OUP user menu

European Heart Journal Supplements: 17 (suppl B)

Editor in chief

Roberto Ferrari

Associate Editors

Francisco Fernández-AvilésJeroen BaxMichael BöhmThomas F. LüscherFrank Ruschitzka

5.640

Published on behalf of

Year 2008 ESC ST-segment elevation myocardial infarction guidelines: implications for the interventional cardiologist—from evidence to recommendations and practice

Frans Van de Werf
DOI: http://dx.doi.org/10.1093/eurheartj/sup013 C31-C37 First published online: 22 May 2009
KEYWORDS
  • ST-elevation acute myocardial infarction
  • Guidelines

Introduction

The management of acute myocardial infarction (MI) continues to evolve, and good clinical practice should be based on reliable evidence resulting from well-conducted clinical trials. Prompted by a substantial number of new, important published studies, the European Society of Cardiology has recently published the 2008 updated guidelines for the management of acute myocardial infarction in patients presenting with persistent ST-segment elevation (STEMI).1 Although the goals of the 2003 and 2008 guidelines1,2 remain the same and include early diagnosis, reperfusion therapy as soon as possible, and optimal secondary prevention, the methods used to achieve them have been modified based on new information from recently published clinical trial data.

When compared with the 2003 guidelines, the new guidelines include significantly more emphasis on early pre-hospital diagnosis, effective triage, and the establishment of transfer networks. Important changes made relate to antithrombotic therapies and the choice between mechanical vs. pharmacological reperfusion. Importantly, the recommendations for angiography in patients not undergoing primary percutaneous coronary intervention (PPCI) are new compared with the 2003 guidelines. The classes of recommendations and the levels of evidence are standardized and have not changed from the earlier versions.1,2

Logistics of care: early pre-hospital diagnosis/triage and networks

The new guidelines emphasize the importance of hospital management and the need for efficient hospital networks to reduce door-to-balloon time. A summary of ideal pre-hospital management is presented in Figure 1. The optimal treatment of patients with STEMI includes utilization of an Emergency Medical System (EMS) with a well-known unique telephone number to avoid delays. Furthermore, the EMS should supervise a network of hospitals which have shared protocols and ensure that the patient is transported to a PCI-capable hospital as soon as possible. Notably, simply having a catheterization laboratory in the hospital is not sufficient; it is important that the centre is capable of providing immediate service. The ambulance service should not be considered simply transport, but also a place for diagnosis, triage, and selection of reperfusion therapy that should be made prior to arrival at the hospital. With such a network in place, the target delay times should be: <10 min for electrocardiographic (ECG) transmission, ≤5 min for tele-consultation, <30 min for ambulance arrival to start fibrinolytic therapy, and ≤120 min for ambulance arrival to first balloon inflation.

Figure 1

Pre-hospital management of patients with symptoms of STEMI. (Reprinted from Van de Werf et al.1 with permission from the European Society of Cardiology).

Reperfusion therapy

The recommendations for reperfusion therapy are summarized in Table 1. Patients presenting with STEMI within 12 h and with persistent ST-segment elevation or (presumed) new left bundle-branch block should undergo early mechanical (PCI) or pharmacological reperfusion. As the exact time of symptom onset as reported by the patient is often unreliable, reperfusion therapy should also be considered if there is clinical and/or ECG evidence of ongoing ischaemia even if the patient-reported symptom onset was >12 h. There is less consensus regarding reperfusion with PCI in stable patients presenting >12 h to 24 h after symptom onset, and therefore this has received a IIb recommendation based primarily on a randomized study demonstrating significant myocardial salvage in patients with STEMI undergoing PCI.3 Finally, PCI of a totally occluded infarct artery in stable patients more than 24 h after symptom onset without signs of ischaemia should not be performed.4

View this table:
Table 1

Reperfusion therapy

RecommendationsClassaLevelb
Reperfusion therapy is indicated in all patients with a history of chest pain/discomfort of <12 h and with persistent ST-segment elevation or (presumed) new left bundle-branch blockIA
Reperfusion therapy should be considered if there is clinical and/or ECG evidence of ongoing ischaemia even if, according to patient, symptoms started >12 h beforeIIaC
Reperfusion using PCI may be considered in stable patients presenting >12 h to 24 h after symptom onsetIIbB
PCI of totally occluded infarct artery >24 h after symptom onset in stable patients without signs of ischaemiaIIIB
Primary PCI
 Preferred treatment if performed by an experienced team as soon as possible after FMCIA
 Time from FMC to balloon inflation should be <2 h in any case and <90 min in patients presenting early (e.g. <2 h) with large infarct and low bleeding riskIB
 Indicated for patients in shock and those with contraindications to fibrinolytic therapy irrespective of time delayIB
Antiplatelet co-therapyc
 AspirinIB
 NSAID and COX-2 selective inhibitorsIIIB
 Clopidogrel loading doseIC
 GP IIb/IIIa antagonist
  AbciximabIIaA
  TirofibanIIbB
  EptifibatideIIbC
Antithrombin therapyc
 HeparinIC
 BivalirudinIIaB
 FondaparinuxIIIB
Adjunctive devices
 Thrombus aspirationIIbB
Rescue PCI
 After failed fibrinolysis in patients with large infarcts if performed within 12 h after onsetIIaA
Fibrinolytic therapyc
 In the absence of contraindications and if primary PCI cannot be performed within the recommended time (see Figure 3)IA
 A fibrin-specific agent should be givenIB
 Pre-hospital initiation of fibrinolytic therapyIIaA
Antiplatelet co-therapyc
 If not already on aspirin oral (soluble or chewable/non-enteric-coated) or i.v. dose of aspirin plusIB
 clopidogrel oral loading dose if age ≤75 yearsIB
 If age >75 years start with maintenance doseIIaB
Antithrombin co-therapyc
 With alteplase, reteplase, and tenecteplase
  Enoxaparin i.v. bolus followed 15 min later by first s.c. dose; if age >75 years no i.v. bolus and start with reduced first s.c. doseIA
  If enoxaparin is not available: a weight-adjusted bolus of i.v. heparin followed by a weight-adjusted i.v. infusion with first aPTT control after 3 hIA
 With streptokinase
  An i.v. bolus of fondaparinux followed by an s.c. dose 24 h later orIIaB
  Enoxaparin i.v. bolus followed 15 min later by first s.c. dose; if age >75 years no i.v. bolus and start with reduced first s.c. doseIIaB
  Or a weight-adjusted dose of i.v. heparin followed by a weight-adjusted infusionIIaC
  • ECG, electrocardiography; PCI, percutaneous coronary intervention; FMC, first medical contact; GP, glycoprotein; NSAID, non-steroidal anti-inflammatory drug.

  • aClass of recommendation.

  • bLevel of evidence.

  • cFor doses, see Table 2.

Primary percutaneous coronary intervention vs. fibrinolytic therapy: selection criteria

Registries and randomized studies have demonstrated that clinical outcomes are worse when there is a long delay to PPCI.5,6 Therefore, the selection of a PPCI strategy vs. pharmacological reperfusion is dependent on a number of timelines and include the patient- and organization-specific delays that are inherent to patient transfer (Figure 2). These include the time between symptom onset and first medical contact (FMC), time from FMC to catheterization laboratory arrival, time from FMC to insertion of the sheath, and time from FMC to balloon inflation.

Figure 2

Reperfusion therapy—important timelines.

A key delay has been called a ‘PCI-related time delay’, a theoretical difference between the time of FMC to balloon inflation minus the time from FMC to the initiation of fibrinolytic therapy. Several post hoc analyses from randomized trials suggest that the survival benefit of PPCI over fibrinolytic therapy will diminish as the PCI-related time delay increases. It has been calculated that the PCI-related time delay that may mitigate the benefit of mechanical intervention varies between 607 and 110 min8 depending on the fibrinolytic agent used, though another analysis calculated a benefit of PCI up to a delay of 120 min.9 This was confirmed by the NRMI 2–4 registry, where a mortality equipose of 114 min was calculated.10

In addition to PCI-related time delay, presentation delay and baseline characteristics should also be considered. In a post hoc analysis of >192 000 patients in the NRMI 2–4 registry,10 the time delay varied considerably according to age, symptom duration, and infarct location. For example, in a patient <65 years with an anterior MI presenting <2 h from symptom onset, PCI need to be performed within <1 h in order to maintain the mortality benefit of mechanical vs. pharmacological reperfusion. However, in a patient >65 years with a non-anterior MI presenting >2 h after symptom onset, a 3 h PCI time delay was acceptable. These data suggest that strategies for reperfusion must be individualized and are reflected in the new guidelines for PPCI and fibrinolytic therapy (Table 1 and Figure 3). PPCI should be performed within 2 h after FMC in any case, and although no specific studies have been performed, a maximum time delay of 90 min after FMC appears to be a reasonable recommendation for patients presenting early with a large infarct and low bleeding risk. PPCI is also indicated for patients in shock and those with contraindications to fibrinolytic therapy irrespective of the time delay. And finally, rescue PCI should be considered after failed fibrinolysis based on clinical signs and evidence of a large infarct, if the procedure can be performed within 12 h after symptom onset.

Figure 3

Reperfusion strategies. The thick arrow indicates the preferred strategy. (Reprinted from Van de Werf et al.1 with permission from the European Society of Cardiology).

Primary percutaneous coronary intervention: adjunctive therapies

Recommended adjunctive therapies and doses are detailed in Tables 1 and 2, respectively.

View this table:
Table 2

Doses of antiplatelet and antithrombin co-therapies

With primary PCI
Antiplatelet co-therapies
 AspirinOral dose of 150–325 mg or i.v. dose of 250–500 mg if oral ingestion is not possible
 ClopidogrelOral loading dose of at least 300 mg, preferably 600 mg
 GP IIb/IIIa inhibitorsAbciximab: i.v. bolus of 0.25 mg/kg followed by 0.125 µg/kg/min infusion (maximum 10 µg/min for 12 h)
Antithrombin co-therapies
 Heparini.v. bolus at a usual starting dose of 100 U/kg weight (60 U/kg if GP IIb/IIIa inhibitors are used). If the procedure is being performed under activated clotting time (ACT) guidance, heparin is given at a dose able to maintain an ACT of 250–350 s (200–250 s if GP IIb/IIIa inhibitors are used). Infusion should be stopped at the end of the procedure
 Bivalirudini.v. bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/h not titrated to ACT and usually terminated at the end of the procedure
With fibrinolytic treatment
Antiplatelet co-therapies
 AspirinOral dose of 150–325 mg or i.v. dose of 250 mg if oral ingestion is not possible
 ClopidogrelLoading dose of 300 mg if age ≤75 years; 75 mg if age >75 years
Antithrombin co-therapies
 EnoxaparinIn patients <75 years and creatinine levels ≤2.5 mg/mL or 221 µmol/L (men) or ≤2.0 mg/mL or 177 µmol/L (women): i.v. bolus of 30 mg followed 15 min later by s.c. dose of 1 mg/kg every 12 h until hospital discharge for a maximum of 8 days. The first two s.c. doses should not exceed 100 mg
In patients >75 years: no i.v. bolus; start with first s.c. dose of 0.75 mg/kg with a maximum of 75 mg for the first two s.c. doses. In patients with creatinine clearance of <30 mL/min, regardless of age, the s.c. doses are repeated every 24 h
 Heparini.v. bolus of 60 U/kg with a maximum of 4000 U followed by an i.v. infusion of 12 U/kg with a maximum of 1000 U/h for 24–48 h. Target aPTT: 50–70 s to be monitored at 3, 6, 12, and 24 h
 Fondaparinux2.5 mg i.v. bolus followed by an s.c. dose of 2.5 mg once daily up to 8 days or hospital discharge if creatinine ≤3 mg/mL or 265 µmol/L
Without reperfusion therapy
Antiplatelet co-therapies
 AspirinOral dose of 150–325 mg
 ClopidogrelOral dose of 75 mg
Antithrombin co-therapies
 EnoxaparinSame dose as with fibrinolytics
 HeparinSame dose as with fibrinolytics
 FondaparinuxSame dose as with fibrinolytics

Antiplatelet co-therapy

Aspirin is recommended in all STEMI patients as soon as possible, while non-steroidal anti-inflammatory drugs and COX-2 inhibitors should be discontinued. Although the use of clopidogrel in patients with STEMI undergoing PPCI has not been fully studied, its advantages in patients undergoing PCI with NSTEMI are well-documented.1113 Therefore, a loading dose of at least 300 mg is recommended (a 600 mg loading dose is preferred) in all patients with STEMI undergoing PCI. Abciximab is the recommended GP IIb/IIIa inhibitor, over eptifibatide or tirofiban, as most studies in STEMI have focused on this agent.

Antithrombin co-therapy

Heparin is the standard anticoagulant therapy during PCI, despite the lack of randomized clinical trials of heparin vs. placebo, and therefore has received a Class I recommendation, Level of evidence C. Doses and ACT considerations are provided in Table 2. There is little evidence to support the use of low-molecular weight heparins in STEMI patients undergoing PPCI, and they are not included in the recommendations.

New to the 2008 guidelines is the inclusion of bivalirudin, a direct thrombin inhibitor, as an adjunct to PPCI. Based on the favourable results of the HORIZONS-AMI trial, bivalirudin has received a Class IIa recommendation for patients with STEMI undergoing PPCI.14 In HORIZONS-AMI, 3602 patients presenting with STEMI undergoing PCI were randomized in an unblinded fashion to receive either bivalirudin with provisional use of a GP IIb/IIIa inhibitor or heparin plus a GP IIb/IIIa inhibitor. At 30 days, bivalirudin significantly reduced the primary endpoint, a composite of major adverse cardiac events (death, MI, revascularization, or stroke) or major bleeding, because of a 40% reduction in major bleeding (P < 0.0047) as well as all-cause mortality (P < 0.001). Recommended dosing is detailed in Table 2.

Fondaparinux, a factor Xa inhibitor, is not recommended as the sole anticoagulant in patients undergoing PPCI based on results of the OASIS-6 trial, in which >12 000 patients with STEMI were treated with fibrinolytic agents or PCI, or no reperfusion therapy.15 In patients undergoing PCI, fondaparinux was associated with a non-significant 1% higher incidence of death or re-infarction at 30 days, as well as an increase in catheter thrombosis.

Adjunctive devices

Thrombus aspiration was given a Class IIb recommendation as an adjunct to PCI, based on the significant mortality reduction demonstrated by 1-year results of the TAPAS trial.16

Fibrinolytic therapy: adjunctive therapies

Aspirin and clopidogrel are recommended in all patients undergoing fibrinolytic therapy (Tables 1 and 2), although the dose of clopidogrel is dependent on the patient's age (300 mg for patients <75 years and 75 mg for patients >75 years). A distinction was made between fibrin-specific (alteplase, reteplase, or tenecteplase) and streptokinase regarding adjunctive antithrombotic therapy. Enoxaparin is recommended for use with fibrin-specific agents based on the ExTRACT-TIMI 25 trial dosing,17,18 or heparin if enoxaparin is not available, with dosing based on the ASSENT-3 trial.19 Fondaparinux, enoxaparin, and heparin are all recommended with streptokinase, with a slight preference for fondaparinux based on the results of the OASIS-6 trial,15 which demonstrated in a large population that fondaparinux was superior to placebo or heparin in preventing death and re-infarction in patients who received fibrinolytic therapy.

Antithrombotic treatment without reperfusion therapy

There are still a significant number of patients who, for different reasons, do not get reperfusion therapy, and the recommendations for treatment are shown in Table 1. Doses of adjunctive antiplatelet and antithrombin therapies are detailed in Table 2.

Angiography after fibrinolytic therapy

A new recommendation to the 2008 guidelines is immediate angiography when there is evidence of failed fibrinolysis or uncertainty about the success of lytic therapy. Immediate angiography is also recommended when there is recurrent ischaemia or re-occlusion after initial successful fibrinolysis. When there is evidence of successful fibrinolysis, angiography is indicated within 3–24 h after the start of fibrinolysis therapy based on data from several trials all demonstrating significantly lower rates of ischaemic events with an invasive vs. conservative strategy.2022 Although this recommendation has been criticized by some and questions have been raised about the 3–24 h timeframe, it would not be optimal to perform angiography too soon after lytic therapy because there is a prothrombotic environment and an increased risk of thrombotic complications, or too long after lytic therapy (i.e, before hospital discharge) because of the increased risk of re-occlusion, re-thrombosis, re-infarction in the first days following the successful fibrinolysis. Finally, angiography should be performed immediately in unstable patients who did not receive reperfusion, and before discharge in stable patients.

Long-term management

Antiplatelet agents are an integral part of the long-term management of patients with STEMI and include aspirin (75–100 mg daily) forever in all patients and clopidogrel (75 mg) for at least 1 year in all patients irrespective of the acute treatment. In patients with contraindication or allergy to aspirin, clopidogrel (75 mg daily) is also recommended. Aspirin can be replaced by oral anticoagulants at the recommended international normalized ratio (INR) when clinically indicated (e.g. atrial fibrillation, LV thrombus, mechanical valve) and at INR 2–3 in patients who do not tolerate aspirin or clopidogrel. In patients with a high risk of thromboembolic events, oral anticoagulation at INR 2–3 in addition to low-dose aspirin (75–100 mg) is recommended. In patients with recent stent placement, an indication for oral anticoagulation, and with or without an increased risk of bleeding, dual-antiplatelet therapy with aspirin and clopidogrel and oral anticoagulation is recommended. It should be noted that if long-term oral anticoagulation is required, the use of a bare metal vs. drug-eluting stent is recommended to reduce the risk of bleeding.

Summary

In summary, compared with the 2003 guidelines, important new recommendations have been formulated in the 2008 updated guidelines for the management of patients with STEMI. The new guidelines emphasize the importance of pre-hospital management and the need for efficient hospital networks to reduce door-to-balloon time. PPCI is the preferable reperfusion therapy as long as the delay from symptom onset is <90–120 min depending on the baseline characteristics of the patient, and, when a substantial delay (e.g. >2–3 h) to PPCI is likely, reperfusion therapy with fibrinolytic agents should be initiated. In addition to the logistic management of patients with STEMI, recommendations regarding optimal pharmacological strategies such as the inclusion of the direct thrombin inhibitor, bivalirudin, have been updated. Finally, angiography is now recommended in all patients after fibrinolytic therapy and in those who did not receive reperfusion therapy. These guidelines were updated to incorporate the latest evidence in STEMI management. Implementation of the guidelines is essential in order to achieve optimal patient management and improve outcomes in STEMI care.

Conflict of interest: none declared.

References