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Antithrombotic and Thrombolytic Therapy, 8th Ed : ACCP Guidelines: ANTITHROMBOTIC AND THROMBOLYTIC THERAPY, 8TH ED: ACCP GUIDELINES |

Acute ST-Segment Elevation Myocardial Infarction*: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) FREE TO VIEW

Shaun G. Goodman, MD; Venu Menon, MD; Christopher P. Cannon, MD, PhD; Gabriel Steg, MD, FCCP; E. Magnus Ohman, MD, FCCP; Robert A. Harrington, MD, FCCP
Author and Funding Information

*From Michael’s Hospital (Dr. Goodman), University of Toronto, and Canadian Heart Research Centre, Toronto, ON, Canada; Cleveland Clinic Foundation (Dr. Menon), Cleveland, OH; Brigham and Women’s Hospital (Dr. Cannon), Boston, MA; Hôpital Bichat (Dr. Steg), Paris, France; and Duke University Medical Center (Drs. Ohman and Harrington), Durham, NC.

Correspondence to: Shaun G. Goodman, MD, St. Michael’s Hospital, Division of Cardiology, 30 Bond St, Room 6-034, Queen, Toronto, ON, Canada M5B 1W8; e-mail: goodmans@smh.toronto.on.ca



Chest. 2008;133(6_suppl):708S-775S. doi:10.1378/chest.08-0665
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This chapter about fibrinolytic, antiplatelet, and antithrombin treatment for acute ST-segment elevation (STE) myocardial infarction (MI) is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading see the chapter by Guyatt et al, CHEST 2008; 133[suppl]:123S–131S). Among the key recommendations in this chapter are the following: for patients with ischemic symptoms characteristic of acute MI of ≤ 12 h in duration and persistent STE, we recommend that all undergo rapid evaluation for reperfusion (primary percutaneous coronary intervention [PCI] or fibrinolytic) therapy and have a reperfusion strategy implemented promptly after contact with the health-care system (Grade 1A). For patients with ischemic symptoms characteristic of acute MI of ≤ 12 h in duration and persistent STE, we recommend administration of streptokinase, anistreplase, alteplase, reteplase, or tenecteplase over no fibrinolytic therapy (all Grade 1A). For patients with symptom duration ≤ 6 h, we recommend the administration of alteplase or tenecteplase over streptokinase (both Grade 1A). We recommend aspirin over no aspirin therapy followed by indefinite therapy (Grade 1A); we also recommend clopidogrel in addition to aspirin for up to 28 days (Grade 1A). In addition to aspirin and other antiplatelet therapies, we recommend the use of antithrombin therapy (eg, unfractionated heparin (UFH), enoxaparin, or fondaparinux) over no antithrombin therapy (Grade 1A), including for those patients receiving fibrinolysis (and regardless of which lytic agent is administered), primary PCI, or patients not receiving reperfusion therapy.

1.0 Reperfusion Therapy

1.0.1. For patients with ischemic symptoms characteristic of acute MI of ≤ 12 h duration and persistent STE, we recommend that all undergo rapid evaluation for reperfusion (primary PCI or fibrinolytic) therapy and have a reperfusion strategy implemented promptly after contact with the health-care system (Grade 1A).

1.1 Fibrinolysis

1.1.1. In patients with acute MI who are candidates for fibrinolytic therapy, we recommend administration as soon as possible (ideally within 30 min) after arrival to the hospital or first contact with the health-care system (Grade 1A).

1.1.2. In health-care settings where prehospital administration of fibrinolytic therapy is feasible, we recommend prehospital administration of fibrinolytic therapy (Grade 1A).

1.1.3. For patients with ischemic symptoms characteristic of acute MI of ≤ 12 h duration and persistent STE, we recommend administration of streptokinase, anistreplase, alteplase, reteplase, or tenecteplase over no fibrinolytic therapy (all Grade 1A).

1.1.4. For patients with symptom duration ≤ 6 h, we recommend the administration of alteplase (Grade 1A) or tenecteplase (Grade 1A), and suggest reteplase (Grade 2B) over streptokinase.

1.1.5. For patients receiving fibrinolytic therapy, we suggest the use of a bolus agent (eg, tenecteplase) to facilitate the ease of administration and potentially reduce the risk of nonintracranial hemorrhage (ICH)-related bleeding (tenecteplase) [Grade 2A].

1.1.6. For patients with ischemic symptoms characteristic of acute MI of ≤ 12 h duration, and left bundle-branch block (BBB) with associated STE changes, we recommend fibrinolytic therapy if primary PCI is not readily available(Grade 1B).

1.1.7. For patients with ischemic symptoms characteristic of acute MI of ≤ 12 h duration and ECG findings consistent with a true posterior MI, we suggest fibrinolytic therapy if primary PCI is not readily available (Grade 2B).

1.1.8. For high-risk patients with ongoing symptoms characteristic of acute MI or hemodynamic compromise and duration of 12 to 24 h who have persistent STE or left BBB with STE changes, we suggest fibrinolytic therapy if primary PCI is not readily available (Grade 2B).

1.1.9. In patients with any history of ICH, or with history of head trauma, or with ischemic stroke within the past 6 months, we recommend against administration of fibrinolytic therapy (Grade 1C).

2.1 Antiplatelet/Antithrombotic Therapy
Aspirin

2.1.1. For patients with acute STE MI whether or not they receive fibrinolytic therapy, we recommend aspirin (160 to 325 mg po) over no aspirin therapy at initial evaluation by health-care personnel (Grade 1A) followed by indefinite therapy (75 to 162 mg/d po)[Grade 1A].

2.2 Clopidogrel

2.2.1. For patients with acute STE MI, we recommend clopidogrel in addition to aspirin (Grade 1A). The recommended dosing for clopidogrel is 300 mg po for patients ≤ 75 years old and 75 mg po for patients > 75 years old if they receive fibrinolytic agents or no reperfusion therapy, followed by 75 mg/d po for up to 28 days (Grade 1A).

2.2.2. For patients with acute STE MI who have not received a coronary stent, we suggest that clopidogrel, 75 mg/d, could be continued beyond 28 days and up to 1 year (Grade 2B).

2.2.3. For patients undergoing primary PCI, we suggest clopidogrel in addition to aspirin with a recommended initial dosing of at least 300 mg (Grade 1B), followed by 75 mg/d daily (for duration of therapy, see chapter by Becker et al in this supplement).

2.3 Antithrombin Therapy

2.3.1. For patients with acute STE MI, in addition to aspirin and other antiplatelet therapies, we recommend the use of antithrombin therapy over no antithrombin therapy (Grade 1A), including for those patients receiving fibrinolysis (and regardless of which lytic agent is administered), primary PCI, or patients not receiving reperfusion therapy.

2.4 UFH

2.4.1. For patients receiving streptokinase, we suggest administration of either IV UFH (5,000-U bolus followed by 1,000 U/h for patients > 80 kg, 800 U/h for < 80 kg) with a target activated partial thromboplastin time (APTT) of 50 to 75 s or subcutaneous (SC) UFH (12,500 U q12h) over no UFH therapy for 48 h (both Grade 1B).

2.4.2. For patients receiving alteplase, tenecteplase, or reteplase for fibrinolysis in acute MI, we recommend administration of weight-adjusted heparin (60 U/kg bolus for a maximum of 4,000 U, followed by 12 U/kg/h [1,000 U/h maximum]) adjusted to maintain an APTT of 50 to 70 s for 48 h (Grade 1B).

2.4.3. For patients with STE MI undergoing primary PCI, we recommend administration of IV UFH over no UFH therapy (Grade 1C). The recommended periprocedural dosing in patients receiving a glycoprotein (GP) IIb/IIIa inhibitor is 50 to 70 U/kg (target activated clotting time [ACT] > 200 s); in patients not receiving a GP IIb/IIIa inhibitor, the recommended periprocedural dosing is 60 to 100 U/kg (target ACT, 250 to 350 s).

2.5 Low-Molecular-Weight Heparin

2.5.1. For patients with acute STE MI, regardless of whether or not they receive reperfusion therapy, we recommend the use of reviparin over no therapy (Grade 1B). Recommended dosing for reviparin is 3,436 IU for < 50 kg, 5,153 IU for 50 to 75 kg, or 6,871 IU for > 75 kg q12h SC up to 7 days. For patients undergoing primary PCI, UFH should be used periprocedurally and reviparin initiated 1 h after sheath removal.

2.5.2. For patients with acute STE MI receiving fibrinolytic therapy who have preserved renal function (≤ 2.5 mg/dL [220 μmol/L] in male patients and < 2.0 mg/dL [175 μmol/L] in female patients), we recommend the use of enoxaparin over UFH, continued up to 8 days (Grade 2A). Recommended dosing for enoxaparin is for age < 75 years, 30-mg IV bolus followed by 1 mg/kg SC q12h (maximum of 100 mg for the first two SC doses); and for age ≥ 75 years, no IV bolus, 0.75 mg/kg SC q12h (maximum of 75 mg for the first two SC doses).

2.6 Fondaparinux

2.6.1. For patients with acute STE MI and not receiving reperfusion therapy, we recommend fondaparinux over no therapy(Grade 1A). Recommended dosing for fondaparinux is 2.5 mg IV for the first dose and then SC qd up to 9 days.

2.6.2. For patients with acute STE MI receiving fibrinolytic therapy and thought not to have an indication for anticoagulation, we recommend fondaparinux over no therapy (2.5 mg IV for the first dose and then SC qd up to 9 days)[Grade 1B].

2.6.3. For patients with acute STE MI receiving fibrinolytic therapy and thought to have an indication for anticoagulation, we suggest fondaparinux (2.5 mg IV for the first dose and then SC qd up to 9 days) could be used as an alternative to UFH (Grade 2B).

2.6.4. For patients with acute STE MI and undergoing primary PCI, we recommend against using fondaparinux (Grade 1A).

2.7 Direct Thrombin Inhibitors

2.7.1. For patients with acute STE MI treated with streptokinase, we suggest clinicians not use bivalirudin as an alternative to unfractionated heparin (Grade 2B).

Underlying values and preferences: This recommendation places a relatively higher value on avoiding excess of major bleeding and a relatively lower value on avoiding reinfarction. Recommended dosing for bivalirudin is 0.25 mg/kg IV bolus followed by an infusion of 0.5 mg/kg/h for the first 12 h and then 0.25 mg/kg/h for the subsequent 36 h; APTTs should be measured at 12 h and 24 h with potential dose reductions as noted (see Section 2.7. below).

2.8 GP IIb/IIIa Inhibitors

2.8.1. For patients with acute STE MI, we recommend against the combination of standard-dose abciximab and half-dose reteplase or tenecteplase with low-dose IV UFH over standard-dose reteplase or tenecteplase (Grade 1B).

2.8.2. For patients with acute STE MI, we suggest clinicians not use the combination of streptokinase and any GP IIb/IIIa inhibitor (Grade 2B).

2.8.3. For patients with acute STE MI undergoing primary PCI (with or without stenting), we recommend the use of abciximab (Grade 1B). Recommended dosing for abciximab is 0.25 mg/kg IV bolus followed by 0.125 μg/kg/min (maximum, 10 μg/min) for 12 h.

3.0 Facilitated PCI

3.0.1. For patients with acute STE MI undergoing primary PCI, we recommend against the use of fibrinolysis, with or without a GP IIb/IIIa inhibitor (Grade 1B).

3.0.2. For patients with acute STE MI who are to undergo primary PCI, we suggest administration of a GP IIb/IIIa inhibitor prior to coronary angiography (Grade 2B). The largest number of patients studied in this setting received abciximab, 0.25 mg/kg IV bolus, followed by 0.125 μg/kg/min (maximum, 10 μg/min) for 12 h; recommended dosing for eptifibatide is two 180 μg IV boluses (10 min apart) followed by 2.0 μg/kg/min infusion for 12 to 24 h; recommended dosing for tirofiban is 25 μg/kg IV bolus followed by 0.15 μg/kg/min for 24 h.

4.0 Rescue PCI

4.0.1. For patients with STE MI who have received fibrinolysis but who have persistent STE (< 50% resolution 90 min after treatment initiation compared with the pretreatment ECG), we recommend rescue PCI should be performed over repeat fibrinolysis or no additional reperfusion therapy (Grade 1B), and suggest as soon as possible and within 2 h of identification of lack of STE resolution (Grade 2C).

Acute ST-segment elevation (STE) myocardial infarction (MI) is caused by coronary plaque disruption with exposure of substances that promote platelet activation, adhesion, and aggregation, thrombin generation, and thrombus formation leading to an occluded epicardial infarct-related artery (IRA).1 Antiplatelet and antithrombotic therapy should be administered to all patients with an acute coronary syndrome (ACS). Patients presenting with persistent STE should also be considered for timely reperfusion therapy (either pharmacologic or catheter- based) in order to restore coronary flow and limit myocardial necrosis. This review will focus mainly on approved agents and the randomized trials that have led to their widespread utilization. Table 1 describes the question definition and eligibility criteria for the studies considered in each section of the article. It is important to note that the grades of recommendation in the STE MI chapter are based on the potential for mortality reduction (benefit) vs bleeding (risk), with relatively less emphasis placed on the reduction in reinfarction, the composite of death, MI, or stroke, or other clinically important outcomes (eg, recurrent ischemia).

Among patients with persistent STE, prompt and complete restoration of flow in the IRA can be achieved with either a pharmacologic (fibrinolysis) or catheter-based (percutaneous coronary intervention [PCI]), pharmacologically supported approach. Regardless of the reperfusion strategy employed, there is strong evidence supporting restoration of IRA flow in a rapid time frame.15 Indeed, the optimal goal of any local medical system is to facilitate rapid recognition and treatment of patients with STE MI such that medical contact-to-needle (or door-to-needle) time for initiation of fibrinolytic therapy can ideally be achieved within 30 min or that medical contact-to-balloon (or door-to-balloon) time for PCI majority of patients within 90 min.6

Reperfusion with primary PCI has emerged as an extremely effective method for re-establishing IRA patency and is suitable for at least 90% of patients.79 When performed by experienced operators in optimal settings, successful TIMI-3 flow can be achieved in 80 to 95% of cases.1014 Primary PCI has been compared with fibrinolysis in > 20 randomized clinical trials of patients with STE MI, and an overview9 demonstrated that patients undergoing PCI compared with fibrinolytic treatment had significantly lower short-term mortality rates (5% vs 7%; odds ratio [OR], 0.70; 95% confidence interval [CI], 0.58 to 0.85; p = 0.038), nonfatal MI (3% vs 6%; OR, 0.42; 95% CI, 0.31 to 0.55), and ICH (0.05% vs 1.0%; OR, 0.05; 95% CI, 0.006 to 0.35; p < 0.0001). There was an increased risk for major bleeding in patients undergoing primary PCI (7% vs 5%; OR, 1.3; 95% CI, 1.02 to 1.65; p = 0.032). The mortality benefit was present in trials testing streptokinase as well as in studies using fibrin-specific agents. The short-term benefits of primary PCI over fibrinolytic therapy appear to be sustained.1517

There is substantial debate, however, regarding the timing of primary PCI relative to symptom onset and hospital presentation; for example, one analysis18of randomized controlled trials that compared primary PCI with fibrin-specific lytic agents suggested that the mortality benefit with PCI was only evident when treatment was delayed by no more than 60 min, while another study19found that primary PCI was associated with significantly lower 30-day mortality regardless of treatment delay. Further, the ongoing investigation and availability of new agents, dosing regimens, devices, adjunctive treatments, and combinations is a dynamic process. Thus, the selection of reperfusion strategy remains controversial and is beyond the scope of these clinical practice guidelines; instead, the focus of this chapter is on antithrombotic therapy, including fibrinolysis. Further, despite the proven benefits of primary PCI, fibrinolytic therapy will continue to have a pivotal role in reperfusion therapy. This is because access to timely20and optimal2122 primary PCI is limited both in the United States and worldwide. In contrast, fibrinolytic therapy is available universally and can be administered in a timely manner by community and emergency physicians. Although most evaluations of PCI have been in patients who are eligible to receive fibrinolysis, there may be substantial value of PCI in patients who may not be suitable for fibrinolytic therapy because of an increased risk of bleeding.23While there are no randomized controlled trials evaluating the outcome of PCI for patients who present with STE MI but who are ineligible for fibrinolytic therapy, these patients are at increased risk for mortality,24 and it has been suggested that PCI be considered for achieving reperfusion in these patients.23,2526

1.0 Reperfusion Therapy
Recommendation

1.0.1. For patients with ischemic symptoms characteristic of acute MI of ≤ 12 h in duration and persistent STE, we recommend that all undergo rapid evaluation for reperfusion (primary PCI or fibrinolytic) therapy and have a reperfusion strategy implemented promptly after contact with the health-care system (Grade 1A).

1.1 Fibrinolysis

More than 150,000 patients have been randomized in trials of fibrinolytics vs placebo/control, or one fibrinolytic regiment compared with another.2741 For patients treated within 12 h of symptom onset, the overall evidence for the benefit of fibrinolytic therapy is overwhelming. The Fibrinolytic Therapy Trialists (FTT) analysis42—a collaborative overview of early mortality and major morbidity results from nine trials2734 of fibrinolysis vs control that randomized > 1,000 patients with suspected MI each (n = 58,600)—described approximately 18 fewer deaths per 1,000 patients treated (Tables 2, 3 ). These mortality benefits were evident despite an excess of deaths during days 0 to 1 (especially among patients presenting > 12 h after symptom onset, and in the elderly); this “early hazard” was far outweighed by a much larger benefit during days 2 to 35. Benefit was observed among patients presenting with STE or bundle-branch block (BBB), irrespective of age, sex, BP (if < 180 mm Hg systolic),,4344 heart rate, or previous history of MI or diabetes.42 The mortality benefit was remarkably consistent across prestratified subgroups; hence, the largest absolute benefit is seen among patients with the highest risk.

The absolute survival benefit in patients > 75 years of age and treated within 24 h was small and not statistically significant; further, two nonrandomized, observational analyses4546 questioned the benefit of fibrinolytic therapy in the elderly, with one of these studies45 suggesting more harm than good. However, a reanalysis by the FTT secretariat indicates that in approximately 3,300 patients over the age of 75 years presenting within 12 h of symptom onset and with either STE or BBB, mortality rates were significantly reduced by fibrinolytic therapy (from 29.4% to 26%, p = 0.03).47Another nonrandomized, observational study48 in 6,891 patients ≥ 75 years old with first registry-recorded STE MI also confirm an overall survival advantage to fibrinolysis in the elderly.

Several randomized trials4954 of prehospital- initiated fibrinolysis have provided important insights regarding the impact of early treatment (Tables 4, 5 ). Indeed, acquisition of 12-lead ECGs in the field and the use of a reperfusion checklist (Fig 1 ),6 could lead to more rapid prehospital and hospital care.5455 Although none of the individual trials demonstrated an early mortality reduction with prehospital- initiated fibrinolysis, a metaanalysis (performed prior to the Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction trial56) of six trials (n = 6,434) demonstrated a significant reduction in all-cause hospital mortality (OR, 0.83; 95% CI, 0.70 to 0.98; p = 0.03).57 These findings were associated with a significantly earlier treatment of patients in the prehospital-treated group when compared to a convention in-hospital strategy (mean, 104 minh vs 162 min; p = 0.007) The Grampain Region Early Anistreplase Trial,51 included in the metaanalysis,57did find a dramatic reduction in 1-year mortality (10.4% vs 21.6%; relative risk reduction [RRR] 52%; 95% CI, 14 to 89%; p = 0.007) among patients randomized within 4 h of symptom onset (n = 311) to prehospital lysis by their general practitioner compared to in-hospital fibrinolysis; this mortality difference was seen in the context of a median 130 min earlier administration of fibrinolytic treatment.58 In the Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction trial,56 patients randomized within 2 h of symptom onset (n = 460) had a trend toward lower 30-day mortality with prehospital fibrinolysis compared to those receiving primary PCI (2.2% vs 5.7%, p = 0.058).59Similarly, patients in the Primary Angioplasty in Patients Transferred From General Community Hospitals to Specialized PTCA Units With or Without Emergency Thrombolysis trial60 who were randomized within 3 h of symptom onset (n = 551) had similar mortality rates whether treated by fibrinolysis or primary PCI (7.4% vs 7.3%).