INTRODUCTION — Most cases of acute myocardial infarction (MI) are caused by coronary artery plaque rupture with subsequent thrombus formation. When thrombosis leads to total occlusion of blood flow, acute ST-elevation MI (STEMI) is often the clinical outcome. Patients with acute STEMI should receive coronary reperfusion therapy with either primary percutaneous coronary intervention (PCI) or fibrinolysis. Reperfusion improves clinical outcomes in nearly all groups who present within 12 hours of symptom onset.
The decision to initiate reperfusion therapy should be based on the clinical presentation and electrocardiographic changes. Supporting evidence such as troponin elevation or imaging abnormalities is not required except in doubtful situations such as possible posterior wall MI or preexisting left bundle branch block.
For most patients with acute STEMI, we prefer primary PCI rather than fibrinolysis. However, fibrinolytic therapy should be used if timely primary PCI is not available. (See "Mechanisms of acute coronary syndromes related to atherosclerosis" and "Acute ST-elevation myocardial infarction: Selecting a reperfusion strategy", section on 'Primary PCI preferred to fibrinolysis' and "Acute ST-elevation myocardial infarction: Selecting a reperfusion strategy", section on 'Fibrinolysis' and "Diagnosis and management of failed fibrinolysis or threatened reocclusion in acute ST-elevation myocardial infarction".)
This topic will discuss the use of fibrinolytic therapy in patients with STEMI. The discussion of failed fibrinolysis is found elsewhere. (See "Diagnosis and management of failed fibrinolysis or threatened reocclusion in acute ST-elevation myocardial infarction".)
OUR APPROACH — After a decision has been made to treat with fibrinolytic therapy rather than primary percutaneous coronary intervention (PCI) (see "Acute ST-elevation myocardial infarction: Selecting a reperfusion strategy", section on 'Fibrinolysis'), we use the following approach:
●Start parenteral anticoagulation with unfractionated heparin or enoxaparin (algorithm 1). (See "Acute ST-elevation myocardial infarction: Management of anticoagulation", section on 'Dosing and duration of therapy'.)
●For patients who arrive initially at a hospital or in whom the diagnosis is made in an ambulance, fibrinolytic therapy should be initiated within 10 minutes of electrocardiographic diagnosis of STEMI. (See 'Timing' below.)
●We prefer fibrin-specific agents over streptokinase, and we prefer the third-generation agents tenecteplase and reteplase over alteplase (table 1) based on their generally favorable benefit-to-risk profile and ease of use. Dosing is provided in a table (table 1). (See 'Choice of agent' below.)
●Administer orally (if possible): aspirin, clopidogrel, and a statin. We give 162 to 325 mg of uncoated aspirin and 300 mg of clopidogrel (75 mg in patients ≥75 years of age). (See 'Concomitant therapies' below.)
●We refer many patients for early diagnostic angiography and PCI after fibrinolysis, particularly those at high risk for a recurrent cardiovascular event. We consult with a cardiologist soon after initiation of fibrinolysis. (See 'Angiography after fibrinolysis' below.)
●Patients deemed to be at lower risk and for whom transfer to a PCI center may be difficult, risk stratification with stress testing is reasonable. Patients with a positive stress test should then be referred for coronary angiography.
BACKGROUND — Fibrinolytic (ie, thrombolytic) therapy, when administered within the first several hours after symptom onset, is capable of reestablishing antegrade coronary artery blood flow in nearly 75 percent of patients with STEMI. The restoration of myocardial blood flow is key to improving cardiovascular outcomes. The benefit of fibrinolytic therapy declines rapidly as the time from onset of symptoms to therapy increases beyond three hours. After 12 hours, the risk may exceed the benefit. (See 'Timing' below.)
All fibrinolytic agents, compared with placebo, reduce mortality in acute STEMI. The magnitude of reduction in risk of death in randomized trials is generally between 15 and 30 percent. The trials supporting this conclusion are described in detail elsewhere. (See "Acute ST-elevation myocardial infarction: Selecting a reperfusion strategy".)
Streptokinase was the first intravenous agent in which a mortality benefit, when compared with placebo, was demonstrated . Subsequently, alteplase, reteplase, and tenecteplase (by comparison with alteplase) were shown to have similar or better clinical outcomes compared with streptokinase [2,3].
INDICATIONS — All STEMI patients who cannot receive primary percutaneous coronary intervention in a timely manner should be considered immediately for fibrinolytic therapy. (See "Acute ST-elevation myocardial infarction: Selecting a reperfusion strategy", section on 'Primary PCI preferred to fibrinolysis'.)
Fibrinolytic therapy should not await the availability of results of cardiac biomarkers if the diagnosis is reasonably certain. (See "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department", section on 'Cardiac biomarkers and other laboratory testing'.)
Patients with chest pain suggestive of acute myocardial ischemia who present up to 12 (and possibly up to 24) hours after symptom onset are candidates for fibrinolytic therapy if the following electrocardiographic evidence is present:
●New ST elevation at the J point in two anatomically contiguous leads using the following diagnostic thresholds: ≥0.1 mV (1 mm) in all leads other than V2 to V3, where the following diagnostic thresholds apply: ≥0.2 mV (2 mm) in men ≥40 years, ≥0.25 mV (2.5 mm) in men <40 years, or ≥0.15 mV (1.5 mm) in women [4,5].
Patients with typical and persistent symptoms in the presence of a new or presumably new left bundle branch block or a true posterior MI are also considered eligible. (See "Electrocardiogram in the diagnosis of myocardial ischemia and infarction" and "Electrocardiographic diagnosis of myocardial infarction in the presence of bundle branch block or a paced rhythm" and "Diagnosis of acute myocardial infarction", section on 'Definitions'.)
USE IN SPECIFIC PATIENT GROUPS — Although concerns have been raised about the use of fibrinolytic therapy in each of the following patient groups, we believe that the benefit outweighs the risk in most.
Older patients — We do not believe that age, in the absence of other risk factors of adverse outcomes with fibrinolytic therapy, is an absolute contraindication.
The mortality associated with STEMI treated with fibrinolytic therapy increases with advancing patient age, and fibrinolytic therapy improves outcomes compared with placebo in older individuals . The frequency of left ventricular free-wall rupture (see "Acute myocardial infarction: Mechanical complications", section on 'Rupture of the left ventricular free wall') or major bleeding, and in particular intracranial hemorrhage, is higher in older patients treated with fibrinolytic therapy.
Similar to our approach to the use of fibrinolytic therapy in the general population, we prefer fibrin-specific agents over streptokinase, and we prefer tenecteplase over other fibrin-specific agents (table 1). (See 'Our approach' above.)
For older patients who receive tenecteplase as part of a pharmacoinvasive approach (eg, fibrinolysis with bolus tenecteplase followed by rescue or elective percutaneous coronary intervention [PCI] within 24 hours), an alternate dosing was evaluated in the STREAM trial  (see "Acute ST-elevation myocardial infarction: Selecting a reperfusion strategy", section on 'Fibrinolysis'). We do not use this dosing in our practices.
In STREAM, which randomly assigned patients to either a pharmacoinvasive approach or primary PCI, a protocol adjustment was made after enrollment that reduced the tenecteplase dose to 50 percent in patients 75 years of age or older due to an excess of intracranial hemorrhage (ICH) in that age group in the early enrollees. This dose adjustment decreased the incidence of ICH. The overall trial results showed no significant difference between the two reperfusion strategies. This approach of reducing the dose of tenecteplase to 50 percent in older patients undergoing a pharmacoinvasive strategy is unproven and is being studied directly in the ongoing STREAM-2 trial (ClinicalTrials.gov identifier: NCT02777580). (See "Acute ST-elevation myocardial infarction: Selecting a reperfusion strategy", section on 'Short duration of symptoms'.)
Cardiogenic shock — In patients with cardiogenic shock, we have a strong preference for primary PCI rather than fibrinolytic therapy. However, for patients who cannot receive timely primary PCI, fibrinolysis followed by PCI (even if there is a delay of up to 24 hours) is the preferred strategy. This is especially the case if the patient presents early (<3 hours) after symptom onset. (See "Prognosis and treatment of cardiogenic shock complicating acute myocardial infarction".)
Menstruating women — For menstruating women with acute STEMI, we use fibrinolytic therapy if that would have otherwise been our preference. Some practitioners are concerned about the use of fibrinolytic agents in menstruating women. In one small study, there was no significant increase in severe bleeding compared with nonmenstruating women . There was a significant increase in moderate bleeding that was offset by the benefits of fibrinolytic therapy.
CONTRAINDICATIONS — Absolute contraindications to fibrinolytic therapy include prior intracranial hemorrhage (ICH), known structural cerebral vascular lesion, known malignant intracranial neoplasm, ischemic stroke within three months, suspected aortic dissection, active bleeding or bleeding diathesis, or significant closed-head or facial trauma within three months (table 2).
Important relative contraindications include (table 2):
●Poorly controlled or chronic sustained hypertension (ie, systolic blood pressure >180 mmHg) [9,10]. This can be mitigated somewhat if the blood pressure is reduced prior to fibrinolytic administration.
●Ischemic stroke more than three months previously. Most patients with a history of stroke were excluded from clinical fibrinolytic trials and, in clinical practice, are less likely to receive a fibrinolytic agent. Data evaluating such patients are extremely limited. In a review of 115 patients with acute MI who had a prior nonhemorrhagic cerebrovascular event, 29 were given fibrinolytic therapy . None of the 29 patients had an intracranial bleed, and these patients had a lower one-year mortality than 46 patients with a prior stroke who did not receive a fibrinolytic agent (18 versus 33 percent).
●Dementia or other intracranial pathology (except as above).
●Traumatic or prolonged cardiopulmonary resuscitation (>10 minutes) or major surgery (within <3 weeks).
●Recent (within two to four weeks) internal bleeding.
●Noncompressible vascular puncture.
●For streptokinase, prior exposure (more than five days previously and up to one year) or prior allergic reaction to these agents.
●Pregnancy. (See "Acquired heart disease and pregnancy".)
●Active peptic ulcer.
●Current use of anticoagulants.
●Intraocular hemorrhage from fibrinolytic therapy in patients with diabetes mellitus is rare, and diabetic retinopathy should not be considered a contraindication to fibrinolytic therapy in acute MI [13,14]. (See "Diabetic retinopathy: Prevention and treatment".)
INITIATION OF THERAPY — For patients with STEMI in whom fibrinolysis is chosen as the reperfusion strategy (ie, when primary percutaneous coronary intervention is not available), treatment should be given as soon as possible after the diagnosis. (See 'Indications' above.)
Administration of fibrinolytic therapy before hospital arrival (eg, in an ambulance) is an established practice in many geographies. The rationale, training, treatment protocols, and quality assurance programs needed to ensure a safe and effective prehospital fibrinolysis program are presented separately. (See "Performance of prehospital fibrinolysis".)
Timing — The time from first medical contact, whether it be in an ambulance capable of delivering fibrinolytic therapy or a hospital emergency department, to drug administration (ie, door-to-needle time) should be less than 30 minutes [4,5,15]. Ideally, fibrinolytic therapy should be delivered within 10 minutes of STEMI confirmation on the electrocardiogram. (See "Performance of prehospital fibrinolysis" and "Acute ST-elevation myocardial infarction: Selecting a reperfusion strategy", section on 'Fibrinolysis'.)
As the length of time between a patient's presentation and delivery of fibrinolytic therapy (ie, door-to-needle time) increases, the benefit from therapy decreases. The survival benefit is greatest when fibrinolytic agents are administered within the first four hours after onset of symptoms [2,16-23], and particularly within the first 70 minutes (figure 1) [18,19]. Although this conclusion is largely derived from clinical trials, similar findings have been noted in the community, as demonstrated in the second National Registry of Myocardial Infarction . Early therapy also has the greatest impact on infarct size and left ventricular ejection fraction [19,20,23,24].
A mortality benefit is less likely with fibrinolytic therapy at 13 to 18 hours. A meta-analysis from the Fibrinolytic Therapy Trialists' Collaborative Group found that the absolute mortality benefit from fibrinolytic therapy at five weeks was 3 percent for those presenting within six hours from symptom onset, 2 percent for those presenting within 7 to 12 hours, and a nonsignificant 1 percent for those presenting within 13 to 18 hours .
However, there may be a benefit in patients presenting 12 hours after symptom onset and possibly up to 24 hours if the patient has ongoing or stuttering chest pain . Although most myocardial necrosis occurs early (ie, within the first 90 to 180 minutes), the advantages of late reperfusion are presumably related to the presence of a patent infarct-related vessel, leading to improved ventricular healing, reduced infarct expansion, and greater electrical stability.
Choice of agent — We prefer fibrin-specific agents over streptokinase, and we prefer the third-generation agents (eg, tenecteplase and reteplase) over alteplase based on their generally favorable benefit-to-risk profile and ease of use. The following conclusions regarding available agents have been reached from randomized trials and support our choice of tenecteplase:
●Alteplase improves survival compared with streptokinase (streptokinase is not available in the United States or Canada). (See "Diagnosis and management of failed fibrinolysis or threatened reocclusion in acute ST-elevation myocardial infarction", section on 'Primary failure'.)
●Tenecteplase has comparable efficacy to alteplase but has a lower rate of noncerebral bleeding events and is easier to use . It is given as a single bolus and is therefore easier to administer than alteplase, which requires a bolus and then two separate drips. Under- or overdosing are possible with tenecteplase when weight has to be estimated, such as in some emergency situations.
Dosing — Dosing is available in a table (table 1).
CONCOMITANT THERAPIES — All STEMI patients receiving fibrinolytic therapy should receive the following therapies as soon as possible after the diagnosis is made.
Anticoagulant therapy — We treat all STEMI patients receiving fibrinolytic therapy with an anticoagulant. It should be started as soon as a decision to treat with fibrinolytic therapy is made. We choose either unfractionated heparin or enoxaparin for patients, including those who may receive PCI after fibrinolysis (algorithm 1). A detailed discussion of anticoagulant therapy in STEMI patients who receive fibrinolytic therapy, including the dosing regimens, is found elsewhere. (See "Acute ST-elevation myocardial infarction: Management of anticoagulation", section on 'Fibrinolytic therapy with or without planned PCI'.)
Antiplatelet therapy — We give nonenteric-coated aspirin (loading dose of 162 to 325 mg) as soon as possible after the diagnosis has been made.
Once fibrinolysis is chosen as the reperfusion strategy, we give clopidogrel as a 300 mg loading dose in those ≤75 years of age and a 75 mg loading dose in those >75 years. Transition to a more potent P2Y12 inhibitor may be appropriate at the time of discharge. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Patients receiving fibrinolytic therapy'.)
Statins — For all patients with an acute coronary syndrome not on treatment with a statin, we initiate high-intensity statin therapy (80 mg of atorvastatin or 20 to 40 mg of rosuvastatin daily) regardless of the baseline low density lipoprotein-cholesterol level. We start therapy as soon as possible after the diagnosis. (See "Low density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome", section on 'Our approach to in-hospital therapy'.)
Beta blocker — For all patients with acute MI, we recommend initiation of oral beta blockers within the first 24 hours, as long as no contraindications are present. However, early initiation of intravenous beta blocker in the emergency department should be avoided in most patients and in particular those with cardiogenic shock. (See "Acute myocardial infarction: Role of beta blocker therapy".)
COMPLICATIONS — Bleeding is the primary complication of fibrinolytic therapy, and hemorrhagic stroke is the greatest concern. Clinically important bleeding modestly reduces the total benefit associated with fibrinolytic therapy. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".)
Bleeding — GUSTO-I, the largest trial of fibrinolytic therapy (eg, streptokinase or alteplase), found a 1.8 percent incidence of severe bleeding . The incidence of moderate bleeding, defined by the need for transfusion but without hemodynamic compromise or need for an intervention, was 11.4 percent. Bleeding was most often procedure related, occurring with coronary artery bypass graft surgery in 3.6 percent and at the groin site of a percutaneous coronary intervention in 2 percent. As the use of the radial artery for access has increased, the risk of significant procedure-related bleeding has decreased. (See "Primary percutaneous coronary intervention in acute ST-elevation myocardial infarction: Periprocedural management", section on 'Radial versus femoral approach'.)
The most common site for spontaneous bleeding is the gastrointestinal tract (1.8 percent) . The risk of moderate or severe bleeding appears to be greater in women than in men (odds ratio 1.43) .
Stroke — The risks of stroke and intracranial hemorrhage (ICH) were 1.2 and 0.7 percent in a non-trial community registry of 12,739 patients . In GUSTO-I, the majority of strokes (95 percent) occurred within five days of therapy [9,32]. The incidence was somewhat higher with alteplase.
Strokes associated with fibrinolysis are also associated with very high rates of mortality and morbidity. In GUSTO-I, the stroke was fatal in 41 percent and produced moderate or severe disability in 31 percent . Similar findings were noted in the (United States) National Registry of Myocardial Infarction 2 .
Risk factors for stroke have been identified from analysis of patients enrolled in randomized trials [9,10,31,33,34]. In GUSTO-I, patients with a previous transient ischemic attack or stroke were at particularly high risk (5.5 and 6.9 percent, respectively) . In the STREAM trial, there was a high incidence of ICH in patients >75 years of age. This risk was reduced after the dose of tenecteplase was reduced by 50 percent in patients 75 years of age or older .
Independent predictors of ICH included the following:
●Age ≥75 years
●Being from a Black population
●Prior history of stroke
●Systolic blood pressure ≥160 mmHg
●Weight ≤65 kg for women or ≤80 kg for men
●International normalized ratio >4 or prothrombin time >24 seconds
●Use of alteplase (versus other fibrinolytic agents)
ICH should be suspected in any patient who develops sudden neurological deterioration, a decline in level of consciousness, new headache, nausea and vomiting, or a sudden rise in blood pressure after fibrinolytic therapy, especially within the first 24 hours of treatment. The management of such patients is similar to that for patients with ICH of any cause. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".)
The central steps in the early management of suspected ICH are as follows:
●Fibrinolytic, antiplatelet, and anticoagulant therapies should be discontinued.
●An emergent noncontrast head computed tomography scan or magnetic resonance imaging scan should be arranged.
●A neurology and/or neurosurgery consultation should be obtained. A hematology consultation may also be of value.
This issue is discussed in detail elsewhere. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use", section on 'Management of symptomatic intracerebral hemorrhage'.)
ANGIOGRAPHY AFTER FIBRINOLYSIS — For most STEMI patients, and particularly those at high risk, we suggest early referral for diagnostic angiography and percutaneous coronary intervention (PCI) compared with a strategy of medical therapy, based on evidence of better outcomes with the former. This issue is discussed in detail elsewhere. (See "Percutaneous coronary intervention after fibrinolysis for acute ST-elevation myocardial infarction", section on 'Pharmacoinvasive strategy'.)
For the patient with evidence that reperfusion has been unsuccessful (ie, failed fibrinolysis), we suggest immediate angiography with intent to perform rescue PCI. Primary failure of fibrinolysis is often manifested clinically by persistent or worsening chest pain (particularly if associated with other symptoms such as dyspnea and diaphoresis), persistent or worsening ST-segment elevation, and/or hemodynamic instability or heart failure. However, these clinical factors are not sufficiently predictive in all patients. As a result, in the absence of clear indications of reperfusion, the clinician must maintain a high index of suspicion for primary failure. This issue is discussed in detail elsewhere. (See "Diagnosis and management of failed fibrinolysis or threatened reocclusion in acute ST-elevation myocardial infarction".)
Successful reperfusion is generally associated with significant improvement in ischemic symptoms, resolution of at least >50 percent ST elevation on the electrocardiogram, hemodynamic stability, improvement in left ventricular function, and the absence of heart failure. For the patient who has responded to fibrinolytic therapy, an important issue is the role of subsequent coronary angiography and revascularization. We suggest diagnostic coronary angiography and possible PCI, generally within 3 to 24 hours, for all patients who receive fibrinolytic therapy. (See "Acute ST-elevation myocardial infarction: Selecting a reperfusion strategy", section on 'Pharmacoinvasive strategy'.)
RECOMMENDATIONS OF OTHERS — Guidelines for the use of fibrinolytic therapy in patients with STEMI have been issued by the American College of Cardiology Foundation/American Heart Association in 2013 [4,5] and the European Society of Cardiology in 2017 [15,35]. Our recommendations are generally in accord with those from these organizations.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: ST-elevation myocardial infarction (STEMI)".)
SUMMARY AND RECOMMENDATIONS
●Indications – Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy for most patients with acute ST-elevation myocardial infarction (STEMI). When timely primary PCI is not available, early fibrinolysis should be carried out. (See 'Indications' above.)
We make the following recommendations for the use of fibrinolytic therapy in patients with acute STEMI:
•Presentation within 12 hours of symptom onset – For patients within 12 hours of STEMI onset who have no absolute contraindications to fibrinolytic therapy and for whom reperfusion with primary PCI cannot be performed within the recommended time, we recommend fibrinolytic therapy as opposed to no reperfusion therapy (Grade 1A). (See 'Initiation of therapy' above.)
•Presentation between 12 to 24 hours of symptoms onset – For symptomatic patients who present after 12 (but before 24) hours of symptom onset and when PCI is not readily available, we suggest fibrinolytic therapy as opposed to no fibrinolytic therapy (Grade 2B). (See 'Timing' above.)
•Goal for administration – Irrespective of whether fibrinolytic therapy is given prehospital or in the hospital (emergency department), it should be started within 30 minutes after the diagnosis of STEMI is made. (See 'Timing' above.)
•Choice of agent – We recommend a fibrin-specific agent instead of streptokinase (Grade 1B).
•Transfer for PCI – After fibrinolysis, early transfer to a center that can perform PCI may be indicated. (See 'Angiography after fibrinolysis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas Levin, MD, who contributed to previous versions of this topic review.
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