Initial Therapy Anti-ischemic and Analgesic therapy Anti-platelet therapy Anti-coagulant therapy

Management of UA/NSTEMI Management Before UA/NSTEMI and Onset of UA/NSTEMI Initial Evaluation and Management of UA/NSTEMI Early Hospital Care Select Management Strategy: Initial Invasive Versus Initial Conservative Strategy Initial Invasive Strategy Initial Conservative Strategy Revascularization and Late Hospital Care Coronary Revascularization Late Hospital Care, Hospital Discharge and Post-Hospital Discharge Care Long-Term Medical Therapy and Secondary Prevention Special Groups

Important Points in Hospital Care Stress test before discharge for assessment of ischemia in initial conservative strategy. Must be free of resting ischemia or HF for 12-24h – Class I, C If not classified as low risk, angiography should be performed – Class I, A Fasting lipid panel within 24 hours – Class I, C Statin regardless of baseline LDL-C pre-discharge Echo or MUGA must be done if no plan for left ventriculography by angiogram – Class I, B

Initial Conservative Strategy: Early Hospital Care (1) ASA; clopidogrel if intolerant (I, A) Anticoagulant therapy should be added to antiplatelet therapy as soon as possible after presentation (I, A) Enoxaparin or UFH (I, A) Fondaparinux (I, B) Enoxaparin or fondaparinux preferable (IIa, B) Initiate clopidogrel, loading dose + maintenance dose (I, A) Consider IV eptifibatide or tirofiban (IIb, B)

Initial Conservative Strategy: Early Hospital Care (2) If LVEF is < 0.40, it is reasonable to perform diagnostic angiography (IIa, B) A stress test should be performed for assessment of ischemia (I, B) If the patient is classified as not as low risk, diagnostic angiography should be performed (I, A) Measurement of BNP or NT-pro-BNP may be considered to supplement assessment of global risk in patients with suspected ACS (IIb, B)

Initial Conservative Strategy: Early Hospital Care (3) Beta blocker therapy Initiate oral therapy within first 24 hr unless HF, low-output state, increased risk for cardiogenic shock, or relative contraindications (I, B) IV therapy for high blood pressure without contraindications (IIa, B) IV therapy may be harmful with contraindications to beta blockade, signs of HF or low-output state, or other risk factors for cardiogenic shock (III, A)

Initial Conservative Strategy: Early Hospital Care (4) Lipid management Fasting lipid profile within 24 hr (I, C) Statin (in absence of contraindications) should be given regardless of baseline LDL-C pre-discharge (I, A) ACE inhibitor (oral) Within 24 hr with pulmonary congestion or LVEF  40, in absence of hypotension (systolic blood pressure <100 mmHg or <30 mmHg below baseline) or known contraindications (I, A) ARB if ACE intolerant (I, A) Can be useful without pulmonary congestion or LVEF < 0.40 (IIa, B) No IV ACE-I in first 24 hr because of increased risk of hypotension (III, B)

More Aggressive Long-Term Antiplatelet Therapy Medical therapy without stenting ASA 75-162 mg/d indefinitely (I, A) + clopidogrel 75 mg/d, at least 1 mo (I, A), ideally up to 1 yr (I, B) Bare metal stent ASA 162-325 mg/d at least 1 mo, 75-162 mg/d indefinitely (I, A) clopidogrel 75 mg/d, at least 1 mo (I, A), ideally up to 1 yr (I, B) Drug-eluting stent ASA 162-325 mg/d at least 3 (sirolimus)-6 (paclitaxel) mo, 75-162 mg/d indefinitely (I, A) clopidogrel 75 mg/d at least 1 yr (I, B)

Treatment Oxygen Aspirin Beta-blocker Nitroglycerin Morphine Heparins, DTIs IIb/IIIa inhibitors Plavix ACE/ARB Aldosterone Blockade Statins Increases oxygen supply to ischemic tissue Start at 4L/min Use caution in COPD patients

Anti-ischemic and Analgesic Therapy Bed/chair rest – Class I, C O2 for SaO2 < 90%, respiratory distress, or hypoxemia – Class I, B NTG 0.4 mg sl q 5 min x 3 doses, then gtt for ongoing ischemic discomfort – Class I, C NTG iv within 48h for persistent ischemia, HF, or HTN. Should not preclude use of BB – Class I, B Oral BB therapy within 24h without 1) HF, 2) low output, 3) risk of shock, 4) relative contraindications – Class I, B

Anti-ischemic and Analgesic Therapy CCB (nondihydropyridine) if contraindication for BB in the absence of contraindications – Class I, B ACE inhibitor for LVEF <0.40 and no hypotension (SBP <100 or <30 below baseline) – Class I, A ARB if intolerant to ACE inhibitor – Class I, A NSAIDS should be discontinued – Class I, C

Anti-Platelet Therapy ASA – started immediately and continued indefinitely – Class I, A Plavix – loading dose (300-600mg)* plus maintenance 75 mg if ASA intolerant – Class I, A If h/o GIB, PPI plus anti-platelet therapy – Class I, B GP IIB/IIIA therapy depends on strategy chosen (more on this later) * Risk/benefit to higher loading dose regimens is yet to be determined

Anti-Coagulant Therapy Anticoagulant Therapy should be added to antiplatelet therapy as soon as possible after presentation Choice of anticoagulant depends on the strategy chosen (more on this later)

Anticoagulants and Antiplatelets – Initial Invasive Strategy Recommendation Evidence Enoxaparin, UFH (I, A), bivalirudin, or fondaparinux (I, B) ASAP Enoxaparin: ESSENCE, TIMI IIB, SYNERGY, OASIS 5, ACUTE II, INTERACT, A to Z Fondaparinux: OASIS 5 Bivalirudin: ACUITY Plavix or IIb/IIIa inhibitor prior to angiography* (I, A) *Abciximab only if no delay to cath and PCI likely (I, B) Plavix: CURE GPIIb/IIIa Inhibitor: ISAR-REACT-2 (abciximab), PURSUIT (ebtifbatide), PRISM PLUS (tirofiban)

Anticoagulants and Antiplatelets – Initial Conservative Strategy Recommendation Evidence Enoxaparin, UFH, (I, A) or Fondaparinux (I, B) ASAP Fondaparinux if increased bleeding risk (I, B) Enoxaparin: ESSENCE, TIMI 11B, A to Z, INTERACT Fondaparinux: OASIS 5 Plavix (loading dose plus maintainence) ASAP, continued for 1 month, ideally up to 1 year (I, A) CURE etifibatide or tirofiban in addition to Plavix (IIb, B), but not abciximab (IIIA) ARMYDA 2

Initial Invasive Strategy: Antiplatelet, Anticoagulant Therapy Initiate anticoagulant therapy as soon as possible after presentation (I, A) Enoxaparin or UFH (I, A) Bivalirudin or fondaparinux (I, B) Prior to angiography, initiate one (I, A) or both (IIa, B) Clopidogrel IV GP IIb/IIIa inhibitor Use both if: Delay to angiography High risk features Early recurrent ischemic symptoms

Molecular Structure Generic: clopidogrel bisulfate Clopidogrel bisulfate is an ADP-receptor antagonist. The empirical formula of clopidogrel bisulfate is C16 H16Cl NO2S•H2SO4 and its molecular weight is 419.9. Clopidogrel is a new thienopyridine derivative and is chemically related to ticlopidine. However, there are no known common metabolites and the active metabolites of the 2 compounds are different. Generic: clopidogrel bisulfate Class: ADP-receptor antagonist Molecular weight = 419.9 Reference: 1. Clopidogrel Prescribing Information, US, February 2002.

The active metabolite exerts its antiplatelet effect by noncompetitive inhibition of the platelet ADP receptor subtype P2Y12 CLOPIDOGREL ASA COX ADP C GPllb/llla (Fibrinogen receptor) Collagen thrombin TXA 2 Activation Clopidogrel: An inactive prodrug requires in vivo conversion in the liver by the cytochrome P450 (CYP) 3A4 enzyme system COX (cyclo-oxygenase) ADP (adenosine diphosphate) TXA2 (thromboxane A2)

The thienopyridine clopidogrel A prodrug that needs to be metabolized by cytochrome P450 (CYP) to 2-oxo-clopidogrel, an intermediate metabolite that is further hydrolyzed to the active thiol metabolite of clopidogrel

The active metabolite irreversibly binds to the P2Y12 receptor The thienopyridine clopidogrel The active metabolite irreversibly binds to the P2Y12 receptor The major circulating metabolite of clopidogrel is a carboxylic acid derivate that completely lacks antiaggregatory activity

Pharmacology of Clopidogrel Absorption (oral): rapid Not affected by food or antacids Metabolism: rapid and extensive hepatic metabolism

Pharmacology of Clopidogrel Half-life: 8 hours (but has an irreversible effect on platelets, with a lifespan of approximately 7–10 days) Excretion: 50% in urine and 46% in feces, after 5 days

Side Effect Of Clopidogrel Rash, or manifestations of a hypersensitivity reaction to clopidogrel

Side Effect Of Clopidogrel Management include: Clopidogrel desensitization Treatment with antihistamines and corticosteroid cream Switching to ticlopidine.

GP IIb/IIIa inhibitors Several GP IIb/IIIa inhibitors exist: abciximab (ReoPro) eptifibatide (Integrilin) tirofiban (Aggrastat)

Eptifibatide (Integrilin)

Eptifibatide (Integrilin)

Eptifibatide (Integrilin)

Eptifibatide (Integrilin)

Tirofiban (Aggrastat)

Tirofiban (Aggrastat)

abciximab (ReoPro)

abciximab (ReoPro)

Long-Term Antithrombotic Therapy at Hospital Discharge after UA/NSTEMI New UA/NSTEMI Patient Groups at Discharge Medical Therapy without Stent Bare Metal Stent Group Drug Eluting Stent Group ASA 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d at least 1 month (Class I, LOE: A) and up to 1 year (Class I, LOE: B) ASA 162 to 325 mg/d for at least 1 month, then 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d for at least 1 month and up to 1 year (Class I, LOE:B) ASA 162 to 325 mg/d for at least 3 to 6 months, then 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d for at least 1 year (Class I, LOE: B) Indication for Anticoagulation? Yes No Add: Warfarin (INR 2.0 to 2.5) (Class IIb, LOE: B) Continue with dual antiplatelet therapy as above Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 11. INR = international normalized ratio; LOE = level of evidence.