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Peter R Sinnaeve
Frans J Van de Werf
Professor and Chairman
Department of Cardiology
University Hospital Gasthuisberg
University of Leuven
Acute myocardial infarction, the leading cause of death in industrialised countries, is generally caused by rupture of an atherosclerotic plaque, triggering the formation of an occlusive coronary thrombus. When the occlusion persists, typical ST-segment elevations appear on the electrocardiogram. In ST-elevation myocardial infarction (STEMI), infarct-related coronary artery patency can be achieved by administration of fibrinolytic agents or by primary percutaneous coronary intervention (PCI). Although primary PCI achieves higher patency rates and carries a lower risk of intracranial bleeding complications, pharmacological reperfusion can be given earlier. In addition, this strategy is less costly, widely available and less dependent on operator experience. Therefore, fibrinolytic therapy is still used for STEMI in the majority of centres worldwide.
Currently, only a few fibrinolytic drugs are being used regularly. Streptokinase is a first-generation nonfibrin-specific fibrinolytic that indirectly activates plasminogen. Because it is produced by streptococci, patients who receive streptokinase develop antistreptococcal antibodies, precluding readministration. Nevertheless, although newer fibrin-specific fibrinolytics have theoretical advantages, streptokinase remains widely used because of its low cost. Compared with streptokinase, the second-generation fibrinolytic agent recombinant tissue-type plasminogen activator (alteplase, rt-PA) has greater fibrin specificity and is associated with significantly higher patency rates at 90 minutes and lower 30-day mortality rates.(1,2)
During the past decade, several new fibrinolytics have been developed. Of these, reteplase and tenecteplase are the most extensively studied agents. Reteplase is a mutant of alteplase in which the finger, the kringle 1 domain and epidermal growth factor domains have been removed. This results in a decreased plasma clearance, which permits double-bolus administration. Tenecteplase, also derived from alteplase, has increased plasma half-life, allowing convenient single-bolus administration, increased fibrin specificity and higher resistance to plasminogen activator inhibitors.
Although reteplase is associated with superior patency rates than alteplase,(3,4) mortality rates at 30 days or one year were not significantly lower in the Global Utilization of Streptokinase and T-PA for Occluded coronary arteries (GUSTO)-III trial.(5,6) Similarly, tenecteplase induced prompt recanalisation in significantly more patients than alteplase,(7) whereas tenecteplase and alteplase were shown to be equivalent for 30-day and one-year mortality in the ASsessment of the Safety and Efficacy of a New Thrombolytic regimen (ASSENT-2) trial.(8,9) Both GUSTO-III and ASSENT-2 trials investigated thrombolytics agents that promised to provide earlier, more complete and sustained coronary patency; however, in terms of outcome, these agents were at best equivalent to alteplase.
New developments in thrombolytic strategies
Since third-generation thrombolytic agents have failed to improve outcome after myocardial infarction, current trials focus on the development and testing of new thrombolytic strategies. New combinations of antithrombotic drugs with full- or reduced-dose thrombolytic agents, prehospital thrombolytic therapy and pharmacoinvasive strategies have been explored.
Antithrombotic cotherapy: enoxaparin and abciximab
Because the formation and lysis of a coronary thrombus results from a complex interplay of different pathways involving platelets and the coagulation system, the use of agents that target each of these separate components could optimise clot lysis and prevent reocclusion. In the recent ASSENT-3 and GUSTO-V trials, the glycoprotein (GP) IIb/IIIa inhibitor abciximab and the low-molecular-weight heparin (LMWH) enoxaparin were compared with standard antithrombotic cotherapy with unfractionated heparin (UFH). LMWH offers several advantages over conventional UFH, including greater bioavailability and increased anti-Factor Xa activity. LMWH drugs are also easier to administrate and have a more stable and predictable anticoagulant response. GP IIb/IIIa inhibitors, on the other hand, induce less systemic plasminogen activation and reverse the platelet-activating effect of fibrinolytic drugs.(10,11)
In the GUSTO-V trial, 16,588 patients were randomised to either reteplase (administered in two boluses) or half-dose double-bolus reteplase with abciximab.(12) Thirty-day and one-year mortality rates were found to be comparable in both groups. Thus, the higher patency rates with the combination therapy reported earlier(13) did not translate into lower mortality rates, although ischaemic complications after myocardial infarction were significantly reduced with the combination therapy. The overall risk of bleeding, however, was significantly higher with reteplase and abciximab than with reteplase alone. Intracranial haemorrhage (ICH) rates were equal, although in patients above 75 years of age the rate of ICH was almost twice as high in the combination treatment arm. Thus, combination therapy with reteplase and abciximab resulted in a significant reduction in ischaemic complications after acute myocardial infarction, but this benefit was offset by an increased risk of bleeding complications, particularly in elderly patients.
In the ASSENT-3 study, enoxaparin, UFH and abciximab were compared in combination with tenecteplase.(14) In this study, 6,095 patients with STEMI received either full-dose tenecteplase with enoxaparin or UFH, or half-dose tenecteplase with abciximab. Both enoxaparin and abciximab reduced the risk for reinfarction and refractory ischaemia, although mortality rates at 30 days and one year were not significantly different.(15) ICH rates were similar in the three treatment arms, but major and minor bleeding complications were more frequent in the abciximab arm. As was observed in the GUSTO-V trial, patients older than 75 years experienced significantly more bleeding complications. Thus, in both trials, patients receiving reduced-dose fibrinolytic in combination with abciximab experienced fewer ischaemic complications after acute myocardial infarction. However, this improvement was offset by an increased incidence of bleeding complications, especially in the elderly.
Time lost between symptom onset and treatment initiation remains a crucial contributor to treatment delay in STEMI. A meta-analysis showed that the time gained with prehospital treatment resulted in a significant 17% mortality reduction compared with in-hospital thrombolysis.(16) The ability to administer fibrinolytic agents in bolus undoubtedly facilitates prehospital reperfusion protocols. Consequently, the combination of single-bolus tenecteplase plus enoxaparin, which emerged as a convenient and attractive therapy in the ASSENT-3 study, has been investigated in the prehospital setting in the ASSENT-3 PLUS trial. In this study, 1,639 patients with acute myocardial infarction received prehospital tenecteplase and were randomised to either enoxaparin or unfractionated heparin.(17)
A time gain of 47 minutes was observed, increasing the fraction of patients treated within two hours of symptom onset from 29% in ASSENT-3 to 52% in ASSENT-3 PLUS. Early treatment (less than two hours from symptom onset) was associated with a lower 30-day mortality, but no significant difference in outcome was observed between enoxaparin and heparin. Unfortunately, a significantly higher incidence of minor bleeding complications with enoxaparin was also seen, especially in the elderly. Currently, enoxaparin is being further evaluated in patients with STEMI receiving fibrinolytic therapy in the Enoxaparin and Thrombolysis Reperfusion for ACute myocardial infarction Treatment thrombolysis in myocardial infarct (ExTRACT) study.
Given the results of ASSENT-3 PLUS, patients over 75 years of age will receive a reduced dose of enoxaparin. The question of whether prehospital thrombolysis compares favourably with transport to a centre with interventional facilities for primary PCI was addressed in the Comparison of primary Angioplasty and Prehospital Thrombolysis In the acute phase of Myocardial infarction (CAPTIM) trial.(18) Although 1 in 4 patients in the prehospital group underwent rescue PCI, primary PCI was not found to be superior to prehospital fibrinolysis in terms of outcome.
Importantly, prehospital thrombolysis was associated with a reduction in mortality in patients randomised within two hours of symptom onset,(19) which emphasises the importance of initiation of reperfusion therapy just as soon as possible after symptom onset.
A recent meta-analysis indicates that primary PCI is superior to fibrinolysis in randomised trials with regard to short- and long-term outcome.(20) Primary PCI allows immediate treatment of the culprit lesion, and is associated with lower mortality rates in qualified high-volume centres. Although the efficacy of primary PCI appears to be less dependent on the time elapsed between symptom onset and treatment initiation than fibrinolysis, symptom-onset-to-balloon-time also appears to be related to outcome in primary PCI.(21) Therefore, recent guidelines recommend primary PCI if the procedure can be performed by an experienced team within 90 minutes after initial medical contact.(22,23) Unfortunately, in daily practice, time is often lost between diagnosis and PCI due to transport to another centre or waiting for a catheterisation laboratory or team to become available.
In primary PCI studies, 10–20% of patients with STEMI appear to have spontaneous epicardial reperfusion before the intervention,(24–26) which is an independent predictor of outcome.(27) Therefore, the next logical step in the treatment of acute myocardial infarction is to combine the advantages of both primary PCI and fibrinolysis. The rationale behind this approach is that reperfusion can be obtained sooner than with PCI alone, while PCI allows immediate recanalisation when fibrinolysis fails. Surprisingly, earlier trials comparing routine immediate angioplasty following fibrinolysis with more conservative treatment showed that the invasive approach was associated with a much higher complication rate.(28–33) Recent studies, however, indicate that routine early intervention after thrombolysis is both safe and effective.(34–36)
In the GRupo de Análisis de la Cardiopatía Isquémica Aguda (GRACIA)-2 trial, a pharmacoinvasive strategy was compared with primary PCI alone.(37) Patients were randomised to primary PCI within three hours or to immediate tenecteplase plus enoxaparin followed by planned PCI after three to a maximum of 12 hours after randomisation. In the pharmacoinvasive group, the percentage of patients without significant culprit stenosis was five times higher than in the PCI-only group, indicating that fibrinolysis before PCI can reduce the thrombus burden. Furthermore, normal coronary blood flow was significantly more frequent in the pharmacoinvasive group. Mortality also appeared to be twice as high in the PCI-only group (6% vs 3%), although this difference was not significant. This attractive strategy of early pharmacological reperfusion followed by planned mechanical intervention is currently being further studied in the ASSENT-4 PCI and Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trials.(38)
Fibrinolytic therapy significantly improves outcome after STEMI. Over the last few years, new fibrinolytics with several theoretical advantages over standard agents have been developed. Although they do not seem to have an impact on mortality, they are easier to administrate and induce fewer side-effects. Further improvements, however, can be expected from novel antithrombotic drugs, reduction of reperfusion injury and reduced time-to-reperfusion through facilitated percutaneous intervention, and prehospital treatment.