The results of an electrocardiogram (ECG) on admission guide the next level of decision-making for the patient with chest pain suspected of myocardial ischaemia. If an occlusive thrombus forms, patients may develop an acute ST-segment-elevation myocardial infarction (STEMI), and the primary goal is to consider reperfusion therapy as quickly as possible. The benefit obtained by effective and early restoration of the global flow (epicardial and microvascular) limits the size of the infarct, reduces the degree of ventricular dysfunction and improves survival.
For patients with STEMI, there are two classic, well-established reperfusion therapies: primary percutaneous coronary intervention (PCI) and thrombolysis. Primary PCI is considered the gold standard of myocardial reperfusion when promptly performed by skilled teams; however, as the efficacy of this therapy is time-dependent, logistical barriers and other constraints limit its use.1 By contrast, intravenous thrombolysis is widely applicable, and has been shown to reduce mortality unequivocally when given within 12 hours of symptoms.2,3 Furthermore, early administration of newer fibrin-specific thrombolytics is at least as effective as primary angioplasty, and can abort infarction and dramatically reduce mortality when given during the first one to two hours from onset (Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction [CAPTIM] trial).4 Consequently, important elements from the current guidelines in Europe and the US recommend that patients with ST-segment elevation or new left bundle branch block should be reperfused either by PCI performed 90–120 minutes after the first medical contact or by thrombolysis within 30 minutes of presentation to hospital.2,3
Nevertheless, it is important that we avoid the competitive dualism (primary PCI versus thrombolysis) by which early reperfusion has been viewed to date. The advantages and disadvantages of these therapies should generate distinct viewpoints on reperfusion strategies for patients with infarction. Based on this consideration, for patients admitted to a hospital with primary PCI facilities, this should be considered the reperfusion strategy. However, options for patients admitted to community hospitals without PCI facilities include administration of thrombolysis complemented by a second-stage PCI or transfer to a tertiary care centre for primary PCI. Therefore, implementation of these strategies should vary based on the mode of transportation of the patient and capabilities at the receiving hospital. The real but not always ideal strategy of reperfusion should be based on the following factors: efficiency, time, applicability and cost.
In this article, the impact of evidence in terms of the latest strategies for coronary reperfusion in patients with STEMI is described, and we propose a pathway to choose the best management option depending on time and the availability of invasive facilities.
Primary Percutaneous Coronary Intervention – The Gold Standard of Reperfusion Under Optimal Conditions
Primary PCI is defined as intervention in the culprit vessel within 12 hours after the onset of chest pain or other symptoms, without prior thrombolytic or other clot-dissolving therapy. Primary PCI should be performed in patients with STEMI or left bundle branch block who can undergo PCI of the infarct artery within 12 hours of symptom onset, if performed in a timely fashion (balloon inflation within 90–120 minutes of first medical contact) by persons skilled in the procedure.
Many trials have documented that primary PCI is superior to intravenous thrombolysis for the immediate management of STEMI (less recurrent myocardial ischaemia, more effective restoration of coronary patency, less coronary reocclusion, less recurrent myocardial infarction, improved residual left ventricular function and better clinical outcome, including strokes).5 When comparing primary angioplasty versus thrombolysis, the benefit on long-term mortality is reduced, and seems to be dependent on an effect on infarct size limitation.5
To achieve optimal results with primary PCI, time from the first hospital door to the balloon inflation should be as short as possible, with a goal of within 90 minutes (up to 120 minutes when the patient is transferred to a second non-PCI-capable hospital).3 However, data from the American College of Cardiology National Cardiovascular Data Registry (2005–2006) show that in the US, primary PCI is failing to achieve the established benchmarks, with >40% of patients achieving a door-to-balloon time of >90 minutes even in the presenting hospital. A greater proportion of patients with longer door-to-balloon times were treated on a weekday between 4pm and 8am, at weekends and at community centres.6 Similar data were presented in Europe.1
Several specific considerations are important when primary PCI is performed. First, although there is no evidence to suggest that primary stenting reduces mortality compared with balloon angioplasty, major adverse cardiac events are reduced, driven by the reduction in subsequent target vessel revascularisation (TVR) with stenting.7 Compared with conventional bare-metal stents, drug-eluting stents decrease TVR with no differences in death, reinfarction or stent thrombosis rates.8
Second, evidence has emerged about the use of bivalirudin as an effective alternative to unfractionated heparin during primary PCI (Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction [HORIZONS-AMI] study).9 The risk of stent thrombosis associated with bivalirudin appeared to be mitigated by the prior use of unfractionated heparin, by the use of a 600mg loading dose of clopidogrel or by the maintenance of bivalirudin shortly after the PCI ending. Third, new thienopyridines (prasugrel) are currently being tested during primary PCI with no clear nested benefit compared with clopidogrel (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel- Thrombolysis In Myocardial Infarction [TRITON-TIMI-38] study).10 Fourth, trials evaluating glycoprotein GPIIb/IIIa antagonists as adjuncts to oral antiplatelet therapy in the setting of primary PCI question whether GPIIb/IIIa antagonists provide significant additional benefit to STEMI patients who have received dual antiplatelet therapy before catheterisation (HORIZONS-AMI, Value of Abciximab in Patients With Acute MI Undergoing PCI After High Dose Clopidogrel Pretreatment [BRAVE-3], Ongoing tirofiban in myocardial infarction evaluation [On- TIME], etc.).9,11–14 Thus, current evidence indicates that adjunctive use of a GPIIb/IIIa antagonist can be useful at the time of primary PCI, but cannot be recommended as routine therapy. Finally, great controversy exists with the use of proton pump inhibitors and dual antiplatelet therapy. Proton pump inhibitors have been found to interfere with the metabolism of clopidogrel.15 Randomised clinical trials are needed to test its clinical implications.
Overall, the time delay from first medical contact to balloon inflation constitutes the Achilles’ heel of primary PCI, especially for patients who need to be transferred. This led researchers to question whether administrating thrombolytics to bridge the delay between first medical contact and primary PCI would improve outcomes. Thus, the concept of facilitated angioplasty came into being. This strategy involves full- or half-dose thrombolytic therapy with or without a GPIIb/IIIa receptor antagonist, followed by primary PCI. Two large studies addressed this matter: Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI)16 and the Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial.13 In the ASSENT-4 PCI trial, therapy with full-dose tenecteplase associated with PCI was randomly compared with primary PCI.
The trial was terminated prematurely because of a higher in-hospital mortality rate in the facilitated PCI group. It has been theorised that some factors could have strongly influenced this observation, i.e. the lack of heparin infusion after the bolus in the facilitated group, the regimen of antithrombotic therapy used with no loading dose of clopidogrel, the prohibition of concomitant treatment with GPIIb/IIIa inhibitors except for bailout and, most importantly, an adequate delay between thrombolysis and PCI. In addition, FINESSE showed that neither PCI preceded by abciximab and reteplase nor PCI preceded by abciximab alone was superior to abciximab used at the time of PCI among patients presenting within four hours of medical contact. Thus, at the moment facilitated PCI offers no evidence-based clinical benefit, but further studies are necessary to clarify these matters. In this sense, we are convinced that the optimal timing between fibrinolysis and PCI is crucial for the results of any pharmaco-invasive PCI.
Thrombolysis as Primary Reperfusion Therapy
It is of critical importance to recognise that worldwide reperfusion continues to be performed with thrombolytics in the vast majority of patients, even when tertiary centres with PCI facilities are available.17 In poor countries, thrombolysis should be administered to STEMI patients with symptom onset within the previous 12 hours, and optimisation of thrombolysis (including promotion of the ‘golden hour’ and reducing the substantial proportion of patients who do not receive reperfusion) can still reduce mortality from acute MI before angioplasty is introduced. Moreover, bearing in mind the current availability of new, more easily administered thrombolytic agents, the efficacy and application of drug reperfusion can be expected to grow substantially in the near future. A strategy of pre-hospital fibrinolysis provides a clinical benefit over in-hospital fibrinolysis in STEMI.18 Furthermore, if the emergency medical services personnel who attempt first patient contact have fibrinolytic capability, we believe that pre-hospital fibrinolysis should always be started immediately in patients with symptom duration of less than three hours.
If thrombolysis is performed as the primary reperfusion therapy, it should not be considered to be the final treatment. In about 45–50% of patients who receive fibrinolytics, adequate coronary reperfusion (epicardial thrombolysis in myocardial infarction [TIMI] 3 flow) is not achieved.19
Therefore, it is important to be aware of the signs of adequate reperfusion in terms of clinical parameters (relief of pain), electrocardiography (ST resolution >50%), enzymatic signs (rapid elevation of myocardial damage markers) and tissue perfusion. The combination of clinical data, electrocardiography and measurement of enzyme activity helps to better evaluate whether or not adequate reperfusion has been achieved, although in the majority of cases clinical and electrocardiographic assessments guided us in estimating the probability of adequate reperfusion. In fact, complete ST resolution is an excellent predictive factor of recovery of coronary patency, with a predictive value of >90% for an epicardial flow of TIMI 2 or 3 and 70–80% for TIMI 3. However, its negative predictive value is very low (about 50%), mainly due to the fact that ST resolution depends not only on epicardial perfusion, but also on microvascular perfusion. In any event, in the absence of clear reperfusion criteria 60–90 minutes after the administration of fibrinolytics, failure to restore patency must be ruled out by emergency catheterisation and PCI. This procedure, known as rescue angioplasty, has been compared with a conservative strategy and re-administration of fibrinolytics, showing that rescue PCI is superior in reducing clinical events (Middlesbrough Early Revascularization to Limit INfarction [MERLIN] and Rescue Angioplasty after Thrombolysis [REACT] trials).20,21 Coronary stenting and use of GPIIb/IIIa are associated with a greater myocardial salvage and should be used.
The usefulness of thrombolysis is strongly threatened not only by a high proportion of failed reperfusion but also by a substantial rate of reocclusion. The early interventional approach to STEMI patients receiving fibrinolysis is based on the hypothesis that mechanical repair of the infarct-related artery allows a stable normal flow and prevents ischaemic events related to reocclusion, which is itself closely associated with the presence of a residual stenosis and its severity. Thus, even if successful, thrombolysis should not be considered to be the final treatment in STEMI patients, and routine invasive evaluation and PCI early after fibrinolysis should be considered for these patients. This procedure, known as post-thrombolysis, adjunctive or early elective PCI, is defined as early percutaneous repair of the culprit artery in routine (i.e. not rescue), planned (i.e. not urgent) procedures and in patients with STEMI treated initially with fibrinolytics to open the artery. The results of the routine invasive strategy within 24 hours of thrombolysis versus ischaemia-guided conservative approach for acute MI with ST-segment elevation (GRACIA-1) trial22 reinforce recent evidence in terms of the benefit of early intervention over a conservative approach for patients with acute coronary syndromes in the era of modern antiplatelets and stenting.
Routine post-thrombolysis PCI within 24 hours after symptoms resulted in a significant reduction in the duration of hospitalisation and in the primary combined end-point of death, reinfarction and revascularisation at 12 months. This strategy could represent a good alternative, comparable to primary PCI,23 for the still high proportion of patients with STEMI for whom primary PCI is not available. Two new trials have provided new information in terms of optimal timing between thrombolysis and PCI in high-risk STEMI patients: the Combined Abciximab RE-teplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI)24 and the Trial of Routine ANgioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI)25 trials. The results of both studies support the benefit of routine, early transfer of high-risk, thombolytic (half or full dose) treated patients to a PCI centre for early (even immediate) PCI under contemporary antiplatelet and antithrombotic therapy.
An Example Reperfusion Pathway
On the basis of this evidence and our logistical barriers, we suggest the pathway in Figure 1 for the care of STEMI patients.
In our example, definitive reperfusion therapy will be decided immediately after first medical contact by the emergency services on the basis of two simple points: the delay from the onset of symptoms to first medical contact and the availability of a skilled interventional centre.
If the delay from onset of symptoms is shorter than three hours, we believe the best choice is to initially administer thrombolysis immediately in the ambulance (pre-hospital) and transfer the patient to a PCI-capable hospital (unless immediate – within 60 minutes – primary PCI is available). If the patient is high-risk (extensive ST-segment elevation, new-onset left bundle branch block, systolic pressure <100mmHg, heart rate >100bpm, Killip class II–III, ECG signs of right ventricle infarction or ejection fraction ≤35%), angiography and PCI on arrival should be immediately performed without waiting to determine whether reperfusion has occurred, always under contemporary antiplatelet treatment. If the patient is a non-high-risk patient, rescue PCI should be performed if symptoms persist and failure to reperfuse is suspected, or elective angiography and PCI in the case of successful thrombolytic reperfusion. In such cases, the procedure could be scheduled according to the convenience of the catheterisation laboratory.
If the delay from onset of symptoms is longer than three hours, we should immediately transfer the patient for primary PCI if we estimate a door-to-balloon delay within 120 minutes. If we consider that access to primary PCI will exceed this window for door-to-balloon time, pre-hospital thrombolysis and transfer of the patient for PCI according to the aforementioned high-risk patient condition should be performed.