The top half of the figure illustrates the chronology of the interface between the patient and the clinician through the progression of plaque formation, onset, and complications of UA/NSTEMI, along with relevant management considerations at each stage. The longitudinal section of an artery depicts the "timeline" of atherogenesis from (1) a normal artery to (2) lesion initiation and accumulation of extracellular lipid in the intima, to (3) the evolution to the fibrofatty stage, to (4) lesion progression with procoagulant expression and weakening of the fibrous cap. An acute coronary syndrome (ACS) develops when the vulnerable or high-risk plaque undergoes disruption of the fibrous cap (5); disruption of the plaque is the stimulus for thrombogenesis. Thrombus resorption may be followed by collagen accumulation and smooth muscle cell growth (6). After disruption of a vulnerable or high-risk plaque, patients experience ischemic discomfort that results from a reduction of flow through the affected epicardial coronary artery. The flow reduction may be caused by a completely occlusive thrombus (bottom half, right side) or subtotally occlusive thrombus (bottom half, left side). Patients with ischemic discomfort may present with or without ST-segment elevation on the ECG. Among patients with ST-segment elevation, most (thick white arrow in bottom panel) ultimately develop a Q-wave MI (QwMI), although a few (thin white arrow) develop a non–Q-wave MI (NQMI). Patients who present without ST-segment elevation are suffering from either unstable angina (UA) or a non–ST-segment elevation MI (NSTEMI) (thick red arrows), a distinction that is ultimately made on the basis of the presence or absence of a serum cardiac marker such as CK-MB or a cardiac troponin detected in the blood. Most patients presenting with NSTEMI ultimately develop a NQMI on the ECG; a few may develop a QwMI. The spectrum of clinical presentations ranging from UA through NSTEMI and STEMI is referred to as the acute coronary syndromes. This UA/NSTEMI guideline, as diagrammed in the upper panel, includes sections on initial management before UA/NSTEMI, at the onset of UA/NSTEMI, and during the hospital phase. Secondary prevention and plans for long-term management begin early during the hospital phase of treatment. *Positive serum cardiac marker. Modified with permission from Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001;104:365 (7); © 2001 Lippincott, Williams & Wilkins; The Lancet, 358, Hamm CW, Bertrand M, Braunwald E. Acute coronary syndrome without ST elevation: implementation of new guidelines, 1533–8. Copyright 2001, with permission from Elsevier (8); and Davies MJ. The pathophysiology of acute coronary syndromes. Heart 2000;83:361–6 (9). © 2000 Lippincott, Williams & Wilkins. CK-MB = MB fraction of creatine kinase; Dx = diagnosis; ECG = electrocardiogram.

To facilitate interpretation of this algorithm and a more detailed discussion in the text, each box is assigned a letter code that reflects its level in the algorithm and a number that is allocated from left to right across the diagram on a given level. ACC/AHA = American College of Cardiology/American Heart Association; ACS = acute coronary syndrome; ECG = electrocardiogram; LV = left ventricular.

If patients experience chest discomfort/pain and have been previously prescribed NTG and have it available (right side of algorithm), it is recommended that they be instructed (in advance) to take 1 dose of NTG immediately in response to symptoms. If chest discomfort/pain is unimproved or worsening 5 min after taking 1 NTG sublingually, it is recommended that the patient call 9-1-1 immediately to access EMS. In patients with chronic stable angina, if the symptoms are significantly improved after taking 1 NTG, it is appropriate to instruct the patient or family member/friend/caregiver to repeat NTG every 5 minutes for a maximum of 3 doses and call 9-1-1 if symptoms have not totally resolved. If patients are not previously prescribed NTG (left side of algorithm), it is recommended that they call 9-1-1 if chest discomfort/pain is unimproved or worsening 5 min after it starts. If the symptoms subside within 5 min of when they began, patients should notify their physician of the episode. (For those patients with new-onset chest discomfort who have not been prescribed NTG, it is appropriate to discourage them from seeking someone else’s NTG [e.g., from a neighbor, friend, or relative].) *Although some trials have used enteric-coated aspirin for initial dosing, more rapid buccal absorption occurs with non–enteric-coated formulations. EMS = emergency medical services; NTG = nitroglycerin.

Reprinted with permission from Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA 2004;291:2727–33 (168). Copyright © 2004 American Medical Association.

The biomarkers are plotted showing the multiples of the cutoff for acute myocardial infarction (AMI) over time. The dashed horizontal line shows the upper limit of normal (ULN; defined as the 99th percentile from a normal reference population without myocardial necrosis; the coefficient of variation of the assay should be 10% or less) The earliest rising biomarkers are myoglobin and CK isoforms (leftmost curve). CKMB (dashed curve) rises to a peak of 2 to 5 times the ULN and typically returns to the normal range within 2 to 3 d after AMI. The cardiac-specific troponins show small elevations above the ULN in small infarctions (e.g., as is often the case with NSTEMI) but rise to 20 to 50 times the ULN in the setting of large infarctions (e.g., as is typically the case in STEMI). The troponin levels may stay elevated above the ULN for 7 d or more after AMI. Modified from Shapiro BP, Jaffe AS. Cardiac biomarkers. In: Murphy JG, Lloyd MA, editors. Mayo Clinic Cardiology: Concise Textbook. 3rd ed. Rochester, MN: Mayo Clinic Scientific Press and New York: Informa Healthcare USA, 2007: 773–80 (70). Used with permission of Mayo Foundation for Medical Education and Research. CK = creatine kinase; CKMB = MB fraction of creatine kinase; CV = coefficient of variation; MI = myocardial infarction; NSTEMI = non–ST-elevation myocardial infarction; UA/NSTEMI = unstable angina/non–ST-elevation myocardial infarction.

Mortality rates are at 42 d (without adjustment for baseline characteristics) in patients with acute coronary syndrome. The numbers at the bottom of each bar are the numbers of patients with cardiac troponin I levels in each range, and the numbers above the bars are percentages. p less than 0.001 for the increase in the mortality rate (and the risk ratio for mortality) with increasing levels of cardiac troponin I at enrollment. Reprinted with permission from Antman EM, 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;335:1342–9 (201). Copyright © 1996 Massachusetts Medical Society. All rights reserved.

When multiple drugs are listed, they are in alphabetical order and not in order of preference (e.g., Boxes B1 and B2). *See dosing Table 13. See Table 11 for selection of management strategy. Evidence exists that GP IIb/IIIa inhibitors may not be necessary if the patient received a preloading dose of at least 300 mg of clopidogrel at least 6 h earlier (Class I, Level of Evidence B for clopidogrel administration) and bivalirudin is selected as the anticoagulant (Class IIa, Level of Evidence B). ASA = aspirin; GP = glycoprotein; IV = intravenous; LOE = level of evidence; UA/NSTEMI = unstable angina/non–ST-elevation myocardial infarction; UFH = unfractionated heparin.

When multiple drugs are listed, they are in alphabetical order and not in order of preference (e.g., Boxes C, C1, and C2). *See dosing Table 13. See Table 11 for selection of management strategy. Recurrent symptoms/ischemia, heart failure, serious arrhythmia. ASA = aspirin; EF = ejection fraction; GP = glycoprotein; IV = intravenous; LOE = level of evidence; LVEF = left ventricular ejection fraction; UA/NSTEMI = unstable angina/non–ST-elevation myocardial infarction; UFH = unfractionated heparin.

*See dosing Table 13. Evidence exists that GP IIb/IIIa inhibitors may not be necessary if the patient received a preloading dose of at least 300 mg of clopidogrel at least 6 h earlier (Class I, Level of Evidence B for clopidogrel administration) and bivalirudin is selected as the anticoagulant (Class IIa, Level of Evidence B). Additional bolus of UFH is recommended if fondaparinux is selected as the anticoagulant (see dosing Table 13). For patients in whom the clinician believes coronary atherosclerosis is present, albeit without any significant, flow-limiting stenoses, long-term treatment with antiplatelet agents and other secondary prevention measures should be considered. ASA = aspirin; CABG = coronary artery bypass graft; CAD = coronary artery disease; GP = glycoprotein; IV = intravenous; LD = loading dose; PCI = percutaneous coronary intervention; pre angio = before angiography; UA/NSTEMI = unstable angina/non–ST-elevation myocardial infarction; UFH = unfractionated heparin.

*Best results group. GPIIb/IIIa with no heparin. All trials except PRISM compared GP IIb-IIIa with UFH versus UFH. Meta-analysis of randomized trials in UA/NSTEMI that have compared ASA with placebo, the combination of UFH and ASA with ASA alone, the combination of an LMWH and ASA with ASA alone, and the combination of a platelet GP IIb/IIIa antagonist, UFH, and ASA with UFH plus ASA. The risk ratio values, 95% CIs, and probability value for each trial are shown. The timing of the end point (death or MI) varied. Results with the platelet GP IIb/IIIa antagonists are reported at the 30-d time point. Incremental gain is observed from single therapy with ASA to double therapy with ASA and UFH and to triple antithrombotic therapy with ASA, UFH, and a platelet GP IIb/IIIa antagonist. In the CAPTURE trial, nearly all patients underwent PCI after 20 to 24 h per study design. Data are taken from PURSUIT (128), PRISM-PLUS (130), Lewis et al. (365), Cairns et al. (366), Théroux et al. (367), RISC group (368), ATACS group (369), Gurfinkel et al. (370), FRISC group (371), CAPTURE (372), PARAGON (373), and PRISM (374). anta. = antagonist; ASA = aspirin; ATACS = Antithrombotic Therapy in Acute Coronary Syndromes; CAPTURE = c7E3 Fab AntiPlatelet Therapy in Unstable REfractory angina; CI = confidence interval; FRISC = FRagmin during InStability in Coronary artery disease; GP = glycoprotein; hep. = heparin; LMWH = low-molecular-weight heparin; MI = myocardial infarction; NA = not applicable; PARAGON = Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network; PCI = percutaneous coronary intervention; PRISM = Platelet Receptor Inhibition in ischemic Syndrome Management; PRISM-PLUS = Platelet Receptor Inhibition in ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms; PURSUIT = Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy; RISC = Research on InStability in Coronary artery disease; UA/NSTEMI = unstable angina/non--ST-elevation myocardial infarction; UFH = unfractionated heparin; VA = Veterans Affairs.

*For aspirin (ASA) allergic patients, use clopidogrel alone (indefinitely), or try aspirin desensitization. For clopidogrel allergic patients, use ticlopidine, 250 mg by mouth twice daily. Continue ASA indefinitely and warfarin longer term as indicated for specific conditions such as atrial fibrillation; LV thrombus; cerebral, venous, or pulmonary emboli. When warfarin is added to aspirin plus clopidogrel, an INR of 2.0 to 2.5 is recommended. INR = international normalized ratio; LOE = Level of Evidence; LV = left ventricular; UA/NSTEMI = unstable angina/non–ST-elevated myocardial infarction.

CI = confidence interval; MI = myocardial infarction; SYNERGY = Superior Yield of the New strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (423); UFH = unfractionated heparin.

*p for noninferiority. ACUITY = Acute Catheterization and Urgent Intervention Triage strategY; CI = confidence interval; GP = glycoprotein; UFH = unfractionated heparin.

ACUITY = Acute Catheterization and Urgent Intervention Triage strategY; CI = confidence interval; GP = glycoprotein; PCI = percutaneous coronary intervention; UFH = unfractionated heparin.

*p for noninferiority. p for superiority. CI = confidence interval; MI = myocardial infarction; OASIS 5 = Fifth Organization to Assess Strategies for Ischemic Syndromes.

Incidence is shown in patients randomly assigned to platelet GP IIb/IIIa receptor antagonist (bold line) or placebo. Data are derived from the CAPTURE, PURSUIT, and PRISM-PLUS trials. Left: events during the initial period of medical treatment until the moment of PCI or CABG. In the CAPTURE trial, abciximab was administered for 18 to 24 h before the PCI was performed in almost all patients as per study design; abciximab was discontinued 1 h after the intervention. In PURSUIT, a PCI was performed in 11.2% of patients during a period of medical therapy with eptifibatide that lasted 72 h and for 24 h after the intervention. In PRISM-PLUS, an intervention was performed in 30.2% of patients after a 48-h period of medical therapy with tirofiban, and the drug infusion was maintained for 12 to 24 h after an intervention. Right: events occurring at the time of PCI and the next 48 h, with the event rates reset to 0% before the intervention. Creatine kinase or creatine kinase-MB elevations exceeding 2 times the upper limit of normal were considered as infarction during medical management and exceeding 3 times the upper limit of normal for PCI-related events. Adapted from Boersma E, Akkerhuis KM, Théroux P, et al. Platelet glycoprotein IIb/IIIa receptor inhibition in non–ST-elevation acute coronary syndromes. Circulation 1999;100:2045–8 (523), CAPTURE (240), PURSUIT (172), and PRISM-PLUS (134). © Lippincott, Williams & Wilkins. CABG = coronary artery bypass graft; CAPTURE = c7E3 Fab AntiPlatelet Therapy in Unstable REfractory angina; GP = glycoprotein; MI = myocardial infarction; N = number of patients; OR = odds ratio; PCI = percutaneous coronary intervention; PRISM-PLUS = Platelet Receptor Inhibition in ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms; PURSUIT = Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy.

Cumulative risk of death or myocardial infarction (top) or of death (bottom) in the RITA 3 trial of patients with non-ST acute coronary syndromes. Reprinted from The Lancet, 366, Fox KAA, Poole-Wilson P, Clayton TC, et al. 5-year outcome of an interventional strategy in non-ST-elevation acute coronary syndrome: the British Heart Foundation RITA 3 randomised trial, 914–20. Copyright 2005, with permission from Elsevier (546). RITA-3 = Third Randomized Intervention Treatment of Angina trial.

A: Relative risk of all-cause mortality for early invasive therapy compared with conservative therapy at a mean follow-up of 2 years. B: Relative risk of recurrent nonfatal myocardial infarction for early invasive therapy compared with conservative therapy at a mean follow-up of 2 years. C: Relative risk of recurrent unstable angina resulting in rehospitalization for early invasive therapy compared with conservative therapy at a mean follow-up of 13 months. Modified from the Journal of the American College of Cardiology, 48, Bavry AA, Kumbhani DJ, Rassi AN, Bhatt DL, Askari AT. Benefit of early invasive therapy in acute coronary syndromes a meta-analysis of contemporary randomized clinical trials, 1319–25. Copyright 2006, with permission from Elsevier (547). CI = confidence interval; FRISC-II = FRagmin and fast Revascularization during InStability in Coronary artery disease; ICTUS = Invasive versus Conservative Treatment in Unstable coronary Syndromes; ISAR-COOL = Intracoronary Stenting with Antithrombotic Regimen COOLing-off study; RITA-3 = Third Randomized Intervention Treatment of Angina trial; RR = relative risk; TIMI-18 = Thrombolysis In Myocardial Infarction-18; TRUCS = Treatment of Refractory Unstable angina in geographically isolated areas without Cardiac Surgery; UA/NSTEMI = unstable angina/non–ST-elevation myocardial infarction; VINO = Value of first day angiography/angioplasty In evolving Non-ST segment elevation myocardial infarction: Open multicenter randomized trial.

Modified with permission from Savonitto S, Ardissino D, Granger CB, et al. Prognostic value of the admission electrocardiogram in acute coronary syndromes. JAMA 1999;281:707–13 (127). Copyright © 1999 American Medical Association.

*There is conflicting information about these patients. Most consider CABG to be preferable to PCI. CABG = coronary artery bypass graft; LAD = left anterior descending coronary artery; PCI = percutaneous coronary intervention UA/NSTEMI = unstable angina/non–ST-elevation myocardial infarction.

*Addition of ASA may not be sufficient protection against thrombotic events. Reproduced with permission. American Heart Association Scientific Statement on the Use of Nonsteroidal Anti-Inflammatory Drugs (NSAIDS)-An Update for Clinicians © 2007, American Heart Association, Inc. (673). ASA = aspirin; COX-2 = cyclooxygenase-1; NSAIDs = nonsteroidal anti-inflammatory drugs; PPI = proton-pump inhibitor.