Other studies have indicated that PCI-capable hospitals receiving patients in transfer can reduce their D2B times by coordinating with the referring hospitals and activating their systems while patients are being transported.78 Currently, it is estimated that almost 90% of patients presenting to a hospital with PCI capability and without a clinical reason for delay have a D2B time 90 minutes.136 Some innovative programs are achieving much faster In addition, with improvements in timeliness of care across the country, racial disparities in reperfusion times have been reduced significantly.140 In an analysis of patients with STEMI reported by hospitals to the Centers for Medicare & Medicaid Services, median D2B times fell from 96 minutes in the year ending December 31, 2005, to 64 minutes in the 3 quarters ending September 30, 2010. This decline was accompanied by an increase in the percent- age of patients with D2B times <90 minutes, from 44.2% to Nevertheless, despite substantial improvements in D2B times, evidence that these efforts have translated into reduced mortality rates is lacking. The absence of demon- strated benefit may relate to reduced power to show change in Checklist. Improving Door-to-Device Times Prehospital ECG to diagnose STEMI is used to activate the PCI team while the patient is en route to the hospital. 2. Emergency physicians activate the PCI team. A single call to a central page operator activates the PCI team. Goal is set for the PCI team to arrive in the catheterization laboratory with in 20 minutes after being paged. Timely data feedback and analysis are provided to members of the STEMI care team. O Gara et al 2013 ACCF/AHA STEMI Guideline e373 survival in a population with a relatively low mortality rate, improved early survival of higher-risk patients, and chang- ing STEMI demographics. These findings support the goal of comprehensive efforts to improve all aspects of acute MI care to improve survival rates. 3.5. Prehospital Fibrinolytic Therapy The time delay from symptom onset to treatment can be short- ened by administration of prehospital fibrinolytic therapy by a trained EMS unit either with a physician on board142 147 or with a hospital-based physician148 152 in direct contact, especially in rural areas. Multiple randomized controlled trials (RCTs) have demonstrated the safety and feasibility of prehospital fibrino- lytic therapy, with decreased treatment times ranging from 30 A meta-analysis of 6 higher- quality RCTs revealed an approximately 60-minute reduction in time from symptom onset to delivery of fibrinolytic therapy with prehospital versus hospital-based administration, with a corresponding 17% reduction in risk of all-cause hospital Analysis of a subgroup of patients enrolled in the CAPTIM (Comparaison de l Angioplastie Primaire et de la Thrombolyse) trial within 2 hours of symptom onset showed a significantly lower 5-year mortality rate for patients treated with prehospital fibrinolysis than for patients managed with primary PCI (P=0.04).123,142 These salutary results for early presenters were confirmed in a subsequent analysis of com- bined data from the CAPTIM and WEST (Which Early ST- Elevation Myocardial Infarction Therapy) trials.155 Data from the USIC (Unit de Soins Intensifs Coronaires) Registry and the Swedish Registry of Cardiac Intensive Care also suggest that prehospital fibrinolytic therapy may lower STEMI mor- At the present time, however, prehospital fibrinolytic ther- apy is not used in most communities in the United States. EMS in rural areas, where prehospital fibrinolysis would poten- tially be of benefit, often have neither the resources to train paramedics nor the funding for necessary equipment. Use of prehospital fibrinolysis is more widespread in some regions of Europe and the United Kingdom. The writing committee endorses the need for further research into the implementation of prehospital strategies to reduce total ischemic time. 3.6. The Relationship Between Sudden Cardiac Death and STEMI 3.6.1. Evaluation and Management of Patients With STEMI and Out-of-Hospital Cardiac Arrest: Recommendations Class I 1. Therapeutic hypothermia should be started as soon as possible in comatose patients with STEMI and out-of-hospital cardiac arrest caused by ventricular fibrillation (VF) or pulseless ventricular tachycar- dia (VT), including patients who undergo primary (Level of Evidence: B) 2. Immediate angiography and PCI when indicated should be performed in resuscitated out-of-hospital cardiac arrest patients whose initial ECG shows (Level of Evidence: B) See Online Data Supplement 2 for additional data on PCI for cardiac arrest. Almost 70% of the coronary heart disease deaths annually in the United States occur out of hospital, usually presenting as sudden death due to cardiac arrest.175 Resuscitation is attempted by EMS personnel in approximately 60% of these out-of-hospital cardiac arrest cases; the remaining patients are deceased on arrival of the EMS team.175 177 Although only 23% of out-of-hospital cardiac arrest cases have a shockable initial rhythm (primarily VF), the majority of neurologically intact survivors come from this subgroup.175,176 The median rate of survival to hospital discharge with any first recorded rhythm is only 7.9%175 ; the rate of survival in patients who are in VF initially is much higher (median 22%, range 8% to 40%), as documented in 10 US and Canadian regions participating in the National Institutes of Health sponsored Resuscitation Survival from out-of-hospital cardiac arrest is optimal when both CPR and defibrillation are initiated early.178 Survival from VF specifically is inversely related to the time interval between its onset and termination, with the odds of survival decreasing 7% to 10% for each minute of delay from onset to The percentage of patients who are found in VF and the likelihood of survival are higher if the patient s collapse is witnessed, if bystander CPR is performed, and if a monitor/defibrillator can be applied quickly.181 Community strategies that improve the delivery of early defibrillation to out-of-hospital cardiac arrest victims include training and equipping first responders (fire and law enforce- ment), EMS personnel, and paramedics to defibrillate, as well as placing automated external defibrillators in highly popu- lated locations such as airports, commercial aircraft, and gam- bling casinos ( public access defibrillation ).182 193 The latter strategy has been shown to approximately double the number of neurologically intact out-of-hospital cardiac arrest sur- vivors when laypersons are trained and equipped to provide early CPR and defibrillation with automated external defibril- lators, compared with providing CPR alone while awaiting arrival of EMS personnel.183 Two RCTs have reported improved rates of neurologi- cally intact survival to hospital discharge when comatose patients with out-of-hospital VF or nonperfusing VT car- diac arrest were cooled to 32 C to 34 C for 12 or 24 hours beginning minutes to hours after the return of spontaneous Additional studies with historical control groups also have shown improved neurological outcomes after therapeutic hypothermia for comatose survivors of VF Accordingly, therapeutic hypothermia should be initiated in patients with STEMI and out-of-hospital cardiac arrest. Cooling should begin before or at the time of cardiac catheterization. Approximately 5% of patients with STEMI who survive to reach the hospital will experience a cardiac arrest during Reports from high-volume PCI centers indicate that 4% to 11% of patients with STEMI who are treated with PCI are brought to cardiac catheterization after being resuscitated from out-of-hospital cardiac arrest.77,197,198 However, the percentage of out-of-hospital cardiac arrest vic- tims whose event is triggered by an acute coronary occlusion is less clear. The majority of out-of-hospital cardiac arrest patients who cannot be resuscitated have significant coronary Coronary atherosclerosis is also present in the majority of cardiac arrest victims who survive and undergo Because of the high prevalence of acute coronary artery occlusions in out-of-hospital cardiac arrest patients who are resuscitated successfully, especially those whose initial rhythm is VF in the setting of STEMI, the AHA 2010 Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care201 recommend emer- gency coronary angiography with prompt opening of the infarct artery. Out-of-hospital cardiac arrest victims with ini- tial VF who survive to hospital admission have a rate of sur- vival to hospital discharge of 60% after early PCI. The AHA issued a policy statement calling for communi- ties to establish regional systems of care for out-of-hospital The statement defines 2 different levels of cardiac resuscitation centers and lists the essential elements of such a system. PCI-capable hospitals become ideal can- didates to serve as Level I cardiac resuscitation centers that can offer a wide range of services, including timely PCI when indicated, a goal-directed care bundle,202,203 therapeutic frequent or continuous electroencephalo- graphic monitoring, a multidisciplinary team approach, and neuropsychiatric evaluation for survivors. All other partici- pating hospitals should be trained and equipped as Level II cardiac resuscitation centers, which are capable of initiating therapeutic hypothermia and transferring patients for primary postresuscitation care. Ideally, out-of-hospital cardiac arrest outcomes should be measured and compared within a dedi- cated registry. Lastly, it is important for organizations that collect and publicly report STEMI and PCI data to consider resuscitated out-of-hospital cardiac arrest patients separately from their hospital and individual operator quality score- cards because such patients, even with optimal care, have a much higher mortality rate than that of patients with STEMI who have not had a cardiac arrest.204 206 Public reporting in this instance might have the unintended consequence of reducing appropriate care.207 4. Reperfusion at a PCI-Capable Hospital 4.1. Primary PCI 4.1.1. Primary PCI in STEMI: Recommendations See Table 2 for a summary of recommendations from this section. Class I 1. Primary PCI should be performed in patients with STEMI and ischemic symptoms of less than 12 hours (Level of Evidence: A) 2. Primary PCI should be performed in patients with STEMI and ischemic symptoms of less than 12 hours duration who have contraindications to fi- brinolytic therapy, irrespective of the time delay (Level of Evidence: B) 3. Primary PCI should be performed in patients with STEMI and cardiogenic shock or acute severe HF, irrespective of time delay from MI onset (Section (Level of Evidence: B) Class IIa 1. Primary PCI is reasonable in patients with STEMI if there is clinical and/or ECG evidence of ongoing ischemia between 12 and 24 hours after symptom on- (Level of Evidence: B) Class III: Harm 1. PCI should not be performed in a noninfarct artery at the time of primary PCI in patients with STEMI who are hemodynamically stable.216 218 (Level of Evidence: B) Primary PCI of the infarct artery is preferred to fibrinolytic therapy when time-to-treatment delays are short and the patient presents to a high-volume, well-equipped center with experienced interventional cardiologists and skilled support staff. Compared with fibrinolytic therapy, primary PCI pro- duces higher rates of infarct artery patency, TIMI 3 flow, and access site bleeding and lower rates of recurrent ischemia, reinfarction, emergency repeat revascularization procedures, intracranial hemorrhage (ICH), and death.82 Early, successful PCI also greatly decreases the complications of STEMI that result from longer ischemic times or unsuccessful fibrinolytic therapy, allowing earlier hospital discharge and resumption of daily activities. Primary PCI has its greatest survival benefit in high-risk patients. PCI outcomes have been shown to be worse with delays to treatment and with low-volume hospitals and operators. Quality metrics for both laboratory and operator performance and considerations with regard to primary PCI at hospitals without on-site cardiac surgery are reviewed in the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coro- nary Intervention, Section 7.219 Table 2. Primary PCI in STEMI COR LOE References Ischemic symptoms <12 h and contraindications to fibrinolytic therapy irrespective of time delay from FMC Cardiogenic shock or acute severe HF irrespective of time delay from MI onset I B 212 215 Evidence of ongoing ischemia 12 to 24 h after symptom onset PCI of a noninfarct artery at the time of primary PCI in patients without hemodynamic compromise III: Harm B 216 218 COR indicates Class of Recommendation; FMC, first medical contact; HF, heart failure; LOE, Level of Evidence; MI, myocardial infarction; PCI, percutaneous coronary intervention; and STEMI, ST-elevation myocardial infarction. O Gara et al 2013 ACCF/AHA STEMI Guideline e375 Potential complications of primary PCI include problems with the arterial access site; adverse reactions to volume loading, contrast medium, and antithrombotic medications; technical complications; and reperfusion events. The no- reflow phenomenon refers to suboptimal myocardial perfu- sion despite restoration of epicardial flow in the infarct artery and has been attributed to the combined effects of inflam- mation, endothelial injury, edema, atheroembolization, vasospasm, and myocyte reperfusion injury.220 No-reflow is associated with a reduced survival rate. Treatment and prevention strategies have included use of the GP IIb/IIIa antagonist abciximab, vasodilators (nitroprusside, vera- pamil, adenosine), and inhibitors of various metabolic path- ways (nicorandil, pexelizumab), albeit without consistent effect. Manual thrombus aspiration at the time of primary PCI results in improved tissue perfusion and more complete (Section 4.2), though not all studies have shown positive results.223 PCI of a noninfarct artery with TIMI 3 flow at the time of primary PCI in hemodynamically stable patients has been associated with worse clinical outcomes in several stud- though others have suggested that it may be Noninfarct artery PCI is not recom- mended in this context unless multiple complex lesions are seen on angiography and ECG localization of the infarct is Clinical stability may be defined broadly as the absence of low output, hypotension, persistent tachycar- dia, apparent shock, high-grade ventricular or symptomatic supraventricular tachyarrhythmias, and spontaneous recurrent ischemia. In patients with cardiogenic shock due to pump fail- ure, PCI of a severe stenosis in a large noninfarct artery might improve hemodynamic stability and should be considered dur- ing the primary procedure (Section 9.1.1). In the majority of patients, delayed PCI can be performed in a noninfarct artery at a later time if indicated by clinical events or the results of 4.2. Aspiration Thrombectomy: Recommendation Class IIa 1. Manual aspiration thrombectomy is reasonable for patients undergoing primary PCI.221,223,234,235 (Level of Evidence: B) and a meta-analysis234 support the use of man- ual aspiration thrombectomy during primary PCI to improve microvascular reperfusion and to decrease deaths and adverse cardiac events. However, infarct size was not reduced by manual aspiration thrombectomy in the INFUSE-AMI (Intra- coronary Abciximab Infusion and Aspiration Thrombectomy in Patients Undergoing Percutaneous Coronary Intervention for Anterior ST-Segment Elevation Myocardial Infarction) trial of patients with large anterior STEMI.223 The trial was underpowered to detect differences in clinical outcomes. No clinical benefit for routine rheolytic thrombectomy has been demonstrated in primary PCI.234,236,237 4.3. Use of Stents in Primary PCI 4.3.1. Use of Stents in Patients With STEMI: Recommendations Class I 1. Placement of a stent (bare-metal stent [BMS] or drug-eluting stent [DES]) is useful in primary PCI for patients with STEMI.238,239 (Level of Evidence: A) 2. BMS should be used in patients with high bleed- ing risk, inability to comply with 1 year of dual an- tiplatelet therapy (DAPT), or anticipated invasive or surgical procedures in the next 1 year. (Level of Evidence: C) Class III: Harm 1. DES should not be used in primary PCI for patients with STEMI who are unable to tolerate or comply with a prolonged course of DAPT because of the increased risk of stent thrombosis with premature discontinua- tion of one or both agents.240 246 (Level of Evidence: B) Coronary stents are used routinely at the time of primary PCI. Compared with balloon angioplasty, BMS implantation during primary PCI decreases the risk for subsequent target-lesion and target-vessel revascularization and possibly the risk for rein- farction, but is not associated with a reduction in the mortal- Compared with BMS, DES implantation decreases restenosis rates and the need for reintervention but does not definitively reduce rates of death or reinfarction. Notably, DES in this setting does not increase the risk of early or late stent Controversy remains as to whether the risk of very late stent thrombosis is higher with first-generation DES than with BMS.249 The lowest rates of stent thrombosis have been reported with cobalt-chromium everolimus-eluting The greatest challenge in deciding the approach at the time of primary PCI, however, is determining emergently whether the patient is a candidate for a prolonged (ie, 1 year) course of DAPT. DES should be avoided in the presence of financial or social barriers that may limit patient compliance, elevated bleeding risk, the anticipated need for invasive or sur- gical procedures in the subsequent 1 year, or an independent indication for long-term anticoagulant therapy. 4.4. Adjunctive Antithrombotic Therapy for Primary PCI See Table 3 for a summary of recommendations from this sec- tion and Online Data Supplement 3 for additional information on antithrombotic therapy. 4.4.1. Antiplatelet Therapy to Support Primary PCI for STEMI: Recommendations Class I 1. Aspirin 162 to 325 mg should be given before pri- (Level of Evidence: B) Balloon angioplasty without stent placement may be used in selected patients. Table 3. Adjunctive Antithrombotic Therapy to Support Reperfusion With Primary PCI COR LOE References Antiplatelet therapy Aspirin 162- to 325-mg load before procedure I B 251 253 81 mg daily is the preferred maintenance dose* IIa B 253, 254, 263, 264 inhibitors Loading doses Clopidogrel: 600 mg as early as possible or at time of PCI I B 253, 258, 259 Prasugrel: 60 mg as early as possible or at time of PCI I B 260 Ticagrelor: 180 mg as early as possible or at time of PCI I B 261 Maintenance doses and duration of therapy DES placed: Continue therapy for 1 y with: Clopidogrel: 75 mg daily I B 260, 262 Prasugrel: 10 mg daily I B 262 Ticagrelor: 90 mg twice a day* I B 261 BMS placed: Continue therapy for 1 y with: Clopidogrel: 75 mg daily I B 260, 262 Prasugrel: 10 mg daily I B 262 Ticagrelor: 90 mg twice a day* I B 261 DES placed: Clopidogrel, prasugrel, or ticagrelor* continued beyond 1 y IIb C N/A Patients with STEMI with prior stroke or TIA: prasugrel III: Harm B 260 IV GP IIb/IIIa receptor antagonists in conjunction with UFH or bivalirudin in selected patients Abciximab: 0.25-mg/kg IV bolus, then 0.125 mcg/kg/min (maximum 10 mcg/min) IIa A 265 267 Tirofiban: (high-bolus dose): 25-mcg/kg IV bolus, then 0.15 mcg/kg/min IIa B 268, 269 In patients with CrCl <30 mL/min, reduce infusion by 50% Eptifibatide: (double bolus): 180-mcg/kg IV bolus, then 2 mcg/kg/min; a second 180-mcg/kg bolus is administered 10 min after the first bolus IIa B 270 In patients with CrCl <50 mL/min, reduce infusion by 50% Avoid in patients on hemodialysis Pre catheterization laboratory administration of IV GP IIb/IIIa receptor antagonist IIb B 103, 268, 271 277 Intracoronary abciximab 0.25-mg/kg bolus IIb B 223, 278 284 Anticoagulant therapy UFH: I C N/A With GP IIb/IIIa receptor antagonist planned: 50- to 70-U/kg IV bolus to achieve therapeutic ACT With no GP IIb/IIIa receptor antagonist planned: 70- to 100-U/kg bolus to achieve therapeutic ACT I C N/A Bivalirudin: 0.75-mg/kg IV bolus, then 1.75-mg/kg/h infusion with or without prior treatment with UFH. An additional bolus of 0.3 mg/kg can be given if needed. I B 248 Reduce infusion to 1 mg/kg/h with estimated CrCl <30 mL/min Preferred over UFH with GP IIb/IIIa receptor antagonist in patients at high risk of bleeding IIa B 248 Fondaparinux: Not recommended as sole anticoagulant for primary PCI III: Harm B 304 *The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily. Balloon angioplasty without stent placement may be used in selected patients. It might be reasonable to provide P2Y12 inhibitor therapy to patients with STEMI undergoing balloon angioplasty alone according to the recommendations listed for BMS. (LOE: C) The recommended ACT with planned GP IIb/IIIa receptor antagonist treatment is 200 to 250 s. The recommended ACT with no planned GP IIb/IIIa receptor antagonist treatment is 250 to 300 s (HemoTec device) or 300 to 350 s (Hemochron device). ACT indicates activated clotting time; BMS, bare-metal stent; CrCl, creatinine clearance; COR, Class of Recommendation; DES, drug-eluting stent; GP, glycoprotein; IV, intravenous; LOE, Level of Evidence; N/A, not available; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; TIA, transient ischemic attack; and UFH, unfractionated heparin. O Gara et al 2013 ACCF/AHA STEMI Guideline e377 2. After PCI, aspirin should be continued indefinite- (Level of Evidence: A) 3. A loading dose of a P2Y12 receptor inhibitor should be given as early as possible or at time of primary PCI to patients with STEMI. Options include a. (Level of Evidence: B); or (Level of Evidence: B); or (Level of Evidence: B) inhibitor therapy should be given for 1 year to patients with STEMI who receive a stent (BMS or DES) during primary PCI using the following main- tenance doses: a. Clopidogrel 75 mg daily260,262 (Level of Evidence: B); or b. Prasugrel 10 mg daily262 (Level of Evidence: B); or c. Ticagrelor 90 mg twice a day.261 (Level of Evidence: B) Class IIa 1. It is reasonable to use 81 mg of aspirin in prefer- ence to higher maintenance doses after primary (Level of Evidence: B) 2. It is reasonable to begin treatment with an intrave- nous GP IIb/IIIa receptor antagonist such as abcix- (Level of Evidence: A), high-bolus-dose (Level of Evidence: B), or double-bolus (Level of Evidence: B) at the time of primary PCI (with or without stenting or clopidogrel pretreatment) in selected patients with STEMI who are receiving unfractionated heparin (UFH). Class IIb 1. It may be reasonable to administer intravenous GP IIb/IIIa receptor antagonist in the precatheteriza- tion laboratory setting (eg, ambulance, ED) to pa- tients with STEMI for whom primary PCI is intend- (Level of Evidence: B) 2. It may be reasonable to administer intracoronary ab- ciximab to patients with STEMI undergoing primary (Level of Evidence: B) 3. Continuation of a P2Y12 inhibitor beyond 1 year may be considered in patients undergoing DES place- ment. (Level of Evidence: C) Class III: Harm 1. Prasugrel should not be administered to patients with a history of prior stroke or transient ischemic (Level of Evidence: B) Although the minimum effective aspirin dose in the setting of PCI for STEMI has not been established prospectively, the writ- ing committee recommends that an empiric dose of 325 mg be given as early as possible before PCI and a maintenance dose continued indefinitely thereafter. It is the consensus of the writ- among patients who receive a stent during primary PCI. This The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily. recommendation is based on evidence of an increased risk of bleeding in most studies comparing higher- with lower-dose as well as the absence of data from RCTs demonstrating superior efficacy of higher aspirin doses in this setting. However, because the CURRENT-OASIS 7 (Clopi- dogrel Optimal Loading Dose Usage to Reduce Recurrent Events Organization to Assess Strategies in Ischemic Syn- dromes) trial did not report differences in either efficacy or safety in patients with STEMI randomized to 81 mg versus 325 mg of aspirin, the committee did not think that the evi- dence favoring 81 mg over higher dosages was sufficiently conclusive to merit a Class I recommendation.253 Loading doses of P2Y12 inhibitors are provided before or at the time of primary PCI. These agents are continued in a maintenance dose for 1 year after PCI with a stent (BMS or DES) in the absence of bleeding. A 600-mg loading dose of clopidogrel is preferred to a 300-mg loading dose, given the more extensive and rapid platelet inhibition achieved with the higher dose, as well as the beneficial effects reported in a CURRENT-OASIS 7 subgroup analysis.259 The underpow- ered ARMYDA-6 MI (Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty Myocardial Infarction) study also reported beneficial surrogate outcomes with the higher clopidogrel loading dose.258 The antiplatelet response to clopidogrel may vary as a function of patient phenotype (obesity, diabetes mellitus), enteric ABCB 1 polymorphisms, hepatic CYP450 enzyme system polymorphisms (predominantly CYP 2C19*2), and medications that interfere with clopidogrel biotransforma- tion. Approximately 25% to 30% of patients may harbor a reduced-function CYP2C19 allele. In TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis In Myocardial Infarction)285 patients who were carriers of the reduced-function CYP2C19*2 allele had significantly lower levels of the active metabolite of clopi- dogrel, diminished platelet inhibition, and increased rates of major adverse cardiovascular events and stent thrombosis.285 The US Food and Drug Administration has changed clopido- grel s prescribing information to highlight the potential impact of CYP2C19 genotype on clopidogrel pharmacokinetics and Nevertheless, other studies have not con- firmed associations between CYP2C19 polymorphisms and adverse outcomes in clopidogrel-treated patients.290 Future studies are needed to further clarify the risk associated with these genetic polymorphisms and to develop effective thera- peutic strategies for carriers of allelic variants of responsible enzyme systems. Proton-pump inhibitors, most prominently omeprazole, can interfere with clopidogrel metabolism and result in diminished in vitro antiplatelet effect,291 but it does not appear that this pharmacokinetic effect translates into worse clinical outcomes.291,292 Prasugrel, an alternative thienopyridine, achieves greater inhibition of platelet aggregation than clopidogrel. In the of prasugrel versus clopidogrel in patients with ACS for whom an invasive strategy was planned, patientswithSTEMIwhowereassignedtoprasugrelhadalower 30-day rate of the composite primary outcome. This difference persisted to 15 months. In addition, the rate of stent thrombosis reported at 30 days was significantly lower with prasug- The loading dose of clopidogrel in TRITON-TIMI 38, which rarely was administered before coronary angiog- raphy and was limited to 300 mg, may have contributed to differences in efficacy and safety between treatment groups.262 The benefits of prasugrel relative to clopidogrel in STEMI must be weighed against the increase in the risk of bleeding associated with its use. Prasugrel should not be administered to patients with a history of stroke or transient ischemic attack and was not shown to be beneficial in patients 75 years of age or patients who weigh <60 kg.260 In TRITON-TIMI 38, interaction testing for efficacy and safety showed no signifi- cant difference in bleeding risk across the spectrum of ACS. Prasugrel may be best suited for younger patients with diabe- tes mellitus or large areas of myocardium at risk, who are also at low bleeding risk, have the ability to continue a regimen of DAPT, and have no anticipation of surgery over the subse- quent 1 year. The package insert for prasugrel suggests that a lower maintenance dose of 5 mg daily might be considered for patients at high risk of bleeding, though this dose has not been Ticagrelor is a reversible, nonthienopyridine P2Y12 receptor antagonist that does not require metabolic conversion to active drug. The PLATO (Platelet Inhibition and Patient Outcomes) study compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) with clopidogrel (300- or 600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovas- cular events in 18624 patients with ACS, of whom 35% had Among the 7544 patients enrolled with ST eleva- tion or LBBB who underwent primary PCI, findings were consistent with the overall trial results. Significant reductions favoring ticagrelor were seen in the primary PCI subgroup for stent thrombosis and total deaths, though there were more strokes and episodes of ICH with ticagrelor.261 A prespecified subgroup analysis in the PLATO trial showed a significant interaction between treatment effect and geographic region, with an apparently smaller ticagrelor effect in North America than in other areas. Although this interaction could have been due to chance alone,295 a contribution from higher aspirin doses, as more commonly used in the United States, cannot be excluded. When provided long term with ticagrelor as a component of DAPT, the dose of aspirin should not exceed Although 1 year of DAPT is recommended after stent implantation during primary PCI for STEMI, earlier discon- tinuation of a P2Y12 inhibitor may be necessary if the risk of morbidity from bleeding outweighs the anticipated benefit of DAPT. Clinical judgment is required, and discussion with the interventional cardiologist is recommended. DAPT with aspirin and either clopidogrel or prasugrel has increased the risk of ICH in several clinical trials and patient populations (especially in those with prior stroke).260,296 298 In PLATO, the number of patients with prior stroke was small, limitingthepowertodetecttreatmentdifferencesinintracranial bleeding in this subgroup.299 Until further data become avail- able, it would seem prudent to weigh the possible increased risk of intracranial bleeding when the addition of ticagrelor to aspirin is considered in patients with prior stroke or transient Evidence to support the use of intravenous GP IIb/IIIa recep- tor antagonists in patients with STEMI was established largely before the use of oral DAPT. Although several studies have failed to show benefit with the administration of upstream GP IIb/IIIa receptor antagonists before primary PCI in the setting of DAPT with either UFH or bivalirudin anticoagula- a meta-analysis restricted to the use of abciximab has suggested it may be useful in this setting.277 The adjunctive use of GP IIb/IIIa agents at the time of PCI can be considered on an individual basis for large thrombus burden or inadequate receptor antagonist loading.265 270,301 For patients receiv- ing bivalirudin as the primary anticoagulant, routine adjunctive use of GP IIb/IIIa inhibitors is not recommended248 but may be considered as adjunctive or bail-out therapy in selected Studies of intracoronary GP IIb/IIIa administra- tion during primary PCI have shown mixed results for a variety of surrogate and combined clinical endpoints. Use of intracoro- nary abciximab may be reasonable in select cases.223,278 284 4.4.2. Anticoagulant Therapy to Support Primary PCI: Recommendations Class I 1. For patients with STEMI undergoing primary PCI, the following supportive anticoagulant regimens are recommended: a. UFH, with additional boluses administered as needed to maintain therapeutic activated clotting time levels, taking into account whether a GP IIb/ IIIa receptor antagonist has been administered (Level of Evidence: C); or b. Bivalirudin with or without prior treatment with (Level of Evidence: B) Class IIa 1. In patients with STEMI undergoing PCI who are at high risk of bleeding, it is reasonable to use bivaliru- din monotherapy in preference to the combination of UFH and a GP IIb/IIIa receptor antagonist.248 (Level of Evidence: B) Class III: Harm 1. Fondaparinux should not be used as the sole antico- agulant to support primary PCI because of the risk of catheter thrombosis.304 (Level of Evidence: B) Intravenous UFH titrated to an appropriate activated clot- ting time is a familiar and well-tested strategy for anticoagu- lant therapy at the time of PCI for STEMI. Enoxaparin and fondaparinux have been studied less extensively in this set- ting. The ATOLL (Acute STEMI Treated with Primary PCI and IV Enoxaparin or UFH to Lower Ischemic and Bleeding Events at Short- and Long-term Follow-up) trial comparing intravenous enoxaparin with UFH for primary PCI failed to meet its primary, composite endpoint.305 Fondaparinux has been associated with catheter thrombosis in this set- On the basis of the findings in the HORIZONS- O Gara et al 2013 ACCF/AHA STEMI Guideline e379 AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial,248 the writing committee considers bivalirudin, in combination with oral DAPT, a reasonable anticoagulant alternative for primary PCI in STEMI, regardless of whether pretreatment was given with UFH, especially for patients at higher risk of bleeding and when avoidance of GP IIb/IIIa antagonists is desired. Bivali- rudin in this setting may provide a long-term survival benefit related to decreased bleeding but with a higher risk of early 5. Reperfusion at a Non PCI-Capable Hospital 5.1. Fibrinolytic Therapy When There Is an Anticipated Delay to Performing Primary PCI Within 120 Minutes of FMC: Recommendations See Table 4 for a summary of recommendations from this section. Class I 1. In the absence of contraindications, fibrinolytic therapy should be given to patients with STEMI and onset of ischemic symptoms within the previ- ous 12 hours when it is anticipated that primary PCI cannot be performed within 120 minutes of (Level of Evidence: A) Class IIa 1. In the absence of contraindications and when PCI is not available, fibrinolytic therapy is reasonable for patients with STEMI if there is clinical and/or ECG evidence of ongoing ischemia within 12 to 24 hours of symptom onset and a large area of myocardium at risk or hemodynamic instability. (Level of Evidence: C) Class III: Harm 1. Fibrinolytic therapy should not be administered to patients with ST depression except when a true pos- terior (inferobasal) MI is suspected or when associ- ated with ST elevation in lead aVR.10,11,81,312,313 (Level of Evidence: B) 5.1.1. Timing of Fibrinolytic Therapy The benefits of fibrinolytic therapy in patients with ST eleva- tion or bundle-branch block MI are well established, with a time-dependent reduction in both mortality and morbidity rates during the initial 12 hours after symptom onset.81,306 As noted in Section 3.2, even when interhospital trans- port times are short, there may be advantages to the immediate delivery of fibrinolytic therapy versus any delay to primary PCI for patients with STEMI and low bleeding risk who pres- ent within the first 1 to 2 hours of symptom onset.123,321 Benefit from fibrinolytic therapy in patients who present >12 hours after symptom onset has not been established,81,307,309,322,323 although there remains consensus that consideration should be given to administering a fibrinolytic agent in symptom- atic patients presenting >12 hours after symptom onset with STEMI and a large area of myocardium at risk or hemody- namic instability if PCI is unavailable.4,48 5.1.2. Choice of Fibrinolytic Agent Fibrin-specific agents are preferred when available. Adjunc- tive antiplatelet and/or anticoagulant therapies are indicated, regardless of the choice of fibrinolytic agent. Table 4. Indications for Fibrinolytic Therapy When There Is a >120-Minute Delay From FMC to Primary PCI (Figure 2) COR LOE References Ischemic symptoms <12 h I A 81, 306 311 Evidence of ongoing ischemia 12 to 24 h after symptom onset, and a large area of myocardium at risk or hemodynamic instability IIa C N/A ST depression except if true posterior (inferobasal) MI suspected or when associated with ST-elevation in lead aVR COR indicates Class of Recommendation; FMC, first medical contact; LOE, Level of Evidence; MI, myocardial infarction; N/A, not available; and PCI, percutaneous coronary intervention. Table 5. Fibrinolytic Agents Fibrinolytic Agent Dose Fibrin Specificity* Antigenic Patency Rate Fibrin-specific: Tenecteplase (TNK-tPA) Single IV weight-based bolus ++++ No 85%328 Reteplase (rPA) 10 U + 10-U IV boluses given 30 min apart ++ No 84%314 Non fibrin-specific: Streptokinase 1.5 million units IV given over 30 60 min No Yes 60% to 68%324, 329 *Strength of fibrin specificity; ++++ is more strong, ++ is less strong. 30 mg for weight <60 kg; 35 mg for 60 69 kg; 40 mg for 70 79 kg; 45 mg for 80 89 kg; and 50 mg for 90 kg. Bolus 15 mg, infusion 0.75 mg/kg for 30 min (maximum 50 mg), then 0.5 mg/kg (maximum 35 mg) over the next 60 min; total dose not to exceed 100 mg. Streptokinase is no longer marketed in the United States but is available in other countries. Streptokinase is highly antigenic and absolutely contraindicated within 6 mo of previous exposure because of the potential for serious allergic reaction. IV indicates intravenous; rPA, reteplase plasminogen activator; TIMI, Thrombolysis In Myocardial Infarction; TNK-tPA, tenecteplase tissue-type plasminogen activator; and tPA, tissue-type plasminogen activator. 5.1.3. Contraindications and Complications With Fibrinolytic Therapy Absolute and relative contraindications to fibrinolytic therapy are listed in Table 6. The decision to use fibrinolytic therapy for patients with STEMI is predicated on a risk benefit analy- sis that integrates time from onset of symptoms, the clinical and hemodynamic features at presentation, patient comorbidi- ties, risk of bleeding, presence of contraindications, and time delay to PCI (Section 3.2). 5.1.4. Adjunctive Antithrombotic Therapy With Fibrinolysis See Table 7 for a summary of recommendations from this section. 5.1.4.1. Adjunctive Antiplatelet Therapy With Fibrinolysis: Recommendations Class I 1. Aspirin (162- to 325-mg loading dose) and clopi- dogrel (300-mg loading dose for patients 75 years of age, 75-mg dose for patients >75 years of age) should be administered to patients with STEMI who receive fibrinolytic therapy.308,330,331 (Level of Evidence: A) 2. Aspirin should be continued indefinitely308,330,331 (Level of Evidence: A) and clopidogrel (75 mg daily) should be continued for at least 14 days330,331 (Level of Evidence: A) and up to 1 year (Level of Evidence: C) in patients with STEMI who receive fibrinolytic therapy. Class IIa 1. It is reasonable to use aspirin 81 mg per day in pref- erence to higher maintenance doses after fibrinolytic (Level of Evidence: B) The beneficial effects of aspirin and clopidogrel with fibrino- lytic therapy are well established.254,257,263,264 These agents should be given before or with the fibrinolytic.330 The recommendation that clopidogrel be continued for up to 1 year is extrapolated from the experience with DAPT in patients with non ST-elevation ACS.330 The coadministra- tion of other P2Y12 antagonists with fibrinolytic therapy has not been prospectively studied. 5.1.4.2. Adjunctive Anticoagulant Therapy With Fibrinolysis: Recommendations Class I 1. Patients with STEMI undergoing reperfusion with fi- brinolytic therapy should receive anticoagulant ther- apy for a minimum of 48 hours, and preferably for the duration of the index hospitalization, up to 8 days or until revascularization if performed.318,332 (Level of Evidence: A) Recommended regimens include a. UFH administered as a weight-adjusted intravenous bolus and infusion to obtain an activated partial thromboplastin time of 1.5 to 2.0 times control, for 48 hoursoruntilrevascularization.(LevelofEvidence:C); b. Enoxaparin administered according to age, weight, and creatinine clearance, given as an intravenous bolus, followed in 15 minutes by subcutaneous in- jection for the duration of the index hospitaliza- tion, up to 8 days or until revascularization.332 335 (Level of Evidence: A); or c. Fondaparinux administered with initial intrave- nous dose, followed in 24 hours by daily subcuta- neous injections if the estimated creatinine clear- ance is greater than 30 mL/min, for the duration of the index hospitalization, up to 8 days or until (Level of Evidence: B) Anticoagulation is recommended in support of fibrin-specific therapy to improve vessel patency and prevent reocclusion.336 Dosing of UFH is predicated on the activated partial throm- boplastin time, and monitoring of platelet counts to avoid the risks of excess bleeding and heparin-induced thrombocytopenia (HIT) is advised.318,337 339 UFH may be given as an intravenous bolus and infusion for patients receiving streptokinase if they are at high risk for systemic embolization. Enoxaparin is pre- ferred over UFH for anticoagulation extending beyond 48 hours. Caution is advised when enoxaparin is administered to patients Table 6. Contraindications and Cautions for Fibrinolytic Therapy in STEMI* Absolute contraindications Any prior ICH Known structural cerebral vascular lesion (eg, arteriovenous malformation) Known malignant intracranial neoplasm (primary or metastatic) Ischemic stroke within 3 mo EXCEPT acute ischemic stroke within 4.5 h Suspected aortic dissection Active bleeding or bleeding diathesis (excluding menses) Significant closed-head or facial trauma within 3 mo Intracranial or intraspinal surgery within 2 mo Severe uncontrolled hypertension (unresponsive to emergency therapy) For streptokinase, prior treatment within the previous 6 mo Relative contraindications History of chronic, severe, poorly controlled hypertension Significant hypertension on presentation (SBP >180 mmHg or DBP >110 mmHg) History of prior ischemic stroke >3 mo Dementia Known intracranial pathology not covered in absolute contraindications Traumatic or prolonged (>10 min) CPR Major surgery (<3 wk) Recent (within 2 to 4 wk) internal bleeding Noncompressible vascular punctures Pregnancy Active peptic ulcer Oral anticoagulant therapy *Viewed as advisory for clinical decision making and may not be all-inclusive or definitive. CPR indicates cardiopulmonary resuscitation; DBP; diastolic blood pressure; ICH, intracranial hemorrhage; SBP, systolic blood pressure; and STEMI, ST- elevation myocardial infarction. O Gara et al 2013 ACCF/AHA STEMI Guideline e381 with impaired renal function.340 Fondaparinux should not be given as the sole anticoagulant to patients referred for PCI and is contraindicated for patients with a creatinine clearance <30 Bivalirudin may be used for patients treated with a fibrinolytic agent who develop HIT and require continued 5.2. Assessment of Reperfusion After Fibrinolysis TIMI 3 flow after fibrinolytic therapy predicts subsequent short- and long-term survival.343 345 Traditional variables that have been used to assess the angiographic response to fibrinolytic therapy are imprecise346 and have included an improvement in or relief of chest pain, resolution of ST elevation, and the pres- ence of reperfusion arrhythmias (eg, accelerated idioventricular rhythm). The relatively sudden and complete relief of chest pain coupled with >70% ST resolution (in the index lead showing the greatest degree of elevation on presentation) is highly sugges- tive of restoration of normal myocardial blood flow. Complete (or near complete) ST-segment resolution at 60 or 90 minutes after fibrinolytic therapy is a useful marker of a patent infarct Conversely, partial or absent improvement in the extent of ST elevation is not as accurate in predicting a closed Lack of improvement in ST resolution is associ- ated with worse prognosis.349,352,353 The combination of <50% ST resolution and the absence of reperfusion arrhythmias at 2 hours after treatment predicts TIMI flow <3 in the infarct artery with a sensitivity of 81%, specificity 88%, positive predictive value 87%, and negative predictive value 83%.347 Lack of resolution of ST elevation by at least 50% in the worst lead at 60 to 90 min- utes should prompt strong consideration of a decision to proceed with immediate coronary angiography and rescue PCI. 5.3. Transfer to a PCI-Capable Hospital After Fibrinolytic Therapy See Figure 2. 5.3.1. Transfer of Patients With STEMI to a PCI-Capable Hospital for Coronary Angiography After Fibrinolytic Therapy: Recommendations See Table 8 for a summary of recommendations from this section; Online Data Supplement 4 for additional data on early catheterization and rescue PCI for fibrinolytic failure in the stent era; and Online Data Supplement 5 for additional Table 7. Adjunctive Antithrombotic Therapy to Support Reperfusion With Fibrinolytic Therapy COR LOE References Antiplatelet therapy Aspirin 81- to 325-mg daily maintenance dose (indefinite) I A 308, 330, 331 81 mg daily is the preferred maintenance dose receptor inhibitors Clopidogrel: I A 330, 331 Age 75 y: 300-mg loading dose Followed by 75 mg daily for at least 14 d and up to 1 y in absence of bleeding I A (14 d) 330, 331 C (up to 1 y) N/A Age >75 y: no loading dose, give 75 mg I A 330, 331 Followed by 75 mg daily for at least 14 d and up to 1 y in absence of bleeding I A (14 d) 330, 331 C (up to 1 y) N/A Anticoagulant therapy UFH: I C N/A Weight-based IV bolus and infusion adjusted to obtain aPTT of 1.5 to 2.0 times control for 48 h or until revascularization. IV bolus of 60 U/kg (maximum 4000 U) followed by an infusion of 12 U/kg/h (maximum 1000 U) initially, adjusted to maintain aPTT at 1.5 to 2.0 times control (approximately 50 to 70 s) for 48 h or until revascularization. Enoxaparin: I A 332 335 If age <75 y: 30-mg IV bolus, followed in 15 min by 1 mg/kg subcutaneously every 12 h (maximum 100 mg for the first 2 doses) If age 75 y: no bolus, 0.75 mg/kg subcutaneously every 12 h (maximum 75 mg for the first 2 doses) Regardless of age, if CrCl <30 mL/min: 1 mg/kg subcutaneously every 24 h Duration: For the index hospitalization, up to 8 d or until revascularization Fondaparinux: I B 304 Initial dose 2.5 mg IV, then 2.5 mg subcutaneously daily starting the following day, for the index hospitalization up to 8 d or until revascularization Contraindicated if CrCl <30 mL/min aPTT indicates activated partial thromboplastin time; COR, Class of Recommendation; CrCl, creatinine clearance; IV, intravenous; LOE, Level of Evidence; N/A, not available; and UFH, unfractionated heparin. data on early catheterization and PCI after fibrinolysis in the stent era. Class I 1. Immediate transfer to a PCI-capable hospital for coronary angiography is recommended for suitable patients with STEMI who develop cardiogenic shock or acute severe HF, irrespective of the time delay from MI onset.354 (Level of Evidence: B) Class IIa 1. Urgent transfer to a PCI-capable hospital for coro- nary angiography is reasonable for patients with STEMI who demonstrate evidence of failed reperfu- sion or reocclusion after fibrinolytic therapy.346,355 357 (Level of Evidence: B) 2. Transfer to a PCI-capable hospital for coronary an- giography is reasonable for patients with STEMI who have received fibrinolytic therapy even when hemodynamically stable and with clinical evidence of successful reperfusion. Angiography can be per- formed as soon as logistically feasible at the receiv- ing hospital, and ideally within 24 hours, but should not be performed within the first 2 to 3 hours after administration of fibrinolytic therapy.358 363 (Level of Evidence: B) 5.3.1.1. Transfer for Cardiogenic Shock The SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial354 demonstrated benefit with coronary angiography and emergency revascu- larization (with either PCI or CABG) compared with imme- diate medical stabilization and delayed revascularization in patients with ST-elevation/Q-wave or new LBBB MI and cardiogenic shock (Section 9.1.1). Of note, nearly 50% of patients randomized to the emergency revascularization arm received preprocedural fibrinolytic therapy, and the benefit of Although individual circumstances will vary, clinical stability is defined by the absence of low output, hypotension, persistent tachycardia, apparent shock, high- grade ventricular or symptomatic supraventricular tachyarrhythmias, and spontaneous recurrent ischemia. emergency revascularization was similar for patients trans- ferred versus those admitted directly to a PCI-capable hospital. For patients with cardiogenic shock, the benefit of emergency revascularization was apparent across a very wide time win- dow, extending up to 54 hours after MI and 18 hours after Although PCI should be performed as soon as possible after MI and shock onset, the time window for benefit in this clinical context is more prolonged because of the ongo- ing downward ischemic spiral associated with shock. 5.3.1.2. Transfer for Failure of Fibrinolytic Therapy Several trials in the stent era and several meta-analyses have examined the role of PCI for fibrinolytic failure346,355 357,364 (Online Data Supplement 4). These studies report a trend toward a lower mortality rate and significantly lower rates of recurrent MI and HF among patients treated with rescue PCI for failed fibrinolysis. For example, in the REACT (Rapid Early Action for Coronary Treatment) study,355 who failed to demonstrate evidence of reperfusion at 90 min- utes by ECG criteria were randomized to 1 of 3 treatment arms: rescue PCI, conservative care, or repeat fibrinolytic therapy. The primary endpoint, a composite of death, rein- farction, stroke, or severe HF at 6 months, was significantly lower among patients randomized to rescue PCI than among those randomized to conservative care or repeat fibrinolysis (event-free survival rate: 84.6% versus 70.1% versus 68.7%, P=0.004). The benefit was driven primarily by a reduction in reinfarction; there was no significant survival benefit. Minor bleeding was significantly higher among patients ran- domized to rescue PCI; however, there were no differences in major bleeding among the 3 groups. Other studies have reported higher rates of periprocedural bleeding and stroke in patients undergoing rescue PCI than in patients treated The benefit of transferring a patient for PCI of a persistently occluded infarct artery likely would jus- tify these risks if cardiogenic shock, significant hypotension, severe HF, or ECG evidence of an extensive area of myo- cardial jeopardy (including an anterior infarction or inferior infarction with either right ventricular [RV] involvement or anterior precordial ST depression) is present. In these cir- cumstances, the benefits are greatest if PCI is initiated early after fibrinolytic failure. On the other hand, conservative treatment might be reasonable in a patient with improving symptoms and a limited inferior infarction despite persis- tence of ST elevation. 5.3.1.3. Transfer for Routine Early Coronary Angiography After Fibrinolytic Therapy With the introduction of coronary stents and aggressive anti- platelet therapies, there has been renewed interest in imme- diate and early catheterization after fibrinolytic therapy. The advantage of this approach is that it can be initiated at non PCI-capable hospitals and affords the healthcare sys- tem additional time to arrange a nonemergency transfer for angiography and PCI. Routine referral for angiography with the intent to perform PCI is supported indirectly by retrospec- tive analyses from trials of fibrinolytic therapy that suggest that patients treated with PCI during the index hospitalization have a lower risk of recurrent MI and a lower 2-year mortality Table 8. Indications for Transfer for Angiography After Fibrinolytic Therapy COR LOE References Immediate transfer for cardiogenic shock or severe acute HF irrespective of time delay from MI onset I B 354 Urgent transfer for failed reperfusion or reocclusion IIa B 346, As part of an invasive strategy in stable* patients with PCI between 3 and 24 h after successful fibrinolysis IIa B 358 363 *Although individual circumstances will vary, clinical stability is defined by the absence of low output, hypotension, persistent tachycardia, apparent shock, high-grade ventricular or symptomatic supraventricular tachyarrhythmias, and spontaneous recurrent ischemia. COR indicates Class of Recommendation; HF, heart failure; LOE, Level of Evidence; MI, myocardial infarction; and PCI, percutaneous coronary intervention. O Gara et al 2013 ACCF/AHA STEMI Guideline e383 The results of RCTs evaluating a strategy of routine catheterization after fibrinolysis are limited by small sample sizes or surrogate endpoints and have provided mixed results. Nevertheless, most trials have demonstrated improvement in clinical outcomes in patients transferred for early cath- eterization, most notably in higher-risk patients357 362,368 371 (Table 8 and Figure 3). In the GRACIA (Grup de Analisis de la Cardiopatia Isquemica Aguda) study,362 early catheteriza- tion within 6 to 24 hours of successful fibrinolysis in stable patients was compared with an ischemia-guided approach. It resulted in improved outcomes, including a significantly lower rate of death, reinfarction, or ischemia-driven revascu- larization at 1 year. The TRANSFER-AMI (Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction) study360 was the largest (n=1059) of the RCTs evaluating transfer for coronary angiography and revascularization among high-risk patients and showed a significant reduction in the combined primary endpoint of death, recurrent MI, recurrent ischemia, new or wors- ening HF, or shock at 30 days with immediate transfer for the angiography group compared with conservative care. The findings from this and other studies indicate that high- risk patients with STEMI appear to benefit from immediate transfer for early catheterization, compared with either an ischemia-guided approach or delayed routine catheterization The reported benefits relate to a reduction in the incidence of recurrent infarction or isch- emia, thus favoring earlier transfer and revascularization when possible. The NORDISTEMI (Norwegian Study on District Treatment of ST-Elevation Myocardial Infarction) investi- examined the effect of immediate routine trans- fer for catheterization versus a conservative strategy with either ischemia-guided treatment in the non PCI-capable hospital or transfer for rescue PCI. Although this study failed to demonstrate a significant difference between the 2 treatment groups in the incidence of the primary com- posite endpoint of death, recurrent MI, stroke, or new or recurrent ischemia at 1 year, the incidence of death, recur- rent MI, or stroke was significantly lower in the immediate- transfer group. Furthermore, the magnitude of reduction in risk was similar to that reported for high-risk patients in the In a meta-analysis359 that included 7 RCTs of early transfer for catheterization, a strategy of routine early catheterization after fibrinolysis was associated with a statistically significant reduction in the incidence of death or MI at 30 days and at 1 year, without an increase in the risk of major bleeding. This meta-analysis was based on a mixture of trials that random- ized high-risk patients360,361,369 and trials that did not mandate the inclusion of high-risk subjects. A meta-regression analy- sis investigating the relative benefit of an invasive strategy after fibrinolysis according to the baseline risk of the enrolled patients for each trial suggested a larger proportional benefit with early catheterization and PCI in trials enrolling higher- It is important to recognize that the clinical trials that have addressed routine invasive evaluation after initial pharmaco- Figure 3. Primary outcome of trials of routine versus ischemia-driven (or delayed) catheterization and PCI after fibrinolytic therapy. The Figure depicts the results of trials comparing routine early catheterization after fibrinolytic therapy with either an ischemia-driven approach or routine delayed catheterization. The y-axis represents the percentage of patients who experienced 1 of the clinical trial endpoints. The Figure includes the average (or median) time from fibrinolytic therapy to PCI, the number of patients randomized in each study, the type of patients enrolled in the study (all patients or high-risk patients), the duration of follow-up for the primary endpoint, and the composite primary endpoint for each trial. The darker bars represent patients who underwent routine early catheterization after fibrinolytic therapy. The lighter bars represent patients who underwent either an ischemia-guided or routine delayed catheterization approach. arrhy indicates arrhythmia; CAPITAL-AMI, Combined Angioplasty and Pharmacological Intervention Versus Thrombolysis Alone in Acute Myocardial Infarction; CARESS-in-AMI, Combined Abciximab Reteplase Stent Study in Acute Myocardial Infarction; CHF, congestive heart failure; D, death; GRACIA, Grup de Analisis de la Cardiopatia Isquemica Aguda; MI, myocardial infarction; NORDISTEMI, Norwegian study on District treatment of ST-Elevation Myocardial Infarction; PCI, percutaneous coronary intervention; revasc, ischemia-driven revasculariza- tion; RI, recurrent ischemia; TLR, target-lesion revascularization; TRANSFER-AMI, Trial of Routine Angioplasty and Stenting after Fibri- nolysis to Enhance Reperfusion in Acute Myocardial Infarction; SIAM-3, Southwest German Interventional Study In Acute Myocardial Infarction; and WEST, Which Early ST-Elevated Myocardial Infarction Therapy.358,360 362,368 370 Reproduced with permission from Granger.370a logical management used a time window of 0 to 24 hours for the early invasive strategy, thus supporting earlier transfer after administration of fibrinolytic therapy even for patients without high-risk features. However, this time window likely was used in the trial designs to create the greatest possible dif- ference in outcome when compared with the control group (rather than an a priori expectation that the benefit would be driven entirely in <24 hours). The writing committee believes that there likely will be continued benefit even beyond 24 hours in those patients with a patent but stenotic infarct artery. In stable patients who are not transferred immediately, catheter- ization can be considered as part of a routine pharmacoinvasive or ischemia-guided approach >24 hours after administration of fibrinolytic therapy. Because of the associated increased bleeding risk, very early (<2 to 3 hours) catheterization after administration of fibrinolytic therapy with intent to perform revascularization should be reserved for patients with evidence of failed fibrinolysis and significant myocardial jeopardy for whom rescue PCI would be appropriate. 6. Delayed Invasive Management 6.1. Coronary Angiography in Patients Who Initially Were Managed With Fibrinolytic Therapy or Who Did Not Receive Reperfusion: Recommendations See Table 9 for a summary of recommendations from this section. Class I 1. Cardiac catheterization and coronary angiography with intent to perform revascularization should be performed after STEMI in patients with any of the following: a. Cardiogenic shock or acute severe HF that devel- ops after initial presentation215,354,372,373 (Level of Evidence: B); b. Intermediate- or high-risk findings on predis- charge noninvasive ischemia testing232,233 (Level of Evidence: B); or c. Myocardial ischemia that is spontaneous or pro- voked by minimal exertion during hospitalization. (Level of Evidence: C) Class IIa 1. Coronary angiography with intent to perform revas- cularization is reasonable for patients with evidence of failed reperfusion or reocclusion after fibrinolytic therapy. Angiography can be performed as soon as (Level of Evidence: B) 2. Coronary angiography is reasonable before hospi- tal discharge in stable patients with STEMI after successful fibrinolytic therapy. Angiography can be performed as soon as logistically feasible, and ideally within 24 hours, but should not be performed within the first 2 to 3 hours after administration of fibrino- (Level of Evidence: B) The indications for coronary angiography in patients man- aged with an initial noninvasive strategy are interwoven with the indications for revascularization (Sections 5.3 and 6.2). Survivors of STEMI with indicators of intermediate or high risk and those with recurrent ischemia or mechanical compli- cations should be considered for coronary angiography and revascularization. In addition, when STEMI is suspected to have occurred by a mechanism other than thrombotic occlu- sion at the site of an atherosclerotic plaque, coronary angiog- raphy may be reasonable to provide diagnostic information and to direct specific therapy. Routine referral for angiography of patients after fibrinolytic therapy is discussed in Section 5.3. Coronary angiography in patients with evidence of failed reperfusion or reocclusion should be performed as soon as 6.2. PCI of an Infarct Artery in Patients Who Initially Were Managed With Fibrinolysis or Who Did Not Receive Reperfusion Therapy: Recommendations See Table 10 for a summary of recommendations from this section. Class I 1. PCI of an anatomically significant stenosis in the infarct artery should be performed in patients with suitable anatomy and any of the following: a. Cardiogenic shock or acute severe HF354 (Level of Evidence: B); b. Intermediate- or high-risk findings on predis- charge noninvasive ischemia testing232,233 (Level of Evidence: C); or c. Myocardial ischemia that is spontaneous or pro- voked by minimal exertion during hospitalization. (Level of Evidence: C) Table 9. Indications for Coronary Angiography in Patients Who Were Managed With Fibrinolytic Therapy or Who Did Not Receive Reperfusion Therapy COR LOE References Cardiogenic shock or acute severe HF that develops after initial presentation Intermediate- or high-risk findings on predischarge noninvasive ischemia testing Spontaneous or easily provoked myocardial ischemia I C N/A Failed reperfusion or reocclusion after fibrinolytic therapy IIa B 346, Stable* patients after successful fibrinolysis, before discharge and ideally between 3 and IIa B 358 363, *Although individual circumstances will vary, clinical stability is defined by the absence of low output, hypotension, persistent tachycardia, apparent shock, high-grade ventricular or symptomatic supraventricular tachyarrhythmias, and spontaneous recurrent ischemia. COR indicates Class of Recommendation; HF, heart failure; LOE, Level of Evidence; and N/A, not available. Although individual circumstances will vary, clinical stability is defined by the absence of low output, hypotension, persistent tachycardia, apparent shock, high- grade ventricular or symptomatic supraventricular tachyarrhythmias, and spontaneous recurrent ischemia. O Gara et al 2013 ACCF/AHA STEMI Guideline e385 Class IIa 1. Delayed PCI is reasonable in patients with STEMI and evidence of failed reperfusion or reocclusion after fibrinolytic therapy. PCI can be performed as soon as logistically feasible at the receiving hospi- (Level of Evidence: B) 2. Delayed PCI of a significant stenosis in a patent infarct artery is reasonable in stable patients with STEMI af- ter fibrinolytic therapy. PCI can be performed as soon as logistically feasible at the receiving hospital, and ideally within 24 hours, but should not be performed within the first 2 to 3 hours after administration of fi- (Level of Evidence: B) Class IIb 1. Delayed PCI of a significant stenosis in a patent in- farct artery greater than 24 hours after STEMI may be considered as part of an invasive strategy in sta- (Level of Evidence: B) Class III: No Benefit 1. Delayed PCI of a totally occluded infarct artery greater than 24 hours after STEMI should not be performed in asymptomatic patients with 1- or 2-ves- sel disease if they are hemodynamically and electri- cally stable and do not have evidence of severe isch- (Level of Evidence: B) Delayed PCI of the infarct artery is performed in patients treated with an initial noninvasive strategy (ie, with fibrinolysis or without reperfusion therapy) who become unstable because of the development of cardiogenic shock, acute severe HF, or unstable postinfarction angina, provided that invasive manage- ment is not considered futile or inappropriate.215,379 Delayed PCI also encompasses interventions performed for fibrinolytic or infarct artery reocclusion, as part of an invasive strategy for patients after successful fibrinolysis,359 361 and for patients who did not receive reperfusion therapy but who did demonstrate significant residual ischemia during hospitaliza- tion. The benefits of routine, ie, non ischemia-driven, PCI of an angiographically significant stenosis in a patent infarct artery >24 hours after STEMI are less well established.232,233,378 Delayed PCI of a totally occluded infarct artery >24 hours after STEMI should not be undertaken in clinically stable patients without evidence of severe ischemia. In OAT (Occluded Artery Trial), there was no difference in the composite end- point of death, reinfarction, or class IV HF at a median follow- up of 5.8 years between patients managed with PCI and those treated medically. Reinfarction rates tended to be higher in the 6.3. PCI of a Noninfarct Artery Before Hospital Discharge: Recommendations Class I 1. PCI is indicated in a noninfarct artery at a time sepa- rate from primary PCI in patients who have spon- taneous symptoms of myocardial ischemia. (Level of Evidence: C) Class IIa 1. 