefit reduced by at least half compared with higher doses 14

15. Aspirin Dosing  Analysis from CURE trial suggested no difference in rate of thrombotic events according to ASA dose, but there was a dose- dependent increase in bleeding  Major bleeding rate 2.0% in patients taking < 100 mg daily 2.3% with 100 mg - 200 mg daily 4.0% with > 200 mg daily  Therefore, maintenance doses of 75 -162 mg PREFERRED 15 Yusuf, S., et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndrome without ST-segment elevation. N Engl J Med 2001;345:494-502.

16. So What is The Recommended Dose of Aspirin in CAD? 16

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18. ACC/AHA Guidelines  ACC and AHA jointly engaged in producing guidelines since1980  ACC/AHA Task Force on Practice Guidelines charged to develop, update, or revise guidelines for important cardiovascular diseases and procedures  Current guidelines include: STEMI (2009), USA/NSTEMI (2007), Chronic stable angina (2007), PCI (2009), chronic heart failure (2009), valvular disease (2008), PAD (2005) 18

19. 19 http://www.americanheart.org/presenter.jhtml?identifier=3004542

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22. Aspirin Recommendations  UA/NSTEMI/STEMI without stenting Aspirin 75 – 162 mg indefinitely (LOE: A)  UA/NSTEMI/STEMI with BMS Aspirin 162 – 325 mg at least one month, then 75 – 162 mg indefinitely (LOE: A)  UA/NSTEMI/STEMI with DES Aspirin 162 mg – 325 mg at least 3 months for sirolimus-eluting, at least 6 months for paclitaxel- eluting, then 75 – 162 mg indefinitely (LOE: A) 22 CLASS I

23. Thienopyridines: Mechanism of Action  Adenosine diphosphate (ADP) receptor antagonists  Prevent adenosine diphosphate from binding to its receptor on platelets  Stops activation of glycoprotein IIb/IIIa complex thereby inhibiting platelet activation  Prodrugs: require metabolism by cytochrome P450 enzyme to become active  Clopidogrel and prasugrel 23

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25. Thienopyridines: Clinical Benefits  Monotherapy and in combination with aspirin Clopidogrel: CAPRIE, CURE, CHARISMA Prasugrel: TRITON-TIMI 38  CAPRIE (1996) Monotherapy with clopidogrel vs. aspirin Primary end-point composite of vascular death, MI, stroke Favored clopidogrel (5.3% vs. 5.8%) 25 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.

26. Thienopyridines: The Evidence  CURE (2001) Dual therapy: aspirin + clopidogrel or aspirin + placebo in ACS patients Clopidogrel: 20% REDUCTION in end point of CV death, MI or stroke at 12 months  CHARISMA (2006) Dual therapy with clopidogrel + aspirin vs. aspirin alone in patients at high risk for atherothrombotic events No statistical difference overall Significant benefit in subset of patients with prior MI 26 Bhatt, DL., et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-1717. Yusuf, S., et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.

27. Prasugrel  FDA approved July 10, 2009  TRITON-TIMI 38 Randomized, double-blind study Compared prasugrel (60 mg LD, 10 mg MD) to clopidogrel (300 mg LD, 75 mg MD) in patients undergoing PCI 19% relative risk reduction in primary composite endpoint of death, nonfatal MI, or nonfatal stroke at expense of significant increase in the risk of major bleeding 27 Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015.

28. Thienopyridine Recommendations  UA/NSTEMI/STEMI without stenting LD: Clopidogrel 300-600 mg/prasugrel (STEMI only) 60 mg (LOE: B) MD: Clopidogrel 75 mg/prasugrel 10 mg for 1 month, ideally for 1 year (LOE: B)  UA/NSTEMI/STEMI with BMS Clopidogrel 75 mg/prasugrel 10 mg (STEMI only) for at least 1 month (LOE: B)  UA/NSTEMI/STEMI with DES Clopidogrel 75 mg/prasugrel 10 mg (STEMI only) for at least 1 year (LOE: B) 28 CLASS I

29. Loading Doses  Clopidogrel 300 mg loading dose Well established for use in patients with acute coronary syndrome Inhibition of platelet aggregation 30% - 40% Time to peak effect 4 to 6 hours  Clopidogrel 600 mg loading dose Inhibits platelet aggregation > 40% Time to peak effect 2 to 3 hours Reduces clopidogrel hyporesponsiveness 29

30. Loading Doses: The Evidence  Meta-analysis of 10 studies 1,567 patients undergoing PCI, variety of loading doses (300 mg – 900 mg) Result: high loading doses significantly reduce early ischemic events in patients scheduled for PCI  HORIZONS-AMI 3,311 patients with STEMI receiving either 300 mg or 600 mg loading dose 600 mg:  30-day mortality, subacute stent thrombosis, major adverse cardiac events, with no increase in bleeding 30 Lotrionte, M., et al. Meta-analysis appraising high clopidogrel loading in patients undergoing percutaneous coronary intervention. Am J Cardiol 2007;100:1199-1206. Dangas, G., et al. Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty. J Am Coll Cardiol 2009;54:1438-1446.

31. Loading Doses: The Evidence  ARMYDA-5 PRELOAD Trial  409 patients randomized to 600 mg clopidogrel 4-8 hours before PCI or in the cath lab after angiography but prior to PCI  No difference in primary end-point of 30-day incidence of cardiac death, myocardial infarction, or unplanned target vessel revascularization 31 Sciascio, G., et al. Effectiveness of in-laboratory high-dose clopidogrel loading versus routine pre-load in patients undergoing percutaneous coronary intervention. J Am Cardio 2010;56:550-557.

32. Beta-Blockers: Mechanism of Action  Block the action of adrenergic catecholamines (norepinephrine and epinephrine) on  - adrenergic receptors   1 receptor mainly in heart   2 receptor mainly in lungs, vascular smooth muscle, skeletal muscle  Cardioselective “selectively” block  1  Nonselective block  1 and  2 32

33. Beta Blockers: Clinical Benefits  Decreased oxygen demand due to reduction in BP, HR, contractility, and relief of chest pain  Decreased risk of VF and sudden cardiac death  Decreased HR prolongs diastole, and enhances coronary artery perfusion  Reduces remodeling, and enhances hemodynamic function 33

34. Beta Blockers: The Evidence  US Carvedilol Study (1996) Carvedilol vs placebo in HF patients 65% REDUCTION IN MORTALITY  CIBIS-II and MERIT-HF (1999) Bisoprolol and metoprolol vs placebo in HF patients 34% REDUCTION IN MORTALITY  CAPRICORN (2001) Carvedilol vs placebo in AMI patients with EF ≤ 40% 23% REDUCTION IN MORTALITY 34

35. Beta Blockers: The Evidence  EPIC (1994), EPILOG (1997), EPISTENT (1998), CAPTURE (1997), RAPPORT (1998) Pooled results of 2894 patients with UA and AMI undergoing PCI 1939 patients received BB, 934 did not 50% REDUCTION IN MORTALITY at 30 days and 6 months 35 Ellis, K. et al. Mortality benefit of beta blockade in patients with acute coronary syndromes undergoing coronary intervention. J Interven Cardiol 2003;16;2999-305

36. Beta Blocker Recommendations  UA/NSTEMI/STEMI It is beneficial to start and continue beta-blocker therapy indefinitely in all patients who have had MI, acute coronary syndrome, or LV dysfunction with or without HF symptoms, unless contraindicated (LOE: A) 36 CLASS I

37. Beta Blocker: Selection  Cardio-selective vs nonselective  Contraindications Marked 1 st degree, 2 nd /3 rd degree AVB, significant sinus bradycardia, hypotension, history of asthma, low output state, severe LV dysfunction Significant COPD: short-acting B 1 agent at low dose Reassess when acute problems have resolved 37

38. Beta-Blocker Selection  Dosing considerations Daily: metoprolol succinate, carvedilol phosphate, atenolol, nevibolol BID: metoprolol tartrate, carvedilol, labetalol  Evidence-based beta blockers HF: metoprolol succinate, carvedilol, bisoprolol 38

39. ACE Inhibitors: Mechanism of Action  Angiotensin converting enzyme inhibitors  Block the enzyme that converts antiogensin I to angiotensin II  Block bradykinin, which increases nitric oxide release, promotes vasodilation  Block aldosterone 39

40. ACE Inhibitors: Clinical Benefit  Inhibits LV remodeling, preserves LV function  Afterload reduction (vasodilation) Reduces blood pressure  Reduce infarct size  Improves endothelial function  Reduces overall cardiovascular mortality 40

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42. ACE Inhibitors: The Evidence  SAVE(1992), AIRE (1993),TRACE (1999) 5966 patients after with LV dysfunction post MI 26% REDUCTION in death, MI, hospital admission for HF  HOPE (2003), QUIET (2001), PART-2 (2000), SCAT (2000), EUROPA (2003), PEACE (2004), CAMELOT (2004) 14% REDUCTION in death, MI 42

43. ACE Inhibitor Recommendations  UA/NSTEMI/STEMI Should be given and continued indefinitely for patients with HF, LV dysfunction (LVEF < 40%), hypertension, diabetes, and chronic kidney disease, unless contraindicated (LOE: A) 43 CLASS I

44. ACE Inhibitor Selection  Contraindications Hypotension, angioedema, hyperkalemia, bilateral renal artery stenosis, acute renal insufficiency  Dosing considerations Daily: lisinopril, ramipril, enalapril, benazepril, fosinopril, quinapril BID/TID: captopril 44

45. Angiotensin Receptor Blockers (ARBs): Mechanism of Action  Angiotensin II causes potent vasoconstriction, aldosterone secretion and sympathetic activation  ARBs bind to specific membrane-bound receptors that displace angiotensin II from its type 1 receptor subtype (AT 1 ) 45

46. ARBs: The Evidence  VALIANT (2003) Valsartan vs captopril Valsartan equally effective at reducing mortality, CV morbidity  Can be used as alternative if ACEI not tolerated ACEI cough secondary to inhibition of bradykinin pathway 46 Pfeffer, M., et al. Valsartan, captopril, or both in myocardial infraction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003:349:1893-1906.

47. ARB Recommendations  UA/NSTEMI/STEMI Angiotensin receptor blocker should be prescribed at discharge to those UA/NSTEMI patients who are intolerant of an ACE inhibitor and who have either clinical or radiological signs of HF and LVEF < 40% (LOE: A) It is beneficial to use angiotensin receptor blocker therapy in other patients who are ACEI intolerant and have hypertension (LOE: B) 47 CLASS I

48. ARB Selection  Contraindications Same as for ACEI  Dosing considerations Candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan All can be given daily None available in generic form 48

49. Statins: Mechanism of Action  HMG CoA reductase inhibitors competitively inhibit the activity of HMG CoA reductase, which reduces cellular cholesterol concentration  Reduced cholesterol causes up regulation of LDL receptors, and increased uptake of plasma LDL  End result: decreased plasma LDL 49

50. Statins: Clinical Benefits  Plaque stabilization Unstable  stable plaque  Reduces inflammation Contributor of atherosclerosis and plaque rupture Reduces CRP levels  Reverses endothelial dysfunction  endothelial nitric oxide  Decreased thrombogenicity Decreased prothrombin activation and thrombin generation 50

51. Statins: The Evidence LIPID trial 9014 patients with CAD Pravastatin vs placebo 22%  MORTALITY 24%  cardiac death, nonfatal myocardial infarction 51

52. Statins: The Evidence 4S Trial 4444 patients with CAD Simvastatin vs placebo 30%  MORTALITY 52

53. Statin Recommendations CLASS I  Statins, in the absence of contraindications, regardless of baseline LDL-C and diet modification, should be given to post-UA/NSTEMI/STEMI patients, including post revascularization patients (LOE: A)  For hospitalized patients, lipid-lowering medications should be initiated before discharge (LOE: A) 53

54. Statin Recommendations CLASS I  For UA/NSTEMI/STEMI patients with elevated LDL-C (≥100 mg per dL), cholesterol-lowering therapy should be initiated or intensified to achieve an LDL-C < than 100 mg per dL (LOE: A) CLASS IIa  Further titration to < than 70 mg per dL is reasonable (LOE: A) 54

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57. Statin Selection  Contraindications Absolute: active or chronic liver disease  Adverse effects Myopathy, increased liver transaminases  Dosing considerations Generic: lovastatin, pravastatin, simvastatin Take any time: atorvastatin, pitavastatin, pravastatin, rosuvastatin Take in the evening: all others 57

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59. Impact of Combination Therapy  Antiplatelet drugs,  -blockers, ACE inhibitors/ARBs, and lipid-lowering agents reduce mortality  Aspirin:  25%  Thienopyridines:  20 %  BB:  35%  ACEI:  20 %  Statins:  25% 59

60. Impact of Combination Therapy  1264 patients with acute coronary syndrome  Compared number of discharge drugs and 6-month mortality  What was the overall reduction in mortality between patients on all evidence-based medications? 60 Mukherjee, D et al, Impact of Evidence-Based Combination Therapy on Mortality in patients With Acute Coronary Syndromes. Circulation, 2004;109;745-749

61. What Was the Reduction in Mortality?  A: 30%  B: 40%  C: 50%  D: > 60% 61

62. So, How are We Doing?  186,000 eligible patients with AMI between July 1, 2000 and June 30, 2002  National Registry of Myocardial Infarction 4 (NRMI-4) database  1247 hospitals  Early and discharge medications 62 Roe, M. et al. Quality of care by classification of myocardial infarction. Arch Intern Med. 2005;165:1630-1636

63. Results 63 5533 misses 21,394 misses 276,277 MISSED OPPORTUNITIES

64. What About After Discharge?  National Disease and Therapeutic Index and National Ambulatory Medical Care Survey (physician prescribing practices)  1990 to 2002  35,295 patients with CAD  Aspirin use increased from 18% in 1990, to 19% in 1995, to 38% in 2001 64 Stafford, R., et al. The underutilization of cardiac medications of proven benefit, 1990 to 2002. J Am Coll Cardiol 2003:41:56-61

65. What About After Discharge?  Duke Databank for Cardiovascular Disease 1995 to 2002  Self-reported  22,539 patients  Consistently used 71% aspirin, 46% ββ, 44% lipid-lowering 65 Newby, K., et al. Long-Term Adherence to Evidence-Based Secondary Prevention Therapies in Coronary Artery Disease. Circulation. 2006;113:203-212.

66. Key Strategies  Ensure patients receive all 5 EVIDENCED- BASED MEDICATIONS  “Missing” medications should be identified, and action taken  Education to providers in all clinical settings Inpatient, outpatient, cardiologists, primary care providers, physicians, nurses, etc. 66

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68. Why Does it Matter?  5 medications can prevent a heart attack  5 medications can prevent stent thrombosis  5 medications can prevent heart failure  5 medications can save a life 68

69. At What Cost? 69

70. $4 Drugs 70

71. Take 5, Costs $6 71

72. Take Home Message  OVERWHELMING body of evidence supports use of Aspirin Thienopyridines Beta blockers ACE inhibitors/ARBs Lipid-lowering therapy 72

73.  5 medications can significantly impact patient outcomes  Share this message with your patients and colleagues 73

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