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

2. 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

3. 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

4. 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)

5. 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)

6. 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)

7. 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 < (IIa, B)
No IV ACE-I in first 24 hr because of increased risk of hypotension (III, B)

8. More Aggressive Long-Term Antiplatelet Therapy
Medical therapy without stenting
ASA 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 mg/d at least 1 mo, 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 mg/d at least 3 (sirolimus)-6 (paclitaxel) mo, mg/d indefinitely (I, A)
clopidogrel 75 mg/d at least 1 yr (I, B)

9. 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

10. 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

11. 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

12. Anti-Platelet Therapy
ASA – started immediately and continued indefinitely – Class I, A
Plavix – loading dose ( mg)* 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

13. 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)

14. 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)

15. 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

16. 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

23. 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
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.

24. 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)

25. 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

26. 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

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

28. 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

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

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

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

32. Eptifibatide (Integrilin)

33. Eptifibatide (Integrilin)

34. Eptifibatide (Integrilin)

35. Eptifibatide (Integrilin)

36. Tirofiban (Aggrastat)

37. Tirofiban (Aggrastat)

38. abciximab (ReoPro)

39. abciximab (ReoPro)

40. 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.