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Claudia P. Hochberg, MD, FACC

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1 Claudia P. Hochberg, MD, FACC
Acute Coronary Syndromes - Recognition, Risk Stratification, and Management Claudia P. Hochberg, MD, FACC August 12, 2013

2 Topics to Cover Identification of the patient with ACS
Initiation of anti-thrombotic therapy and anti-ischemic therapy Risk stratification as it relates to the decision of early invasive vs. conservative strategy Secondary prevention/risk factor modification We could talk about a number of topics; however, given time constraints, will focus on the most critical issues that relate to the role of the PCP in ACS: (1) initial evaluation (2) initiation of therapy (3) risk stratification (as it relates to invasive vs conservative approaches) and (4) secondary prevention/risk factor modification Controversial areas are highlighted in red

3 124 Class I recommendations
23 Class III recommendations

4 Acute Coronary Syndrome
An ischemic myocardial event that is a direct consequence of atherosclerotic plaque activation and/or local thrombus formation May be divided into that association with ST segment elevation and that associated with ST segment depression Spectrum: UANSTEMISTEMI “Acute coronary syndrome” has evolved as a useful operational term to refer to any constellation of clinical symptoms that are compatible with acute myocardial ischemia (Fig. 1). It encompasses MI (ST-segment elevation and depression, Q wave and non-Q wave) and UA.

5 Acute Myocardial Infarction: Definition
1. Typical rise and fall of biochemical markers of myocardial necrosis (troponin or CK-MB) with at least one of the following: a) ischemic symptoms b) development of pathologic Q waves on EKG c) ischemic EKG changes (ST depression or elevation) d) coronary intervention 2. Pathologic findings of an acute MI

6 Unstable Angina: Guideline Definition
Three principal presentations: Rest angina >20 minutes in last week New onset angina in last 2 months Increasing angina - increased frequency, duration, or severity

7 Hospital Admissions for ACS: Unstable Angina/NSTEMI vs STEMI
Acute Coronary Syndrome 2.3 Million Hospital Admissions ACS UA/NSTEMI STEMI Approximately 2.3 million Americans will present to the emergency department with chest pain due to acute coronary syndrome.1 Of these patients, twice as many (1.43 million) will be admitted and diagnosed with unstable angina (UA) or non–ST-segment elevation myocardial infarction (NSTEMI) compared with 829,000 patients who will be diagnosed with ST- segment-elevation myocardial infarction (STEMI).1 According to the American Heart Association, 1.1 million new or recurrent coronary attacks (defined as MI or coronary heart disease) will occur this year.2 Of these cases, 650,000 will be first cases and 450,000 will be recurrent cases. Additionally, about 150,000 new cases of UA will be diagnosed.2 1.43 million Admissions per Year 829,000 Admissions per Year Sodnick EJ, et al. National Center for Health Statistics

8 Mr JS 65 yo male with h/o HTN, hyperlipidemia
Had 1st episode of chest pain (a “pressure” with radiation to his left shoulder) 2 weeks prior to admit, while shoveling snow. Over the 3 days prior to admit he had 4 episodes of chest pain, initially with mild exertion, and finally at rest. The pain resolved spontaneously in 3-4 minutes. Meds: atenolol, amlodipine, HCTZ, atorvastatin, aspirin BP: 136/95 HR: 92 No vascular bruits, no murmur, +S4, no congestion 65 yo AAM with h/o HTN, hyperlipidemia, presents with likely UA/ACS. notes first episode of chest pain 2 weeks ago while shoveling snow. Over the past 3 days has had 4 episodes of chest pain, occurring with mild exertion (1 episode at rest). Today had an episode after climbing stairs. In ER was hypertensive -> iv labetolol with improvement. Exam currently with HR in 60s, SBP 140. No vascular bruits. No congestion. Faint SEM at LLSB. ECG with diffuse Twave inversion in precordium (concordant with the major deflection of the QRS). Labs with troponin 0.1, creat 1.38, hct 42. CXR negative, head CT (for dizziness) negative for acute abnormality. Bedside echo with apical and anterior HK. Given stuttering pattern of chest pain with significant ECG changes, wall motion abnormality, and mild troponin leak, I would favor an aggessive/invasive approach. Currently he is chest pain free and ate lunch at ~ 12:30 pm. Thus would medically manage today and plan cath in am. How can we tell if this man is having an ACS?

9 Labs normal except troponin 0.15, CK: 370
Acute presentation Baseline Labs normal except troponin 0.15, CK: 370

10 Chest Pain History and Diagnosis of Acute Myocardial Infarction (AMI)
This article concluded that the character of the CP cannot fully distinguish those patient who are having an ACS from those who are not. However, there are some characteristics that remain helpful. Swap, C. J. et al. JAMA 2005;294:

11 Likelihood that Signs and Symptoms Represent ACS Secondary to CAD
HIGH Left arm or chest pain typical of prior angina Hx of CAD or MI CHF Transient MR murmur Hypotension New ECG changes (ST deviation > 1mm; Twave inversion in many leads) Elevated biomarkers (troponin/CK-MB) Intermediate Left arm or chest pain Age > 70 years Male Diabetes PVD,CVA Q waves on ECG ST deviation mm, Twave inversion > 1 mm Normal biomarkers The efficient diagnosis and optimal management of these patients must derive from information readily available at the time of the initial clinical presentation. When a patient presents with symptoms, how do we distinguish which patients are have ACS from those that are likely to have nonischemic symptoms CLASS I 1. A rapid clinical determination of the likelihood risk of obstructive CAD (i.e., high, intermediate, or low) should be made in all patients with chest discomfort or other symptoms suggestive of an ACS and considered in patient management. (Level of Evidence: C) Circulation. 2007;116:e148–e304.

12 Likelihood that Signs and Symptoms Represent ACS Secondary to CAD
Low Probable ischemic symptom in absence of intermediate risk markers Recent cocaine use Pain reproduced by palpation T wave inversion < 1 mm Normal ECG Normal biomarkers The initial challenge in managing patients with ACS is to identify those patients likely to have ACS. Circulation. 2007;116:e148–e304.

13 Initial Anti-Ischemic Therapies (Class I)
Bed Rest (~ 24 hours) Oxygen Nitrates Morphine Sulfate Beta-blocker (within the 1st 24 hours in patients without contraindications) Non-dihydropyridine CCB (verapamil/dilt) in patients with contraindications to BB ACE inhibitor for HTN, low LVEF or CHF or DM Discontinue NSAIDs Bed rest x 24 hrs (until r/in or r/out) Nitrates for anginal control, CHF BB: iv x 3 doses if BP and HR allow, then oral dose orallly q8hrs for 1st 24 hours, especially in patients without prior BB transition to long acting med at d/c if LVEF<40%, consider carvedilol (slow titration and monitor BP) A. ANTI-ISCHEMIC AND ANALGESIC THERAPY CLASS I 1. Bed/chair rest with continuous ECG monitoring is recommended for all UA/NSTEMI patients during the early hospital phase. (Level of Evidence: C) 2. Supplemental oxygen should be administered to patients with UA/NSTEMI with an arterial saturation less than 90%, respiratory distress, or other high-risk features for hypoxemia. (Pulse oximetry is useful for continuous measurement of SaO2.) (Level of Evidence: B) 3. Patients with UA/NSTEMI with ongoing ischemic discomfort should receive sublingual NTG (0. 4 mg) every 5 min for a total of 3 doses, after which assessment should be made about the need for intravenous NTG, if not contraindicated. (Level of Evidence: C) 4. Intravenous NTG is indicated in the first 48 h after UA/NSTEMI for treatment of persistent ischemia, heart failure (HF), or hypertension. The decision to administer intravenous NTG and the dose used should not preclude therapy with other proven mortality-reducing interventions such as beta blockers or angiotensin-converting enzyme (ACE) inhibitors. (Level of Evidence: B) 5. Oral beta-blocker therapy should be initiated within the first 24 h for patients who do not have 1 or more of the following: 1) signs of HF, 2) evidence of a low-output state, 3) increased risk* for cardiogenic shock, or 4) other relative contraindications to beta blockade (PR interval greater than s, second or third degree heart block, active asthma, or reactive airway disease). (Level of Evidence: B) Based on the COMMIT/CCS2 trial, the largest randomized trial of BB in MI, it seems reasonable to defer treatment with BB in patients who are hemodynamically compromised, in whom BB may be assoc with increased mortality. 6. In UA/NSTEMI patients with continuing or frequently recurring ischemia and in whom beta blockers are contraindicated, a nondihydropyridine calcium channel blocker (e.g., verapamil or diltiazem) should be given as initial therapy in the absence of clinically significant left ventricular (LV) dysfunction or other contraindications. (Level of Evidence: B) 7. An ACE inhibitor should be administered orally within the first 24 h to UA/NSTEMI patients with pulmonary congestion or LV ejection fraction (LVEF) less than or equal to 0.40, in the absence of hypotension (systolic blood pressure less than 100 mm Hg or less than 30 mm Hg below baseline) or known contraindications to that class of medications. (Level of Evidence: A) 8. An angiotensin receptor blocker should be administered to UA/ NSTEMI patients who are intolerant of ACE inhibitors and have either clinical or radiological signs of HF or LVEF less than or equal to (Level of Evidence: A) 9. Because of the increased risks of mortality, reinfarction, hypertension, CHF, and myocardial rupture associated with their use, nonsteroidal anti- inflammatory drugs (NSAIDs), except for ASA, whether nonselective or cyclooxygenase (COX)-2–selective agents, should be discontinued at the time a patient presents with UA/NSTEMI. (Level of Evidence: C) Circulation. 2007;116:e148–e304.

14 What Anti-Thrombotic Therapy Should be Used in the Initial Hours of Management of ACS?

15 The Vulnerable Plaque Plaque rupture Platelet adhesion
Images from Falk E, et al. Circulation. 1998;92: Plaque rupture Platelet adhesion Platelet activation Platelet aggregation Thrombotic occlusion A cross-section of a coronary artery demonstrating the vulnerable plaque, with its large lipid core and thin fibrous cap

16 Characteristics of Unstable and Stable Plaque
Lack of inflammatory cells Inflammatory cells Thin fibrous cap Thick fibrous cap Few SMCs More SMCs Unstable plaques are characterized by a large lipid core and thin fibrous cap. Inflammatory cells and activated macrophages are believed to be involved in destabilizing the plaque and the fibrous cap. Intact endothelium Eroded endothelium Activated macrophages Foam cells Adapted with permission from Libby P. Circulation. 1995;91: Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at:

17 Plaque Rupture, Thrombosis, and Microembolization
Marker Cholesterol LDL C-Reactive Protein Adhesion Molecules Interleukin 6, TNFα, sCD-40 ligand MDA Modified LDL D-dimer, Complement, Fibrinogen, Troponin, CRP, CD40L Quiescent plaque Process Plaque formation Inflammation Multiple factors ? Infection Plaque Rupture ? Macrophages Metalloproteinases Thrombosis Platelet Activation Thrombin Lipid core Vulnerable plaque TF → Clotting Cascade Inflammation Collagen → platelet activation Foam Cells Macrophages Metalloproteinases Plaque rupture Platelet-thrombin micro-emboli Courtesy of David Kandzari.

18 Thrombus Formation and ACS
UA NQMI QWMI Plaque Disruption/Fissure/Erosion Thrombus Formation Non-ST-Segment Elevation Acute Coronary Syndrome (ACS) ST-Segment Elevation Acute Coronary Syndrome (ACS) Old Terminology: New It is now recognized that unstable angina (UA), non-Q-wave myocardial infarction (NQMI), and ST-segment elevation myocardial infarction (STE-MI) are all parts of the spectrum of clinical manifestations of acute coronary syndrome (ACS). The older terminology has now been replaced with terminology that divides ACS into non-ST-elevation ACS (NSTE-ACS) and ST-segment-elevation. All the slides in this teaching set deal with NSTE-ACS.

19 Pathogenesis of Acute Coronary Syndromes: The integral role of platelets
Plaque Fissure or Rupture Platelet Adhesion Platelet Activation Platelet Aggregation Platelets are recognized to play an integral role in acute coronary syndromes and arterial thrombosis. After plaque fissure or rupture, there is platelet adhesion and activation. This leads to platelet aggregation within the coronary artery, and ultimately partial or complete occlusion of the coronary artery. Thrombotic Occlusion

20 Antiplatelet Therapy in ACS
Act by inhibiting different platelet functions (aggregation, release of granule contents, platelet-mediated vascular constriction) Aspirin: blocks cyclooxygenase which mediates the first step in the biosynthesis of prostaglandins and thromboxanes from arachidonic acid     P2Y12 receptor blockers:clopidogrel, ticlopidine, prasugrel, ticagrelor all block the binding of ADP to P2Y12R-->inhibits activation of the GP IIb/IIIa complex and platelet aggregation GP IIb/IIIa inhibitors:inhibit the final common pathway of platelet aggregation (cross-bridging of platelets by fibrinogen) 20

21 Region of vascular injury
Collagen vWF ? Anti-vWF ? Anti-GpIb GpIb Thrombin Aspirin TSI TXA2 UF heparin LMWH Thrombin inhibitors AA PGH TXA2 TXA2 receptor antagonist ADP Fibrinogen Epi ADP GPIIb/IIIa thienopyridine There are multiple mediators which can result in platelet activation, including ADP, epinephrine, collagen, arachidonic acid, and thrombin. Aspirin blocks activation of platelets by arachidonic acid. The thienopyridines (ticlopidine and clopidogrel) block ADP-mediated platelet activation. Antithrombin therapy (heparin, low-molecular-weight heparin, or direct thrombin inhibitors) block thrombin-mediated platelet activation. The glycoprotein IIb/IIIa inhibitors block platelet aggregation by inhibiting fibrin from binding to the GP IIb/IIIa receptor GpIIB/IIIA inhibitors Fibrin GPIIb/IIIa Awtry EH, Loscalzo J 2003

22 Aspirin The Antithrombotic Trialists' Collaboration
Aspirin ( mg daily) in 200,000 patients Antiplatelet therapy produced a significant 46% reduction in the combined end point of subsequent nonfatal myocardial infarction (MI), nonfatal stroke, or vascular death (8.0 vs 13.3%) in patients with unstable angina 30 percent reduction in patients with acute myocardial infarction (10.4 vs 14.2 %) No significant difference in efficacy between lower and higher daily doses (75 to 325 versus 500 to 1500 mg) The addition of a second antiplatelet agent (eg, dipyridamole, ticlopidine, or intravenous glycoprotein IIb/IIIa inhibitor) significantly lowered the combined end point Text Antithrombotic Trialists' Collaboration. BMJ 2002; 324:71. 22

23 Treatment of Unstable Angina
Results of a study from the Montreal Heart Institute In multiple studies aspirin significantly reduces risk of: - subsequent MI - cardiac death - overall mortality (>50% reduction) 12 10 8 6 % Developing MI 4 Studies, including this one from the Montreal Heart Institute, demonstrated that treating patients with aspirin could reduce ischemic complications in patients with unstable angina. 2 placebo aspirin Theroux P, et al. N Engl J Med. 1988;319:

24 Aspirin Class I mg should be given on day one and continued indefinitely (may be decreased to 81mg daily after the acute event if no PCI, or after PCI). Class IIb 1. Other antiplatelet agents such as clopidogrel ( mg po loading dose, then 75 mg QD) or prasugrel may be substituted if true aspirin allergy is present. Circulation. 2007;116:e148–e304.

25 P2Y12 Receptor Blockers CURE trial: randomly assigned 12,562 patients who presented within 24 hours after the onset of a NSTEMI to aspirin alone (75 to 325 mg/day) or with clopidogrel (300 mg loading dose followed by 75 mg/day) for 9 to 12 months High risk patients : electrocardiogram (ECG) changes elevated cardiac enzymes 60 % did not receive revascularization Primary endpoint: cardiovascular death, myocardial infarction, or stroke At an average follow-up of nine months, combination therapy led to a significant reduction in the combined primary endpoint (9.3 vs 11.4%), largely due to fewer MIs (5.2 vs 6.7%) Clopidogrel increased the rate of major bleeding (3.7 vs 2.7 %) but not in life-threatening bleeding or hemorrhagic stroke 25 Yusuf S, et al. N Engl J Med. 2001;345:

26 CURE: Primary Composite End Point (CV Death/MI/Stroke)
Placebo + Aspirin 20% RRR 14 12 P=.00009 10 8 % With Event Clopidogrel + Aspirin 6 4 The CURE study demonstrated that in population treated predominantly with medical therapy alone (without early cardiac catheterization and revascularization), and without up-front GP IIb/IIIa therapy, the addition of clopidogrel (to aspirin and heparin) resulted in a 20% relative reduction in the composite ischemic endpoint. Approximately half of the benefit occurred over the first thirty days, and approximately half of the overall benefit occurred during the remaining duration of treatment However, the trial also revealed that in patients going to CABG, the risk of bleeding was significantly increased. 2 3 6 9 12 Follow-up (months) Yusuf S, et al. N Engl J Med. 2001;345:

27 CURE Bleeding Complications
Major bleeding was increased in the CURE study in those patients treated with a combination of aspirin and clopidogrel when compared to those treated with aspirin and placebo Data from Yusuf S, Zhao F, Mehta SR, 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:

28 ACC/AHA Recommendations - Antiplatelet Therapy for NSTE-ACS
Class I Clopidogrel if ASA-allergic or intolerant Clopidogrel in addition to ASA if early invasive approach not planned (for 1–12 months) Clopidogrel in addition to ASA, if invasive approach is planned Clopidogrel should be withheld for 5-7 days if CABG planned INCLUDE IN HANDOUT, NOT IN LECTURE The ACC/AHA Guidelines Update for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction make several recommendations regarding anti-platelet therapy in patients with NSTE-ACS. There are subtle differences with regard to GP IIb/IIIa therapy, depending upon whether on not the patient is to undergo early cardiac catheterization and PCI, and upon whether or not the patient has been treated with clopidogrel. The issue of whether to treat all patients with NSTE-ACS in the ER with clopidogrel and accept that some will have to have CABG delayed until the clopidogrel effects abate, or whether to wait until the coronary arteries are defined before starting clopidogrel, is subject to debate, although at present the ACC/AHA guidelines are as listed in the slide. Up-front GP IIb/IIIa therapy should be with either eptifibatide or tirofiban. Circulation. 2007;116:e148–e304.

29 Comparison of Heparin + ASA
vs ASA Alone Theroux RISC Cohen 1990 ATACS Holdright Gurfinkel Summary Relative Risk Individual studies and cumulative data strongly suggest the additional benefit of risk reduction (risk of MI) in patients with unstable angina when unfractionated heparin is added to treatment with aspirin. 0.67 ( ) 0.1 1 10 Heparin + ASA 55/698=7.9% RR: Death/MI ASA Alone 68/655=10.4% Oler A, et al. JAMA. 1996;276:

30 Anticoagulants Unfractionated Heparin (UFH)
Most widely used Most widely used antithrombotic antithrombotic agent agent Disadvantages include: Disadvantages include: Poor Poor bioavailability bioavailability No inhibition of clot-bound thrombin No inhibition of clot-bound thrombin Dependent on Dependent on antithrombin antithrombin III (ATIII) cofactor III (ATIII) cofactor INCLUDE IN HANDOUT NOT IN LECTURE Variable effects Variable effects Frequent monitoring ( Frequent monitoring ( aPTT aPTT ) to ensure therapeutic levels ) to ensure therapeutic levels Rebound Rebound ischemia ischemia after discontinuation after discontinuation Risk of heparin-induced Risk of heparin-induced thrombocytopenia thrombocytopenia (HIT) (HIT)

31 Anticoagulants Low-Molecular-Weight Heparin (LMWH)
Fraction of standard (UFH) heparin Fraction of standard (UFH) heparin Advantages over UFH: Advantages over UFH: Greater Greater bioavailability bioavailability No need to closely monitor No need to closely monitor Resistant to inhibition by activated platelets Resistant to inhibition by activated platelets Lower incidence of HIT Lower incidence of HIT INCLUDE IN HANDOUT NOT IN LECTURE Enhanced anti-factor Enhanced anti-factor Xa Xa activity activity Effective subcutaneous administration Effective subcutaneous administration Enoxaparin Enoxaparin , , dalteparin dalteparin , , reviparin reviparin , , nadroparin nadroparin , , fraxiparin fraxiparin , others , others Differ in anti- Differ in anti- Xa Xa /anti- /anti- IIa IIa ratios ratios

32 Urgent Revascularization
UFH vs LMWH ESSENCE TIMI 11B 30% 25% 20% 15% 10% 9 13 Days After Randomization 17 21 5 5% 25 29 Unfractionated Heparin Enoxaparin (Lovenox) Recurrent Angina Death, MI or P = 0.02 Risk Reduction 16.2% Urgent Revascularization Death, MI or Unfractionated Heparin Enoxaparin (Lovenox) Days 20 16 12 8 4 2 6 10 14 1 . 7 % p = 0.03 Relative Risk Reduction = 15% Cohen M, et al. N Engl J Med. 1997;337: Antman EM, et al. Circulation. 1999;100:

33 Guidelines for the Use of Enoxaparin in Patients with NSTE-ACS
1 mg/kg SQ q12 hours (actual body weight) An initial 30 mg IV dose can be considered Adjust dosing if CrCl <30 cc/min 1 mg/kg SQ q24 hours Do not follow PTT; do not adjust based on PTT Stop if platelets < by 50% or below 100,000/mm3 If patient to undergo PCI: 0-8 hours since last SQ dose: no additional antithrombin therapy 8-12 hours since last SQ dose: 0.3 mg/kg IV during PCI Guidelines for the use of enoxaparin in patients with NSTE-ACS.

34 Low Molecular Weight Heparin in ACS Effects on Triple Endpoints
Day FRIC (dalteparin; n=1482) FRAXIS (nadroparin; n=2357) ESSENCE (enoxaparin; n=3171) (p=0.032) 14 TIMI 11 B (enoxaparin; n=3910) (p=0.029) 14 _________________________________________________________________ 15% (ESSENCE) and 16% (TIMI 11B) risk reduction LMWH better UFH better Triple endpoints: Death, MI, recurrent ischemia

35 TIMI Risk Score For UA/NSTEMI
4.7 8.3 13.2 19.9 26.2 40.9 3.5 8.6 14.9 20 28.8 14.1 10 30 40 50 0/1 2 3 4 5 6/7 D/MI/ Urg Revasc (%) Number of Risk Factors UFH ENOX Antman et al JAMA 284 : 835, 2000 Age > 65 y 3 CAD Risk Factors Prior Stenosis > 50 % ST deviation Anginal events < 24 h ASA in last 7 days Elev Cardiac Markers ESSENCE and TIMI 11B: Rate of increase in composite events was less inpatients treated with enoxaparin than in patients treated with UFH

36 ACC/AHA Recommendations for Antithrombin Therapy in Patients with NSTE-ACS
Class I: Anticoagulation should be added to antiplatelet therapy as soon as possible after recognition of ACS If early invasive strategy: may use UFH (60-70 U/kg to max 5000 IV followed by infusion of U/kg/hr (initial max 1000 U/hr) titrated to aPTT times control), enoxaparin (1 mg/kg subcutaneously q12 hr) If conservative strategy: may use UFH, enoxaparin, or fondaparinux Class IIa Enoxaparin or fondaparinux is preferable to UFH as an anticoagulant unless CABG is planned within 24 hours Fondaparinox is a synthetic heparin pentasaccharide The ACC/AHA Guidelines Update for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction make several recommendations regarding antithrombin therapy in patients with NSTE-ACS. The use of either unfractionated heparin (UFH) or a low molecular weight heparin (LMWH) is a class I recommendation. Based primarily on the ESSENCE and TIMI 11B studies, a class IIa recommendation was that enoxaparin was preferable to UFH. Whether this preferential recommendation changes as a result of the SYNERY study remains to be determined. CLASS I Anticoagulant therapy should be added to antiplatelet therapy in UA/NSTEMI patients as soon as possible after presentation. a. For patients in whom an invasive strategy is selected, regimens with established efficacy at a Level of Evidence: A include enoxaparin and UFH (Fig. 6; Box B1), and those with established efficacy at a Level of Evidence: B include bivalirudin and fondaparinux (Fig. 7; Box B1). b. For patients in whom a conservative strategy is selected, regimens using either enoxaparin* or UFH (Level of Evidence: A) or fondaparinux (Level of Evidence: B) have established efficacy. (Fig. 8; Box C1)* See also Class IIa recommendation below. c. In patients in whom a conservative strategy is selected and who have an increased risk of bleeding, fondaparinux is preferable. (Level of Evidence: B) (Fig. 7; Box C1) Circulation. 2007;116:e148–e304.

37 ACC/AHA Recommendations for Antithrombin Therapy in Patients with NSTE-ACS
Class I: Anticoagulation should be added to antiplatelet therapy as soon as possible after recognition of ACS If early invasive strategy: may use UFH (60-70 U/kg to max 5000 IV followed by infusion of U/kg/hr (initial max 1000 U/hr) titrated to aPTT times control), enoxaparin (1 mg/kg subcutaneously q12 hr), or direct thrombin inhibitors (bivalirudin or fondiparinux) If conservative strategy: may use UFH, enoxaparin, or fondaparinux Class IIa Enoxaparin or fondaparinux is preferable to UFH as an anticoagulant unless CABG is planned within 24 hours ** Unfractionated heparin preferred in patients with creatinine > 2.0 (Cr clearance <30) or weight >120 kg Fondaparinox is a synthetic heparin pentasaccharide The ACC/AHA Guidelines Update for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction make several recommendations regarding antithrombin therapy in patients with NSTE-ACS. The use of either unfractionated heparin (UFH) or a low molecular weight heparin (LMWH) is a class I recommendation. Based primarily on the ESSENCE and TIMI 11B studies, a class IIa recommendation was that enoxaparin was preferable to UFH. Whether this preferential recommendation changes as a result of the SYNERY study remains to be determined. CLASS I Anticoagulant therapy should be added to antiplatelet therapy in UA/NSTEMI patients as soon as possible after presentation. a. For patients in whom an invasive strategy is selected, regimens with established efficacy at a Level of Evidence: A include enoxaparin and UFH (Fig. 6; Box B1), and those with established efficacy at a Level of Evidence: B include bivalirudin and fondaparinux (Fig. 7; Box B1). b. For patients in whom a conservative strategy is selected, regimens using either enoxaparin* or UFH (Level of Evidence: A) or fondaparinux (Level of Evidence: B) have established efficacy. (Fig. 8; Box C1)* See also Class IIa recommendation below. c. In patients in whom a conservative strategy is selected and who have an increased risk of bleeding, fondaparinux is preferable. (Level of Evidence: B) (Fig. 7; Box C1) Circulation. 2007;116:e148–e304.

38 IIb/IIIa Inhibitors in ACS
PURSUIT PRISM PRISM PLUS PARAGON B PARAGON A Theroux COMBINED 1998 (n = 23,967) 0.88 ( ) 0.25 0.50 1.0 2.0 4.0 Odds Ratio for 30-day Death or MI Relative to Control

39 ACC/AHA Recommendations - Antiplatelet Therapy for NSTE-ACS
Class I Clopidogrel OR GP IIb/IIIa inhibitor, in addition to ASA, if invasive approach is planned Class IIa GP IIb/IIIa inhibitor in patients with high-risk features if invasive strategy not planned GP IIb/IIIa inhibitor in patients receiving clopidogrel if cardiac cath and PCI planned Class IIb GP IIb/IIIa inhibitor in patients without high-risk features and PCI not planned INCLUDE IN HANDOUT, NOT IN LECTURE The ACC/AHA Guidelines Update for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction make several recommendations regarding anti-platelet therapy in patients with NSTE-ACS. There are subtle differences with regard to GP IIb/IIIa therapy, depending upon whether on not the patient is to undergo early cardiac catheterization and PCI, and upon whether or not the patient has been treated with clopidogrel. The issue of whether to treat all patients with NSTE-ACS in the ER with clopidogrel and accept that some will have to have CABG delayed until the clopidogrel effects abate, or whether to wait until the coronary arteries are defined before starting clopidogrel, is subject to debate, although at present the ACC/AHA guidelines are as listed in the slide. Up-front GP IIb/IIIa therapy should be with either eptifibatide or tirofiban. Available at:

40 GP IIb/IIIa Dosing and Administration for Up-Front Therapy in Patients with NSTE-ACS
Integrilin: 180 mcg/kg bolus (over 1-2 min), then 2 mcg/kg/min continuous infusion Aggrastat: Initial 0.4 mcg/kg/min for 30 min, then continuous infusion at 0.1 mcg/kg/min Always also treat with ASA and some form of heparin (UFH or LMWH) Patients most commonly treated 2-4 days Follow platelet count qD and D/C for significant fall Adjust doses for renal insufficiency: Integrilin: For creatinine 2-4 mg/dL, decrease infusion to 1 mcg/kg/min; avoid if creatinine >4 mg/dL Aggrastat: For CrCl < 30 mL/min, cut all doses in 1/2 INCLUDE IN HANDOUT, NOT IN LECTURE Dosing and administration guidelines for the two GP IIb/IIIa inhibitors approved for “up-front” therapy in patients with NSTE-ACS.

41 Contraindications to GP IIb/IIIa Rx
Active or recent bleeding (4-6 weeks) Severe hypertension (SBP > mm Hg; DBP >110 mm Hg) Any hemorrhagic CVA (+/- intracranial neoplasm, AVM, or aneurysm) Any CVA within 30 days–2 years Major surgery or trauma within 4-6 weeks Thrombocytopenia ( <100,000/mm3 ) Bleeding diathesis/warfarin with elevated INR INCLUDE IN HANDOUT, NOT IN LECTURE The specific contraindications for each of the three glycoprotein (GP) IIb/IIIa inhibitors varies somewhat, but can be generally summarized in the above slide.

42 IIb/IIIa Inhibitors in ACS
PURSUIT PRISM PRISM PLUS PARAGON B PARAGON A Theroux COMBINED 1998 (n = 23,967) 0.88 ( ) EARLY ACS ACUITY Timing EARLY ACS + ACUITY 0.92 ( ) EARLY ACS Background Glycoprotein IIb/IIIa inhibitors are indicated in patients with acute coronary syndromes who are undergoing an invasive procedure. The optimal timing of the initiation of such therapy is unknown. Methods We compared a strategy of early, routine administration of eptifibatide with delayed, provisional administration in 9492 patients who had acute coronary syndromes without ST- segment elevation and who were assigned to an invasive strategy. Patients were randomly assigned to receive either early eptifibatide (two boluses, each containing 180 µg per kilogram of body weight, administered 10 minutes apart, and a standard infusion 12 hours before angiography) or a matching placebo infusion with provisional use of eptifibatide after angiography (delayed eptifibatide). The primary efficacy end point was a composite of death, myocardial infarction, recurrent ischemia requiring urgent revascularization, or the occurrence of a thrombotic complication during percutaneous coronary intervention that required bolus therapy opposite to the initial study-group assignment ("thrombotic bailout") at 96 hours. The key secondary end point was a composite of death or myocardial infarction within the first 30 days. Key safety end points were bleeding and the need for transfusion within the first 120 hours after randomization. Results The primary end point occurred in 9.3% of patients in the early-eptifibatide group and in 10.0% in the delayed-eptifibatide group (odds ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.23). At 30 days, the rate of death or myocardial infarction was 11.2% in the early-eptifibatide group, as compared with 12.3% in the delayed-eptifibatide group (odds ratio, 0.89; 95% CI, 0.79 to 1.01; P=0.08). Patients in the early-eptifibatide group had significantly higher rates of bleeding and red-cell transfusion. There was no significant difference between the two groups in rates of severe bleeding or nonhemorrhagic serious adverse events. Conclusions In patients who had acute coronary syndromes without ST-segment elevation, the use of eptifibatide 12 hours or more before angiography was not superior to the provisional use of eptifibatide after angiography. The early use of eptifibatide was associated with an increased risk of non–life-threatening bleeding and need for transfusion. (ClinicalTrials.gov number, NCT [ClinicalTrials.gov] .) COMBINED 2009 (n = 42,666) 0.89 ( ) 0.25 0.50 1.0 2.0 4.0 Odds Ratio for 30-day Death or MI Relative to Control

43 Early ACS - Conclusions
Among high-risk NSTE ACS patients, a strategy of routine, early eptifibatide compared with delayed, provisional eptifibatide at PCI did not significantly reduce the primary composite of death, MI; resulted in a trend toward reduction in death or MI at 30 days, but no difference in 30-day mortality; resulted in higher rates of non-life-threatening bleeding and transfusions The results of EARLY ACS do not support a strategy of routine early eptifibatide use in high-risk NSTE ACS patients managed with an invasive strategy NEJM on line March 30, 2009

44 How Best to Risk Stratify Patients with ACS?
Because patients with ischemic discomfort at rest as a group are heterogeneous in terms of risk of cardiac death and nonfatal ischemic events, an assessment of the prognosis guides the initial evaluation and treatment. An estimation of risk is useful in 1) selection of the site of care (coronary care unit, monitored step-down unit, or outpatient setting) and 2) selection of therapy, including platelet glycoprotein (GP) IIb/IIIa inhibitors (see Section 3.2) and invasive management strategy (see Section 3.3).

45 Risk Stratification Based on validated risk prediction models that include the most important predictors of outcomes Certain patients that are such high risk that they need not be risk stratified: cardiogenic shock overt CHF or LV dysfunction Rest angina despite max medical therapy Hemodynamic instability, mechanical complications Unstable ventricular arrythmias 43

46 TIMI Risk Score for UA/NSTEMI
Age >65 years 3 or more CAD risk factors HTN, DM, Hyperlipidemia, smoking, + family hx Prior CAD (cath stenosis>50%) ASA in last 7 days 2 or more anginal events in last 24 hours ST deviation on admission ECG Elevated cardiac markers (troponin/CK-MB) Our patient had a TIMI score of 5 (>65 yrs, asa, 2+ episodes, ST abn, + trop) – point out risk on next next slide Antman EM, et al. JAMA ;284:

47 14 day Death, MI, or Urgent Revascularization (%)
The TIMI Risk Score and Incidence of Adverse Ischemic Events in Patients with NSTE-ACS 50 40.9 40 30 26.2 14 day Death, MI, or Urgent Revascularization (%) 19.9 20 13.2 8.3 10 4.7 The greater the number of TIMI Risk Score criteria, the greater the risk of adverse cardiac event. Our patient had a TIMI score of 5 (>65 yrs, asa, 2+ episodes, ST abn, + trop) – point out risk The curves for individual risk are similar: Rates of all-cause mortality, myocardial infarction (MI), urgent revascularization, and all-cause mortality or nonfatal MI through 14 days after randomization were calculated for the entire population in the Thrombolysis in Myocardial Infarction (TIMI) 11B trial based on the TIMI risk score. There was a progressive, significant increase in the rate of events for each end point as the TIMI risk score increased (P<.001 by 2 for trend for all). C statistics for the 4 end points shown were 0.74 (all-cause mortality), (MI), 0.68 (urgent revascularization), and 0.63 (all-cause mortality/MI), respectively. 0/1 2 3 4 5 6/7 # of Risk Factors Antman EM, et al. JAMA ;284: Download at:

48 TIMI Risk Score for UA/NSTEMI
Higher TIMI risk scores correlated with more severe angiographic disease PRISM-PLUS: Increasing TIMI risk scores from 0-2 (low risk) to 5-7 (high risk) were associated with increases in the frequency of high-risk angiographic findings: >70 % culprit stenosis (from 58 to 81%) multivessel disease (43 to 80%) visible thrombus (30 to 41%) left main disease The TIMI risk score can also identify patients most likely to benefit from particular therapies: In TACTICS-TIMI 18, only patients with score ≥3 benefited from early invasive strategy The degree of troponin elevation and magnitude of ST segment deviation were independent predictors of an adverse outcome and of benefit from an early invasive strategy In TIMI 11B and ESSENCE, enoxaparin was associated with better 14-day and six- week post-discharge outcomes compared to UFH; these benefits were primarily seen in high-risk patients with risk scores ≥4 and ≥5, respectively Our patient had a TIMI score of 5 (>65 yrs, asa, 2+ episodes, ST abn, + trop) – point out risk on next next slide

49 GRACE Risk Calculator Estimates the risk of in-hospital and six-month mortality among all patients with an ACS This end point is different from the composite end point in the TIMI risk score of all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring revascularization While the GRACE prediction model is well validated and its use is recommended by multiple guideline organizations, its complexity makes it somewhat difficult to use in some clinical settings 47

50 GRACE Risk Calculator – 6 month mortality after ACS
Eagle et al. JAMA 2004;291:2727–33.

51 GRACE Risk Calculator – 6 month mortality after ACS
55 15 14 11 3 112 32% If you make the patient 80 with a h/o CHF, the risk increases significantly 4% Eagle et al. JAMA 2004;291:2727–33. Download at:

52 Prognostic Value of Troponin T or I in ACS: A Meta-Analysis
1.9 6.7 6.4 20.8 5 10 15 20 25 Death Death/MI % RR 3.9 ( ) RR 3.8 ( ) Neg Pos (Trop I + T) Troponin is an extremely powerful risk-stratifier. In one meta-analysis, the relative risks of death or of the combined endpoint of death+MI were 3.9 and 3.8, respectively, in patients who presented with NSTE-ACS Heidenreich PA, et al. JACC. 2001;38:

53 Troponin I Levels and Mortality in Patients with NSTE-ACS
8 6 4 % Mortality at 42 Days 2 As illustrated in this analysis by Antman from the TIMI IIIB study, the greater the troponin level in patients who present with NSTE-ACS, the greater the risk of future mortality. Note though that even small elevations of troponin are associated with significantly increased risk. 0- <0.4 0.4- <1.0 1.0- <2.0 2.0- <5.0 5.0- <9.0 >9.0 Troponin I Level Adapted with permission from Antman EA, Tanasijevic MJ, Thompson B, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med. 1996;335: Copyright © 1996, Massachusetts Medical Society. All rights reserved.

54 B-type Natriuretic Peptide (BNP) and Mortality in ACS Patients
10 Quartile 4 (n=630) P<.001 >138 pg/ml 8 6 Quartile 3 (n=632) Mortality (%) 4 Quartile 2 (n=632) Other risk stratifiers for patients who present with NSTE-ACS include the level of B-type natriuretic peptide (BNP) Figure 1. Kaplan–Meier Curves Showing the Cumulative Incidence of Death at 10 Months, According to the Quartile of B-Type Natriuretic Peptide Level at Enrollment. The range of B-type natriuretic peptide levels was as follows: 5.0 to 43.6 pg per milliliter (quartile 1), 43.7 to 81.2 pg per milliliter (quartile 2), 81.3 to pg per milliliter (quartile 3), and to pg per milliliter (quartile 4). P<0.001 for the trend among the quartiles. Background Brain (B-type) natriuretic peptide is a neurohormone synthesized predominantly in ventricular myocardium. Although the circulating level of this neurohormone has been shown to provide independent prognostic information in patients with transmural myocardial infarction, few data are available for patients with acute coronary syndromes in the absence of ST-segment elevation. Methods We measured B-type natriuretic peptide in plasma specimens obtained a mean (±SD) of 40±20 hours after the onset of ischemic symptoms in 2525 patients from the Orbofiban in Patients with Unstable Coronary Syndromes–Thrombolysis in Myocardial Infarction 16 study. Results The base-line level of B-type natriuretic peptide was correlated with the risk of death, heart failure, and myocardial infarction at 30 days and 10 months. The unadjusted rate of death increased in a stepwise fashion among patients in increasing quartiles of base-line B-type natriuretic peptide levels (P<0.001). This association remained significant in subgroups of patients who had myocardial infarction with ST-segment elevation (P=0.02), patients who had myocardial infarction without ST-segment elevation (P<0.001), and patients who had unstable angina (P<0.001). After adjustment for independent predictors of the long-term risk of death, the odds ratios for death at 10 months in the second, third, and fourth quartiles of B-type natriuretic peptide were 3.8 (95 percent confidence interval, 1.1 to 13.3), 4.0 (95 percent confidence interval, 1.2 to 13.7), and 5.8 (95 percent confidence interval, 1.7 to 19.7). The level of B-type natriuretic peptide was also associated with the risk of new or recurrent myocardial infarction (P=0.01) and new or worsening heart failure (P<0.001) at 10 months. Conclusions A single measurement of B-type natriuretic peptide, obtained in the first few days after the onset of ischemic symptoms, provides predictive information for use in risk stratification across the spectrum of acute coronary syndromes. Cardiac neurohormonal activation may be a unifying feature among patients at high risk for death after acute coronary syndromes 2 Quartile 1 (n=631) 50 100 150 200 250 300 Days After Randomization Lemos JA,, et al. N Engl J Med. 2001;345:

55 Predictive Value of hs-CRP for Mortality from ACS in FRISC Substudy
CRP >10mg/l (n=309) 20 CRP 2-10mg/l (n=294) Cumulative Probability of Death (%) 10 CRP <2mg/l (n=314) hs-CRP level has been shown to help to long-term risk-stratify patients with NSTE-ACS, with levels > 10 mg/l associated with a notable increase in the risk of long-term death Background In patients with unstable coronary artery disease, there is a relation between the short-term risk of death and blood levels of troponin T (a marker of myocardial damage) and C-reactive protein and fibrinogen (markers of inflammation). Using information obtained during an extension of the follow-up period in the Fragmin during Instability in Coronary Artery Disease trial, we evaluated the usefulness of troponin T, C-reactive protein, and fibrinogen levels and other indicators of risk as predictors of the long- term risk of death from cardiac causes. Methods Levels of C-reactive protein and fibrinogen at enrollment and the maximal level of troponin T during the first 24 hours after enrollment were analyzed in 917 patients included in a clinical trial of low-molecular-weight heparin in unstable coronary artery disease. The patients were followed for a mean of 37.0 months (range, 1.6 to 50.6). Results During follow-up, 1.2 percent of the 173 patients with maximal blood troponin T levels of less than 0.06 µg per liter died of cardiac causes, as compared with 8.7 percent of the 367 patients with levels of 0.06 to 0.59 µg per liter and 15.4 percent of the 377 patients with levels of at least 0.60 µg per liter (P= and P=0.001, respectively). The rates of death from cardiac causes were 5.7 percent among the 314 patients with blood C- reactive protein levels of less than 2 mg per liter, 7.8 percent among the 294 with levels of 2 to 10 mg per liter, and 16.5 percent among the 309 with levels of more than 10 mg per liter (P= 0.29 and P=0.001, respectively). The rates of death from cardiac causes were 5.4 percent among the 314 patients with blood fibrinogen levels of less than 3.4 g per liter, 12.0 percent among the 300 with levels of 3.4 to 3.9 g per liter, and 12.9 percent among the 303 with levels of at least 4.0 g per liter (P=0.004 and P=0.69, respectively). In a multivariate analysis, levels of troponin T and C-reactive protein were independent predictors of the risk of death from cardiac causes. Conclusions In unstable coronary artery disease, elevated levels of troponin T and C-reactive protein are strongly related to the long-term risk of death from cardiac causes. These markers are independent risk factors, and their effects are additive with respect to each other and other clinical indicators of risk. 6 12 18 24 30 36 42 48 Months Lindahl B, et al.. N Engl J Med. 2000;343:

56 Therapeutic Approaches
Invasive vs Conservative

57 Invasive vs Conservative Strategy for UA/NSTEMI
ISAR- COOL 2003 RITA-3 VANQWISH VINO MATE TRUCS TIMI IIIB TACTICS- TIMI 18 FRISC II Conservative Numerous studies involving over 7,000 patients have now consistently demonstrated that a strategy of early cardiac catheterization and revascularization in appropriately selected patients with NSTE-ACS leads to fewer adverse cardiac events than an initial strategy of medical therapy alone. Invasive UA indicates unstable angina, NSTEMI, non–ST-segment myocardial infarction; ISAR, Intracoronary Stenting and Antithrombic Regimen Trial; RITA, Randomized Intervention Treatment of Angina; VANQWISH, Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital study; MATE, Medicine vs Angioplasty for Thrombolytic Exclusions trial; TACTICS-TIMI18, Treat Angina with Aggrastat® and Determine Cost of Therapy with Invasive or Conservative Strategy; and FRISC, Fragmin during InStability in Coronary artery disease. Slide reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at:

58 TACTICS TIMI 18 20% 19.4% Initial Medical Rx 16% 15.9% 12%
Patients (%) 20% 19.4% Initial Medical Rx 16% 15.9% 12% Early Cath + PTCA 8% 4% The primary results from the TACTICS-TIMI 18 study demonstrated that the strategy of early cardiac catheterization and revascularization resulted in a statistically significantly lower incidence of adverse ischemic events at 6 months than a strategy of initial medical therapy. 5 6 1 2 3 4 Months Cumulative Incidence of the Primary Endpoint of Death, Nonfatal MI, rehospitalization for an ACS within 6 months Cannon CP, et al. N Engl J Med. 2001;344:

59 TACTICS Trial Results Based on Troponin
Initial Medical Rx Early Cath + PTCA P<0.001 25% 20% P=NS 15% 10% In TACTICS TIMI-18, patients with positive troponins experienced dramatically lower major ischemic events when treated with a strategy of early cardiac catheterization and revascularization 5% Negative Troponin Positive Troponin Cannon CP, et al. N Engl J Med. 2001;344:

60 Benefit of Invasive Strategy by Troponin and ST Changes
Death, MI, or Rehospitalization for ACS at 6 Months Conservative P<.001 P<.001 Invasive 30 30 P=NS 25.0* P=NS 24.5* 25 25 20 20 16.0 16.6 16.4* 15.3* 15.1 CV Events (%) 15 15 12.4 10 10 Subgroup analysis from the TACTICS-TIMI 18 Study demonstrated that a strategy of early cardiac catheterization and revascularization reduced ischemic complications in patients with positive troponin T levels and in those with ischemic ST segment abnormalities. There was no significant difference in outcome in patients who lacked these risk markers. 5 5 TnT – TnT + No ST change ST change Morrow DA, et al. JAMA. 2001;286: and Cannon CP, et al. N Engl J Med. 2001;344:

61 The Primary Composite Ischemic End Point in RITA-3
The RITA-3 trial also randomized patients with NSTE-ACS to either a strategy of early cardiac catheterization and revascularization, or to initial medical therapy. Those randomized to early intervention experienced a lower incidence of death, myocardial infarction, or recurrent unstable angina. Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Lancet. 2002;360:

62 Meta-Analysis of Trials of Early Cardiac Cath and Revascularization Versus Initial Medical Therapy Alone in Patients with NSTE-ACS Individual trials and metaanalysis of trials comparing strategies of early cardiac catheterization and revascularization with initial medical therapy alone in patients with NSTE-ACS. Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Lancet. 2002;360:

63 TACTICS-TIMI18: Rates of Death, Nonfatal MI, or Rehospitalization for an ACS at Six Months, According to Base-Line Characteristics Figure 2. Rates of the Primary End Point of Death, Nonfatal Myocardial Infarction, or Rehospitalization for an Acute Coronary Syndrome at Six Months, According to Base-Line Characteristics. Odds ratios and 95 percent confidence intervals were determined by logistic-regression analysis. P values for the interaction were significant only for prior aspirin use (P=0.02) and ST-segment changes (P=0.006). For the analysis of the TIMI risk score, which assesses the risk of death and ischemic events in patients with unstable angina and myocardial infarction without ST-segment elevation, the upper bound of the confidence interval for a score of 3 to 4 was (P=0.048; P for the interaction among the three risk groups=0.15). Troponin T was measured at base line in a total of 1826 patients. MI denotes myocardial infarction. Cannon C et al. N Engl J Med 2001;344:

64 Early Invasive Therapy: Class I Recommendations
Recurrent angina despite rx* Elevated cardiac markers* New ST-segment depression* Positive stress test* Symptoms of ischemic CHF, rales, MR EF < 40% Sustained VT Hypotension/hemodynamic instability PCI within 6 mos, prior CABG High risk score (TIMI, GRACE) In the absence of any of the above high-risk indicators, either an early conservative or an early invasive strategy is appropriate An important recent advance in the management of NSTEASC has been the recognition that high risk patients benefit from early (before discharge) invasive investigation and coronary revascularisation compared with a more conservative, "ischaemia guided" strategy, whereby coronary arteriography and revascularisation are reserved for patients with ischaemia refractory to drug therapy or with evidence of inducible ischaemia on early non-invasive testing. Five prospective randomised studies have investigated this issue. The earliest, the TIMI IIIb trial, showed no difference between strategies in terms of rates of myocardial infarction and mortality.66 Hospital readmission was significantly reduced by the invasive approach. The veterans affairs non-Q-wave infarction strategies in hospital (VANQWISH) investigators reported an increased risk of death or non-fatal myocardial infarction with an early invasive strategy.67 This may be explained by the unusually high 30 day mortality rate after CABG in this study (12%). Both the TIMI IIIB and VANQWISH trials were conducted before the routine use of stents and GPIIb/IIIa inhibitors during percutaneous coronary intervention. As such, the results have to be interpreted with caution in the current day. Three subsequent studies have all shown superiority of early, "modern" invasive management. The fragmin and fast revascularisation during instability in coronary artery disease (FRISC) II study showed a significant reduction in all cause mortality and myocardial infarction at one year follow up, attributable to an invasive strategy.68 The TACTICS-TIMI 18 investigators randomised 2220 patients to early coronary arteriography followed by revascularisation as appropriate or a more conservative strategy in which catheterisation was only performed for recurrent ischaemia or positive stress testing.7 All patients received tirofiban for 48 hours before randomisation and cardiac catheterisation was carried out comparatively early (at a mean interval of 22 hours after randomisation) compared with the FRISC II study (mean interval six days). Again a benefit in favour of the invasive strategy was found with an absolute risk reduction of 3.5% in the rate of the primary end point (death, non-fatal myocardial infarction, or rehospitalisation for ACS). Of note, this benefit was restricted to high risk patients—that is, those with TIMI risk score 3, raised troponins, or ST segment deviation. Most recently, Fox et al published the results of the randomised intervention trial of unstable angina (RITA) 3 study.69 All 1810 patients studied were treated with subcutaneous enoxaparin and in the invasive arm, cardiac catheterisation took place at a mean of two days after enrolment. A primary end point of death, (re)infarction, or refractory angina at four months was prespecified and was observed in 9.6% of patients in the invasive arm compared with 14.5% of those in the conservative arm (p = 0.001). The remarkably consistent results observed by the FRISC II, TACTICS-TIMI 18, and RITA 3 investigators form a large, concrete evidence base on which it is recommended that in-patient coronary arteriography and revascularisation should be made available to all high risk NSTEACS patients. Low risk patients can be safely managed with an initial conservative approach with cardiac catheterisation reserved for those who develop recurrent ischaemia or who subsequently have a positive stress test. Selection for Coronary Angiography In contrast to the noninvasive tests, coronary angiography provides detailed structural information to allow an assessment of prognosis and to provide direction for appropriate management. When combined with LV angiography, it also allows an assessment of global and regional LV function. Indications for coronary angiography are interwoven with indications for possible therapeutic plans, such as PCI or CABG. Coronary angiography is usually indicated in patients with UA/NSTEMI who either have recurrent symptoms or ischemia despite adequate medical therapy or are at high risk as categorized by clinical findings (HF, serious ventricular arrhythmias) or noninvasive test findings (significant LV dysfunction: ejection fraction less than 0.35, large anterior or multiple perfusion defects; Tables 19, 20, and 21), as discussed in Section Patients with UA/NSTEMI who have had previous PCI or CABG also should generally be considered for early coronary angiography, unless prior coronary angiography data indicate that no further revascularization is likely to be possible. The placement of an IABP may allow coronary angiography and revascularization in those with hemodynamic instability (see Section ). Patients with suspected Prinzmetal’s variant angina also are candidates for coronary angiography (see Section 6.7). In all cases, the general indications for coronary angiography and revascularization are tempered by individual patient characteristics and preferences. Patient and physician judgments regarding risks and benefits are particularly important for patients who might not be candidates for coronary revascularization, such as very frail older adults and those with serious comorbid conditions (i.e., severe hepatic, pulmonary, or renal failure; active or inoperable cancer). Circulation. 2007;116:e148–e304.

65 Patient Up Date Treated with aspirin, clopidogrel, heparin
Beta-blocker titrated to resting HR ~ bpm High dose statin given Cardiac catheterization performed.

66 Cath PCI

67 What About After Discharge?

68 Secondary Prevention - Risk Factor Modification
Smoking Cessation Achieve optimal weight Increase physical activity level, cardiac rehab AHA diet HTN control to BP <130/85 mm Hg Statin with goal LDL< 70 Tight glycemic control in diabetics ** Consider referral to cardiac rehab program Circulation. 2007;116:e148–e304.

69 Long-Term Medical Therapy: Class I Indications
Aspirin 81 mg/day Clopidogrel 75 mg QD when ASA intolerant Combination ASA and clopidogrel/ticagrelor/prasugrel for 12 months after UA/NSTEMI/STEMI, 1 month BMS and 12 months DES Beta-blocker Lipid-lowering and diet (if LDL>100) ACE Inhibitor if CHF, LV EF < 40%, HTN, DM NTG prn with clear instructions on use Circulation. 2007;116:e148–e304.

70 Guideline Compliance and Outcomes
Figure 2. Link between American College of Cardiology/American Heart Association guideline adherence (hospital composite quality quartiles) and in-hospital mortality. Every 10% increase in guideline adherence was associated with a 10% reduction in in-hospital mortality (adapted from Peterson et al. [31]). *Adjusted for age, gender, body mass index, race, insurance status, family history of coronary disease, hypertension, diabetes, smoking, hypercholesterolemia, prior myocardial infarction/percutaneous coronary intervention/coronary bypass surgery/congestive heart failure/stroke, renal insufficiency, blood pressure, heart rate, ST-segment shift, and positive cardiac biomarkers. Tricoci P Et al. Am J Cardiol 2006;98:S30-S35.

71 Summary Thrombosis is central in the pathophysiology of ACS and mandates antithrombotic and antiplatelet therapy All patients with ACS should be treated with aspirin and heparin. Consider treatment with Clopidogrel in patients who will be treated conservatively or those likely to undergo PCI Use of the TIMI risk score helps identify those patients that benefit from invasive therapies Improved adherence to guidelines results in improved outcomes

72 Recommended Strategy in ACS: Boston Medical Center Guidelines
Coronary Angiography PCI/CABG UA/ NSTEMI High Risk Elevated Troponin Recurrent Ischemia Dynamic EKG changes TIMI score > 3 Aspirin Nitrates Beta-blockers UFH/LMWH ? Clopidogrel Low Risk Normal Troponin on admission and at 12 h TIMI score <2 Stress Test Pre-dc


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