Among patients with acute myocardial infarction (AMI), the efficacy of treatments that decrease mortality by coronary reperfusion and control of arrhythmia is dependent on time and access to acute medical care. Coronary reperfusion requires early administration of fibrinolytic agents or angioplasty, while defibrillation and other methods of cardiac arrhythmia control require trained personnel and equipment in an appropriate clinical setting. Although the “time is muscle” concept is well recognized, rapid access to emergency medical care remains a major problem. The majority of time lost (a median of 140 minutes) is in the patient delay from the onset of symptoms to presentation in a medical facility. These delays impede the early implementation of life-saving procedures and compromise the efficacy of these treatments.1 In many institutions, treatment of patients with AMI may be delayed further by cardiology consultation, logistic difficulties in performing nonelective cardiac catheterization procedures after hours, and the lack of triage and treatment protocols in many emergency departments. Such delays can be both frustrating to practitioners and hazardous to patients, and may also increase the costs of hospital care.2 Until recently, aspirin, heparin and nitrates have been the mainstays of pharmacotherapy for the treatment of AMI. Aspirin irreversibly inhibits cyclooxygenase and the production of thromboxane A2 (TxA2), a potent stimulator of platelet aggregation and vasoconstriction. Although aspirin has been shown to improve survival rates and reduce the incidence of recurrent infarction in patients with AMI, it is a relatively weak antiplatelet agent; it also inhibits the synthesis of prostacyclin, a potent vasodilator, and can cause gastric irritation and gastrointestinal hemorrhage.3 Heparin binds to antithrombin, increasing its ability to inactivate thrombin, and prevents the enzymatic conversion of fibrinogen to fibrin. Heparin may also maintain vessel patency after successful coronary fibrinolysis, but like aspirin, has several limitations. The variable dose-response relationship of heparin, secondary to nonspecific protein and cellular binding, requires frequent monitoring of activated partial thromboplastin time (aPTT) and dose adjustments to optimize coagulation status. Heparin has also been associated with thrombocytopenia, and may actually stimulate platelet activation and aggregation in some patients.3,4 Management strategies aimed at the prompt restoration of coronary blood flow — fibrinolytic and catheter-based therapies—have provided substantial reductions in 30-day mortality.5,6 Over the past decade, a large body of evidence has established the unquestionable mortality benefit to be gained by the administration of intravenous (IV) fibrinolytic therapy. Given its widespread availability and ease of administration, even in the absence of highly trained specialists, fibrinolytic monotherapy is the current mainstay of medical treatment for ST-segment elevation myocardial infarction. Nevertheless, coronary reperfusion strategies are in a constant state of evolution. Newly developed bolus fibrinolytic agents offer greater ease of administration, resulting in a shorter time to treatment and potentially fewer medication errors than alteplase. However, despite initial studies suggesting more expedient and greater rates of coronary reperfusion with some of these newer agents, large-scale comparative trials have not demonstrated superior safety and efficacy comparable to front-loaded alteplase.7,8 Thus, the mortality ceiling for fibrinolytic monotherapy appears to have been reached at approximately 6–7% at 30 days. Breaking through this ceiling pharmacologically will likely require alternative approaches. Table 1 details the differentiation between fibrinolytics.7–24 The Established Benefits of Fibrinolytics in the Treatment of AMI Initially, intracoronary administration of streptokinase was shown to provide a substantial reduction in mortality, but the logistic limitations of this approach led to the pursuit of IV fibrinolytic administration. Subsequently, several large-scale, placebo-controlled trials established the unquestionable mortality benefit associated with IV fibrinolytic therapy. The initial Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI) trial demonstrated that streptokinase produced an 18% reduction in in-hospital mortality versus standard therapy at 21 days.9 Similarly, the Second International Study on Infarct Survival (ISIS)-2 trial demonstrated a 25% risk reduction for mortality at five weeks.10 The potential for improved survival with the next generation agent was suggested by the first Thrombolysis in Myocardial Infarction (TIMI) trial, which showed a 60% patency rate in patients who received alteplase compared with 35% of those who received streptokinase (p 15 The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-I trial compared front-loaded alteplase (15 mg bolus, 0.75 mg/kg for 30 minutes, then 0.5 mg/kg for 60 minutes) with streptokinase (1.5 million U with either IV or subcutaneous heparin) or alteplase (1 mg/kg infusion for 60 minutes) plus streptokinase (1.0 million U) among 41,021 patients with ST-segment elevation MI. Beyond demonstrating the superior mortality reduction of front-loaded alteplase compared with streptokinase or the combination of streptokinase and alteplase, this study provided insight into the importance of time to treatment and the connection between infarct vessel patency, preservation of ventricular function and mortality reduction. Patients treated within the first 2 hours of symptom onset experienced the lowest rate of 30-day mortality (5.5% vs 9.0% among those treated after 4 hours).14,25 In a post-hoc analysis, this equated to a 1% increase in mortality with each additional hour of delay between symptom onset and treatment initiation between 2–6 hours. This association was confirmed by a subsequent meta-analysis demonstrating that the greatest mortality gains (30% reduction in mortality at 30 days) were associated with treatment within the first hour of symptom onset, with a progressive attenuation of 1.6 lives per 1,000 lost with each hour of delay.5 Furthermore, as observed in the angiographic substudy of GUSTO-I, mortality reduction is dependent upon the early restoration of epicardial infarct artery patency. This substudy included 2,431 patients undergoing angiography at 90 minutes, 180 minutes, 24 hours or 5–7 days after thrombolytic administration. Patients assessed at 90 minutes also underwent repeat angiography at 5–7 days. Front-loaded alteplase and the alteplase plus streptokinase combination were associated with greater patency rates and preservation of left ventricular (LV) function compared with streptokinase alone at 90 minutes but not at any other time points. Moreover, correlation between 90-minute coronary flow rates and 30-day mortality revealed significantly lower mortality rates among patients achieving TIMI 3 flow at 90 minutes (4.0%) compared with patients attaining TIMI 2 (7.9%) or TIMI 1 (9.2%) (p = 0.007).26 These important observations have driven the development of novel fibrinolytic agents aimed at enabling bolus administration that would allow for easier and more rapid administration (shortening treatment delays and possibly facilitating pre-hospital treatment) while achieving a greater rate of epicardial artery reperfusion. Molecular modification of the recombinant tissue plasminogen activator has provided agents such as reteplase and tenecteplase with characteristics that include: a greater plasma half-life, enabling single- or double-bolus administration; and either reduced or increased fibrin specificity. For example, a lower fibrin affinity is thought to provide reteplase with improved clot penetration. Greater rates of coronary patency were observed with reteplase in the Reteplase Angiographic Phase II International Dose-finding (RAPID) clinical trials, which showed 90-minute TIMI 3 flow rates of 62.7% for reteplase versus 49.0% for alteplase (p = 0.05) in RAPID-I and 59.9% for reteplase versus 45.2% for alteplase (p = 0.011) in RAPID-II.17,18 Moreover, significantly fewer patients treated with reteplase required percutaneous coronary intervention (PCI) within the first 6 hours of treatment in comparison with alteplase (13.6% versus 26.5%; p = 0.004). No difference in bleeding complications was observed. Administration of reteplase is further simplified relative to alteplase because weight adjustment is not required, reducing the process of preparation and therefore time to administration.27 Consequently, in a recent retrospective study of 500 patients receiving either alteplase or reteplase for AMI, time from presentation to initiation of treatment was significantly lower among patients treated with reteplase (34 ± 7 minutes versus 51 ± 13 minutes; p 28 Thus, bolus fibrinolytic regimens may currently offer the best opportunity to meet practice guidelines that target a door-to-needle time less than 30 minutes.29 Modification of amino acids in the alteplase molecule through point mutations at three sites led to the development of tenecteplase. Alterations in kringle-1 substantially increased the plasma half-life of this agent, while further mutations provided a molecule with 14-fold greater fibrin specificity and an 80-fold increase in plasminogen activator inhibitor (PAI)-1 resistance. The reported potential clinical advantages of these characteristics included an improved safety profile due to less systemic fibrinolysis and possibly greater clot lysis potency. Figure 1 shows the molecular structures of alteplase, reteplase and tenecteplase.30 The angiographic efficacy of tenecteplase was assessed in TIMI-10B, in which a total of 886 patients with MI p = 0.035).22 Concurrently, within the phase-II Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-1 trial designed to assess the safety of 30 mg and 40 mg tenecteplase in 3,235 patients, the investigators observed an ICH rate of 0.94% and 0.62%, respectively, at 30 days. Lower rates of ICH were observed in patients treated with tenecteplase within 6 hours of symptom onset (1.61% for 30 mg; 0.83% for 40 mg). Results of Comparative Phase-III Trials As shown in Table 27,8,21 and Figures 27,8,14,21,24 and 3,7,8,14,21,24 despite the bioengineering of fibrinolytic agents with more favorable characteristics, improvements in 30-day survival rates have not been observed in phase-III clinical trials with these agents. GUSTO-III. The GUSTO-III study was designed to test the superiority of reteplase over accelerated alteplase. This randomized comparison of double-bolus reteplase (10 U + 10 U 30 minutes later) and accelerated alteplase [in a bolus dose of 15 mg, followed by infusion of 0.75 mg/kg of body weight over 30 minutes (not to exceed 50 mg) then an infusion of 0.5 mg/kg (up to 35 mg) over the next 60 minutes] among 15,059 patients demonstrated no improvement in 30-day mortality (reteplase 7.47% versus alteplase 7.24%; p = 0.54) or 1-year mortality (11.21% versus 11.0%, respectively). Rates of ICH, bleeding and reinfarction were all similar between the reteplase and alteplase groups.7 InTIME-II. The Intravenous n-PA for the Treatment of Infarcting Myocardium Early (InTIME)-II trial enrolled 15,078 patients randomized to lanoteplase 120 U/kg single bolus or front-loaded alteplase in a study designed to test the equivalence of these treatments. All patients received aspirin and heparin bolus 70 U/kg with 15 U/kg infusion. At 30 days, the treatments provided a similar rate of mortality (6.75% lanoteplase versus 6.61% alteplase). Although the rate of reinfarction and urgent revascularization was reduced with lanoteplase, a significant increase in ICH was seen (1.12% lanoteplase versus 0.64% alteplase; p = 0.004).21 Subsequent analysis revealed that lanoteplase was associated with substantially higher aPTT levels, suggesting that over-anticoagulation may contribute to this bleeding excess. However, commercial development of this agent has ceased. ASSENT-2. The ASSENT-2 trial, an equivalence study of 16,949 patients presenting with MI of p = 0.0003) and need for transfusion (tenecteplase 4.25% versus alteplase 5.49%; p = 0.0002).8 Conclusion. Thus, the results of GUSTO-III7, InTIME-II21 and ASSENT-28 raise the question of why improvements in pharmacokinetic characteristics of the plasminogen activators have not translated into improvements in 30-day mortality rates. These trials have demonstrated a therapeutic ceiling for mortality benefit derived from fibrinolytic monotherapy and have set the stage for an evolving paradigm shift towards the incorporation of glycoprotein (GP) IIb/IIIa receptor inhibition into pharmacologic reperfusion strategies. The Mortality Benefit Ceiling As with any coronary reperfusion strategy, the aim of restoring flow in the epicardial vessel is to return effective delivery of oxygen to the cardiac myocytes, which are ultimately nourished by the coronary microvasculature. Unfortunately, with fibrinolysis as monotherapy, the goal of rapid, complete and sustained restoration of infarct vessel patency (TIMI 2 or 3 flow) with adequate myocardial tissue perfusion is achieved in only a small number of patients. Although coronary patency may be achieved in 85% of patients 90 minutes after initiating an accelerated regimen of alteplase, only 75% of patients will have achieved patency at 60 minutes — which is a more rigorous standard of rapid reperfusion — and only 57% of patients will attain complete patency with TIMI-3 flow at 90 minutes.31 Several aspects of reperfusion therapy contribute to this failure to achieve rapid, complete and sustained reperfusion. First, many patients presenting with AMI either lack diagnostic electrocardiogram (ECG) criteria or have contraindications to fibrinolytic therapy. Therefore, with the limited availability of catheter-based reperfusion, these patients do not receive any rapid implementation of reperfusion therapy. Second, epicardial patency is often incomplete, with 20–30% of patients failing to achieve TIMI 2–3 flow.17,18 This high rate of fibrinolytic failure is less surprising when the components of the thrombotic process are considered — the fibrin network that binds a composite of platelets and thrombin together; the platelet-rich thrombus that is an abundant source of PAI-1; and the release of clot-bound thrombin into the fluid phase after fibrinolytic therapy has digested the fibrin network. Increased fluid-phase thrombin is then free to recruit and activate platelets, augmenting platelet aggregation while promoting further coagulation.32 Hence, these factors may contribute to the 10% reocclusion rate seen with fibrinolysis monotherapy.31 Third, bleeding complications, and in particular ICH, are key stumbling blocks in the development of an optimally effective reperfusion regimen for AMI. These concerns limit the use of these regimens in many patients and compromise the mortality benefits associated with achieving vessel patency. Cumulative data from several large-scale randomized trials indicate an ICH rate of 0.5–0.9%, although this rate may be somewhat higher in clinical practice, especially in the elderly, among patients with diabetes and in those with hypertension and low body weight. Recent attempts to improve the pharmacologic profile of these agents have not provided significant reductions in the risk for ICH. Importantly, while the dose and mode of administration of alteplase or tenecteplase may be associated with the rate of ICH, concurrent heparin therapy also appears to play a role, as observed in the GUSTO-IIa,33 GUSTO-IIb,6 TIMI-9a,34 TIMI-9b,35 TIMI-10b22,36 and ASSENT-123,36 trials. Finally, evolving methods for assessing microvascular perfusion have demonstrated that the success of any reperfusion strategy depends on effective restoration of perfusion to the myocardium, which is not necessarily guaranteed by the prompt restoration of infarct-related epicardial artery flow. Landmark studies using myocardial contrast echocardiography (MCE) demonstrate the disparity between epicardial vessel patency and myocardial perfusion. Ito et al. demonstrated that despite epicardial flow, TIMI 2 flow was not associated with perfusion at the myocardial level, and despite TIMI 3 (angiographically normal) epicardial blood flow, 16% of patients did not achieve microvascular perfusion in the previously occluded vascular segment.37 This failure to achieve microvascular perfusion has been attributed to distal embolization of platelets and inflammatory cells following lysis of the occlusive epicardial thrombus. Other contributing factors are the ischemia and reperfusion injury that follow inflammatory cell infiltration and tissue edema. These notions are supported by the demonstration of atherothrombotic microemboli within the distal microvascular bed of patients who had died from AMI.38 Although the introduction of non-weight-adjusted bolus fibrinolytic agents may have reduced the time to treatment and potential for medication errors, improvements in fibrinolytic therapies alone may not be sufficient to overcome the problems of fibrinolytic resistance. Rescue Percutaneous Coronary Intervention Early percutaneous transluminal coronary angioplasty (PTCA) after clinical failure of thrombolysis has been shown to improve patency of the infarct-related artery in up to 90% of patients. Successful rescue PTCA may also salvage myocardium and reduce later ischemic events and mortality. However, in spite of these potential benefits, early PTCA was also associated with angiographic restenosis in up to 50% of vessels and the need for repeat target vessel revascularization in approximately 20% of patients.39 A retrospective analysis of the GUSTO-III trial examined the effects of abciximab treatment during early angioplasty after clinically failed thrombolysis in patients with AMI. Patients who received abciximab had anterior infarction less often than those who did not, and tended to have lower 30-day mortality rates (3.6% versus 9.7%, respectively; p = 0.076). The composite rates of death, stroke or reinfarction did not differ between the abciximab and non-abciximab treatment groups (12% versus 14%, respectively; p = 0.07), but tended to occur less often in abciximab-treated patients who had received reteplase compared to those who had been treated with alteplase (7% versus 21%, respectively; p = 0.08). Abciximab-treated patients tended to experience more severe bleeding (3.6% versus 1.0%, respectively; p = 0.08) in spite of reduced use of heparin.40 Continued on next page
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