National Clinical Guidelines: An Update in Coronary Artery Disease

1. National Clinical Guidelines: An Update in Coronary Artery Disease June 19, 2011 Joseph P. Bryant, Pharm.D., BCPS LCDR, U.S. Public Health Service Indian Health Service

2. Objectives • Review Updated Guidelines for the Management of Coronary Artery Disease (CAD) • ACC/AHA STEMI and NSTEMI Guidelines • Review Key Drug Interactions Impacting CAD • Proton Pump Inhibitors (PPIs) & Clopidogrel • Review important FDA guidance Impacting CAD • Drug Safety Communication – Simvastatin 80mg

3. Background Information

4. Importance of Managing Heart Disease • Cardiovascular (CV) disease is the leading cause of hospitalizations in the U.S. at ~ 6.2 million discharges per year • Is a major contributor to morbidity, morality & healthcare cost • Each year there are more than 1.3 million myocardial infarctions (MIs) • An estimated 2200 Americans die from CV diseases per day • In 2010, the cost of Heart Disease in the U.S. was ~ $316.4 billion

5. STEMI vs. NSTEMI • Classification: • STEMI – ST segment elevation MI • ST segmented elevated on ECG • NSTEMI – Non-ST segment elevation MI • ST segment not elevated, but rather may see ST segment depression, T-wave inversion or no change on ECG • STEMI • Are at the greatest risk of death and reinfarction • Initiate reperfusion therapy as soon as possible • NSTEMI • Initiate therapy based upon risk stratification

6. Risk Stratification in NSTEMI • Thrombosis in Myocardial Infarction (TIMI) Risk Score • Based upon clinical presentation & medical history • Medical Presentation: • ST-segment depression (0.5mm or greater) • Two or more episodes of chest discomfort with past 24 hours • Positive biochemical markers (troponin I or T)

7. Risk Stratification in NSTEMI • Patient History: • Age 65 years or older • Three or more of the following risk factors for CAD: • Hypercholesterolemia • Hypertension • Diabetes Mellitus • Smoking • Family history of premature CHD • Known CAD (50% or greater stenosis of a coronary artery) • Use of aspirin with the past 7 days

8. Risk Stratification in NSTEMI • Score Assessment: • 1 point is assigned for each of the 4 medical history & clinical presentation factors • Total number of points are calculated together which assigns the patient’s risk for the composite end point of death, MI or urgent need for revascularization within 14 days • High risk: 5-7 points • Medium risk: 3-4 points • Low risk: 0-2 points

9. Levels of Recommendations • Class I: Evidence and/or general agreement that procedure or treatment is useful & effective • Class II: Evidence is conflicting and/or there is divergence of opinion regarding the usefulness or efficacy of the procedure or treatment • Class IIa: Recommendations and the weight of evidence or opinion is in favor of the procedure or treatment • Class IIb: Recommendations and the weight of evidence are less established be evidence or opinion • Class III: Recommendation that the treatment or procedure should not be completed • Either not useful or may be harmful

10. Objectives • Review Updated Guidelines for the Management of Coronary Artery Disease (CAD) • ACC/AHA STEMI and NSTEMI Guidelines • Review Key Drug Interactions Impacting CAD • Proton Pump Inhibitors (PPIs) & Clopidogrel • Review important FDA guidance Impacting CAD • Drug Safety Communication – Simvastatin 80mg

11. STEMI Treatment Algorithm

12. NSTEMI Treatment Algorithm

13. NSTEMI Treatment Algorithm

14. Therapeutic Treatment Options

15. Platelet Activation • Platelets adhere to the vascular injury • ADP is released from the platelet • ADP binds to P2Y12 receptors helping activate platelets • Activated platelets expose glycoprotein IIb/IIIa • Exposed GPIIb/IIIa crosslink with fibrin to form platelet aggregates • Aggregates embolize and cause obstructions leading to myocardial ischemia and infarction.

16. Clotting Cascade

17. Aspirin Therapy • MOA: Thromboxane A2 Inhibitor • Recommendation: Class I – STEMI or NSTEMI • Contraindications: • Hypersensitivity, active bleed or severe risk for bleeding • Dosing & Duration of Therapy: • Day 1 (regardless of therapy): 160-325mg • Non-PCI: 75-162mg on day 2 and continue definitely • PCI: Based upon type of stent • Bare metal: 162-325mg for 30 days; then 75-162mg daily • Sirolimus-eluting: 162-325mg for 3months; then 75-162mg daily • Paclitaxel-eluting: 16 -325mg for 6months; then 75-162mg daily • Continue therapy indefinitely

18. Thienopyridine Antiplatelets • MOA: • Irreversibly bind to P2Y12 class of ADP receptors, which prevents GPIIb/IIIa receptor complex and thus reducing platelet aggregation • Effect is for the life of the platelet ~ 7-10 days • FDA Approved Products: • Ticlopidine (Ticlid®) • Clopidogrel (Plavix®) • Prasugrel (Effient®)

19. Clopidogrel (Plavix®) • Contraindications: • Hypersensitivity, active bleeding or severe bleeding risk • Warnings: • Diminished antiplatelet effect due to impaired CYP2C19 function • General risk of bleeding • Patients with recent TIA or stroke • Thrombotic thrombocytopenic purpura • Consider potential PPI interaction • Recommendations: Class I • STEMI & NSTEMI (with or without PCI) with aspirin • Patients with aspirin hypersensitivity • Discontinue 5 days before elective CABG surgery

20. Clopidogrel (Plavix®) • Dosing: • STEMI • Patients receiving fibrinolytic or no reperfusion • 300mg on Day 1; followed by 75mg daily • Patients receiving PCI: • 300-600mg on Day 1; followed by 75mg daily • NSTEMI: • PCI or Non-PCI: • 300-600mg on Day 1, followed by 75mg daily • Duration of Therapy: • Continue for minimum of 12 months (Class I) and up to 15 months if necessary (Class IIb) • Continue indefinitely in patients with aspirin allergy

21. Prasugrel (Effient®) • Contraindications: • Hypersensitivity, active bleeding, prior stroke/TIA • Warnings: • General risk of bleeding • Age >75* • CABG or other surgical procedure • Body weight <60kg • Propensity to bleed • Medications that increase risk of bleeding • Thrombotic thrombocytopenia purpura • Recommendations: Class I • STEMI & NSTEMI with PCI in conjunction with aspirin • Discontinue 7 days before elective CABG surgery

22. Prasugrel (Effient®) • Dosing: • Patients >60kg: 60mg day 1, then 10mg daily • Patients <60kg: 60mg day 1, then 5mg daily • Duration of Therapy: • Continue for a minimum of 12 months (Class I) and up to 15 months if necessary (Class IIb) • Miscellaneous: • Avoid in patients greater than 75 years of age unless patient has Diabetes Mellitus or history of an MI • Pivotal trial for FDA approval –TRITON-TIMI

23. TRITON-TIMI 38 Study • Study design: • MC, International, DB, PG • Patient population: • 13,608 patients with moderate to high-risk ACS who received PCI • Treatment Arms: • Prasugrel 60mg loading dose then 10mg maintenance dose or • Clopidogrel 300mg loading dose and 75mg maintenance dose for 6-15 months • Duration of Therapy: 6-15 months • Both arms where on aspirin daily • Primary outcome: • Death from CV causes, nonfatal MI or nonfatal stroke • Secondary endpoints: • Composite of CV death, nonfatal MI, nonfatal stroke or urgent target revascularization

24. TRITON-TIMI 38 • Pts were followed for a median of 14.5 months • 74% presented with UA/NSTEMI and 26% with STEMI • Sub-Analysis Groups • Diabetes Mellitus • STEMI • Hx of TIA/Stroke

25. TRITON-TIMI Results Primary Endpoint *Post-Hoc analysis

26. TRITON-TIMI Sub-Analysis

27. TRITON-TIMI Sub-Analysis *p<0.05, +non-fatal and fatal MI

28. TRITON-TIMI 38 • Safety Endpoints – non-CABG related TIMI major and life-threatening bleeding and TIMI major and minor bleeding, CABG related TIMI fatal and life-threatening bleeding

29. TRITON-TIMI 38 *non-CABG

30. TRITON-TIMI 38 Conclusions • Dual-antiplatelet therapy with aspirin and prasugrel showed significantly reduced rates of death from CV causes, nonfatal MI or nonfatal stroke versus and stent thrombosis then clopidogrel/aspirin. • Prasugrel/aspirin showed an increased risk of major bleeding ,including fatal bleeding versus clopidogrel/aspirin. • Patients who may not benefit from prasugrel are those >75 years old, weight <60kg, prior hx of TIA/stroke • Patients who may benefit are those with DM or STEMI

31. Unfractionated Heparin • MOA: Potentiates the inhibitory action of Antithrombin III (heparin cofactor) which in turn inhibits clotting factors XIIa, XIa, IXa, Xa & IIa • Contraindications: Active bleed, h/0 of heparin-induced thrombocytopenia (HIT) severe bleeding risk & recent stroke • Recommendations: • STEMI: Patients undergoing PCI or fibrinolytic therapy (Class I) • NSTEMI: Patients undergoing PCI (Class I) or conservative therapy (non-PCI) • Dosing: • Can vary, but typical dose is 60 units/kg IV bolus (max of 4000 units) followed by IV infusion of 12 units/kg/hour (max of 1000 units) • Maintain aPTT at 1.5-2 times control

32. Enoxaparin (Lovenox®) • MOA: • Potentiates the inhibitory action of Antithrombin III (heparin cofactor) • Possesses higher anti-factor Xa to anti-factor IIa activity (3:1) than heparin • Contraindications: Active bleed, h/0 HIT, severe bleeding risk & recent stroke • Recommendations: • STEMI: Patients with PCI (Class IIa) or fibrinolytic therapy (Class I) • NSTEMI: Patients with PCI (Class IIa) or conservative therapy (non-PCI) (Class IIb) • Dosing: • CrCl > 30 mL/minute: 1mg/kg every 12 hours • CrCl < 30 mL/minute: 1mg/kg every 24 hours • Miscellaneous: • Avoid if CrCl is < 15mL/minute (use heparin) • Avoid if CABG is planned (longer t1/2)

33. Fondaparinux (Arixtra®) • MOA: • Potentiates the inhibitory action of Antithrombin III (heparin cofactor) for inhibition of Factor Xa • Does not effect Factor IIa (no anticoagulant effect) • Contraindications: Active bleed, severe bleeding risk, serum creatinine > 3 mg/dL or CrCl < 30mL/minute • Recommendations: • STEMI: Patients undergoing fibrinolytic therapy (Class I) • NSTEMI: Patients undergoing invasive therapy (early or delayed) or conservative therapy (non-PCI) (Class I) • Dosing: • STEMI: 2.5mg IV bolus followed by 2.5mg SC once daily • NSTEMI: 2.5mg SC once daily • Miscellaneous: • Preferred if patient has high bleeding risk

34. Bivalirudin (Angiomax®) • MOA: Direct (Reversible) Thrombin Inhibitor • Contraindications: Active bleed & severe bleeding risk • Recommendations: • STEMI: Patients undergoing PCI (Class I) • NSTEMI: Patients undergoing early evasive or delayed PCI (Class IIa) • Dosing: • STEMI: 0.75mg/kg IV bolus followed by 1.75mg/kg/hour • NSTEMI: 0.1mg/kg IV bolus followed by 0.25mg/kg/hour; when PCI is initiated, give 0.5mg/kg IV bolus followed by 1.75mg/kg/hour • Miscellaneous: • Option for patients with or history of HIT or high bleeding risk • Wait 30 minutes before administering if switching from UFH

35. Thrombolytics or Tissue Plasminogen Activators (TPAs) • MOA: • Activates the endogenous fibrinolytic system by cleaving arginine-valine bond in plasminogen to produce plasmin • Plasmin in turn degrades fibrin clot, fibrinogen &plasma proteins • Overall effect: lyses of fibrin deposits (aka “clot busters”) • FDA Approved Products: • Alteplase (Activase®) • Reteplase (Retevase®) • Streptokinase (Streptase®) • Tenecteplase (Tnkase®)

36. Thrombolytics or Tissue Plasminogen Activators (TPAs) • Contraindications: • Any prior intracranial hemorrhage • Known structural cerebrovascular lesions • Known intracranial malignant neoplasm • Ischemic stroke within past 3 months • Active bleeding • Significant closed head or facial trauma within 3 months • Recommendations: • STEMI: • Patients presenting with symptoms < 12 hours (Class I) • Patents presenting with symptoms 12-24 hours (Class IIa)

37. Glycoprotein (GP) IIb/IIIa Inhibitors • MOA: • Inhibits platelet aggregation by reversibly binding to the platelet receptor GP IIB/IIIa, thus preventing the binding of fibrinogen and interfering platelet aggregation • FDA Approved Products: • Abciximab (Reopro®) • Eptifibatide (Integrilin®) • Tirofiban (Aggrastat®) • Contraindications: • Active bleeding, thrombocytopenia, prior stroke and renal dialysis (eptifibatide)

38. Glycoprotein (GP) IIb/IIIa Inhibitors • Recommendations: • STEMI: • Patients undergoing primary PCI (Class IIa) • NSTEMI: • Patients undergoing primary PCI (Class I) • Patients without high risk and not undergoing PCI (Class IIb) • Miscellaneous: • Dosing is weight based • Renal dosing is applicable for eptifibatide & tirofiban

39. Adjunctive Therapy • Nitroglycerin (NTG) • Decreases myocardial oxygen demands via venous (predominately) and arterial dilation • Recommended for all STEMI/NSTEMI patients with continuing ischemic discomfort • 0.4mg SL, repeated every 5 minutes times 3 doses • Beta Blockers • Decreases cardiac workload • Recommended for all STEMI/NSTEMI patients with 24 hours if not contraindicated • Target resting pulse rate 50-60 beats/minute • Metoprolol, propranolol, atenolol, carvedilol

40. Adjunctive Therapy • Calcium Channel Blockers • Recommended for patients on max doses of Beta Blocker and NTG or those who are unable to tolerate a Beta Blocker • Continue to target resting pulse of 50-60 beats/minute • Diltiazem SR, verapamil SR, nifedipine SR or amlodipine • Aldosterone Antagonists • Recommended for patients with MI and ejection fraction (EF) < 40% and either DM or heart failure symptoms who are already receiving an ACE inhibitor • Spironolactone: Initial dose – 12.5mg/day with target of 25 - 50mg/day • Eplerenone: Initial dose – 25mg/day with target of 50mg/day

41. Adjunctive Therapy • ACE Inhibitors • Recommended for all patients with heart failure, left ventricular dysfunction and EF < 40%, type 2 DM, or chronic kidney disease in the absence of contraindications • Captopril • Target dose: 50mg BID to TID • Enalapril: • Target dose: 10mg BID • Lisinopril: • Target dose: 10-20mg daily • Ramipril: • Target dose: 5mg BID or 10mg daily • Trandolapril: • Target dose: 4mg daily

42. Adjunctive Therapy • Angiotensin Receptor Blockers (ARBs) • Patients with clinical signs of hear failure or left ventricular EF < 40% and with or without intolerant to an ACE inhibitor • Candesartan • Target dose: 32mg daily • Valsartan: • Target dose: 160mg twice daily • Statin Therapy • “Stabilizes” the “hot” plaque • Treatment of dyslipidemia (cardiovascular risk factor)

43. Discharge Summary • Aspirin Therapy • Dose varies if PCI completed • Continue indefinitely • Clopidogrel/Prasugrel Therapy • Duration for 12 months and possibly up to 15 months • Statin Therapy • “stabilizes” the plaque and treatment of dyslipidemia • NTG Therapy • As needed for ischemic discomfort • Beta Blocker Therapy • Reduce cardiac workload & target heart rate of 50-60 beats/min. • Other Adjunctive Therapy as warranted • ACE/ARB • Aldosterone Antagonist

44. STEMI Treatment Algorithm

45. NSTEMI Treatment Algorithm

46. NSTEMI Treatment Algorithm

47. Objectives • Review Updated Guidelines for the Management of Coronary Artery Disease (CAD) • ACC/AHA STEMI and NSTEMI Guidelines • Review Key Drug Interactions Impacting CAD • Proton Pump Inhibitors (PPIs) & Clopidogrel • Review important FDA guidance Impacting CAD • Drug Safety Communication – Simvastatin 80mg

48. Background • January 26, 2009, the FDA issued an “Early Communication” regarding the potential for certain PPIs to reduce the efficacy of clopidogrel • November 17, 2009, the FDA issued an informational document to health-care providers about an update to the Plavix label • Discussed the interaction of clopidogrel and omeprazole

49. Interaction • Clopidogrel is metabolized to its active metabolite by the CYP450 system via multiple isoenzymes, with extensive action via the CYP2C19 • Omeprazole is a potent inhibitor of CYP2C19 • Providers should consider other CYP2C19 inhibitors when prescribing clopidogrel, which include: cimetidine, fluconazole, ketoconazole and fluoxetine (among others) • Label warns against using CYP2C19 inhibitors and specifically notes omeprazole

50. Interaction • What about other PPI’s? • FDA recommendation specific about omeprazole (and esomeprazole) because of its potent inhibitory effect on CYP2C19 • Others have varying effect on CYP2C19