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Thrombolysis and Adjunctive Therapy in Acute Myocardial Infarction : The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy FREE TO VIEW

Venu Menon, MD; Robert A. Harrington, MD; Judith S. Hochman, MD; Christopher P. Cannon, MD; Shaun D. Goodman, MD; Robert G. Wilcox, MD; Holger J. Schünemann, MD, PhD, FCCP; E. Magnus Ohman, MD, FCCP
Author and Funding Information

Correspondence to: E. Magnus Ohman, MD, FCCP, Division of Cardiology, University of North Carolina; e-mail: mohman@med.unc.edu

Chest. 2004;126(3_suppl):549S-575S. doi:10.1378/chest.126.3_suppl.549S
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This chapter about antithrombotic therapy for acute myocardial infarction (MI) is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients’ values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S–187S). Among the key recommendations in this chapter are the following: For patients with ischemic symptoms characteristic of acute MI of < 12 h in duration, and ST-segment elevation or left bundle-branch block (of unknown duration) on the ECG, we recommend administration of any approved fibrinolytic agent (Grade 1A). We recommend the use of streptokinase, anistreplase, alteplase, reteplase, or tenecteplase over placebo (all Grade 1A). For patients with symptom duration < 6 h, we recommend the administration of alteplase over streptokinase (Grade 1A). For patients with known allergy or sensitivity to streptokinase, we recommend alteplase, reteplase, or tenecteplase (Grade 1A). For patients with acute posterior MI of < 12 h duration, we suggest fibrinolytic therapy (Grade 2C). In patients with any history of intracranial hemorrhage, closed head trauma, or ischemic stroke within past 3 months, we recommend against administration of fibrinolytic therapy (Grade 1C+). For patients with acute ST-segment elevation MI whether or not they receive fibrinolytic therapy, we recommend aspirin, 160 to 325 mg po, at initial evaluation by health-care personnel followed by indefinite therapy, 75 to 162 mg/d po (both Grade 1A). In patients allergic to aspirin, we suggest use of clopidogrel as an alternative therapy to aspirin (Grade 2C). For patients receiving streptokinase, we suggest administration of either IV unfractionated heparin (UFH) [Grade 2C] or subcutaneous UFH (Grade 2A). For all patients at high risk of systemic or venous thromboembolism (anterior MI, pump failure, previous embolus, atrial fibrillation, or left ventricular thrombus), we recommend administration of IV UFH while receiving streptokinase (Grade 1C+).

Figures in this Article

Acute ST-segment elevation myocardial infarction (MI) is caused by coronary plaque rupture/erosion and resultant thrombosis leading to an occluded epicardial infarct-related artery (IRA).12 Timely fibrinolytic therapy can re-establish coronary flow in this setting and salvage jeopardized myocardium. Large randomized clinical trials (RCTs) as well as the Fibrinolytic Therapy Trialists overview have clearly demonstrated a statistically significant mortality benefit with thrombolytic therapy over placebo in this clinical setting.3 Despite dramatic strides in the area of percutaneous intervention, thrombolysis remains the most utilized form of reperfusion treatment worldwide. This review will focus on approved agents and the randomized trials that have led to their widespread utilization. The utility of adjunctive antithrombotic therapies, such as aspirin, clopidogrel, IV unfractionated heparin (UFH), low molecular weight heparin (LMWH), glycoprotein (GP) IIb/IIIa inhibitors, and direct thrombin inhibitors (DTIs) will also be discussed. This section will detail limitations and complications associated with fibrinolytic therapy. We will also compare outcomes with thrombolysis and primary angioplasty, although a complete review of the two different reperfusion strategies is beyond the scope of this document. Table 1 describes the question definition and eligibility criteria for the studies considered in each section of the article.

The initial description of a prolonged infusion of streptokinase for patients with acute MI appeared in 1958.4Several smaller studies followed, but no definitive benefit was discernable. A metaanalysis5of these early studies, however, suggested a significant mortality benefit. This coupled with angiographic observations of reperfusion among patients receiving intracoronary streptokinase ushered in the modern era of reperfusion therapy for acute MI.6It was soon recognized that intracoronary fibrinolytic therapy could salvage jeopardized ischemic myocardium, and that early restoration of patency of the IRA resulted in better preserved left ventricular function.79 Thereafter, a significant mortality benefit with IV fibrinolysis was demonstrated and confirmed. This led to worldwide adoption of IV fibrinolysis for acute ST-segment elevation MI.1013 Observations from these trials helped define the therapeutic windows and risk-benefit ratios for an array of patient subgroups. The role of adjunctive medications was clarified, and the limitations and complications of therapy became apparent. In the past decade, attention has focused on improving the potency, efficacy, and administrative ease of fibrinolytic agents. A therapeutic ceiling of reperfusion success was recognized and has led to the testing of newer adjunctive therapies like GP IIb/IIIa inhibitors and LMWH in this clinical setting. The current endeavor is to synergistically combine the merits of fibrinolysis and percutaneous intervention into a seamless reperfusion strategy. Adoption of this “facilitated angioplasty” strategy, however, remains to be tested in RCTs. This yet unproven strategy, if beneficial, will make percutaneous intervention available to a larger proportion of patients with acute MI, while preserving the potential benefit of restoration of flow in the early hours following coronary occlusion. The 2001 American College of Chest Physicians guidelines describes the pharmacology of common thrombolytic agents and the evaluation of therapeutic success with fibrinolytic therapy.14

The field of IV fibrinolytic therapy was transformed when it became possible to examine the efficacy of therapy with angiography during the acute phase of MI. The initial trials of urokinase and streptokinase were carried out with dosages established on a theoretical basis. In fact, IV streptokinase was not subjected to a true form of dose-ranging angiographic trial until well into the 1980s. Nevertheless, the placebo-controlled trials of streptokinase were very powerful in showing a significant mortality reduction with IV streptokinase for acute MI. In this section, we will briefly review the clinical trial experience with all of the currently established fibrinolytic agents (Table 2 and previous CHEST Supplement14).

1.1 Thrombolysis with streptokinase, tissue plasminogen activator, anistreplase, reteplase, and tenecteplase
Metaanalysis data.

The Fibrinolytic Therapy Trialists’ Collaborative Group combined trials investigating streptokinase for treatment of acute MI in a metaanalysis.3 The authors observed an overall benefit among patients with ST-segment elevation or bundle-branch block irrespective of age, sex, BP, heart rate, or prior MI, or diabetic status. Furthermore, the treatment benefit was greater the earlier treatment was initiated. For patients treated within 6 h, the absolute reduction in mortality was 30 lives saved per 1,000 patients treated; for patients treated within the first 7 to 12 h after symptom onset, it was 20 lives saved per 1,000 treated. Consistent across these trials, the treatment benefit observed in the first 21 to 42 days was maintained up to 1 year. For patients treated between 13 h and 18 h after symptom onset, there was an uncertain trend toward mortality reduction of approximately 10 lives saved per 1,000 treated. Fibrinolytic therapy was associated with approximately four extra strokes per 1,000 patients treated, most of which occurred within 2 days. About 50% were associated with an early death, and so were already accounted for in the overall mortality reduction. Of the remaining patients with stroke, 25% were moderately or severely disabled and the other 25% were not. The metaanalysis3 thus suggested a treatment benefit for most patients who present with acute MI within 12 h of symptom onset.

Individual large-scale trials.

The efficacy of streptokinase with regard to mortality was evaluated in four large, placebo-controlled trials13,1517 (Table 3 ). The first true mortality trial for streptokinase was the Gruppo Italiano per lo Studio Streptokinasi nell’Infarto Miocardico (GISSI)-1 trial,,13 an open-label, randomized trial of 11,806 patients. Of note, only 14% of patients received aspirin and only 62% received any heparin in this study; all adjunctive therapies were at the investigator’s discretion. Nevertheless, in-hospital mortality (14 to 21 days) was reduced by 18% compared with standard therapy (10.7% vs 13.0%, p = 0.002). The reduction in mortality was time dependent, decreasing from a 47% reduction in patients treated within 1 h, to 23% for those treated within 3 h, and to 17% for those treated within 6 h of symptom onset. The reduction in mortality was maintained over 12 months (17.2% with streptokinase vs 19.0% for control subjects, p = 0.008). At 10 years of follow-up, benefits of a single IV infusion of streptokinase were still evident. An absolute benefit of 19 (95% confidence interval [CI], 1 to 37) lives saved per 1,000 patients treated was observed. This mortality benefit largely reflected early gains observed prior to index hospital discharge (relative risk [RR], 0.81; 95% CI, 0.72 to 0.90).18

The IV Streptokinase in Acute Myocardial Infarction (ISAM) study16 was a blinded, randomized trial of streptokinase vs placebo in 1,741 patients with ST-segment elevation MI. Streptokinase was less effective, but consistent with the GISSI-1 findings; there was a nonsignificant 11% reduction in 21-day mortality.

The second International Study of Infarct Survival (ISIS) study15 was a large, blinded, placebo-controlled study of IV streptokinase in patients with suspected MI. There were no specific entry criteria other than the physician’s clinical suspicion of an acute MI. Most patients, however, had ST-segment elevation or left bundle-branch block on the presenting ECG. In all, 17,187 patients were randomized in 417 hospitals worldwide. Patients were enrolled up to 24 h after symptom onset, but most were randomized in the first 12 h. The study used a 2 × 2 factorial design testing aspirin alone (162.5 mg/d for 1 month), streptokinase alone (1.5 MU over 1 h), both, or neither. Patients randomized to streptokinase had a 25% reduction in 35-day vascular mortality compared with those who received placebo (9.2% vs 12.0%, p < 0.001). The study also showed that aspirin alone could reduce mortality by a relative 23% (p < 0.001). The most important part of this trial was the synergistic effects of aspirin with streptokinase, which produced a 42% reduction in vascular mortality (8.0% vs 13.2%, p < 0.001). Additional benefits with aspirin in this trial included reduced rates of reinfarction, cardiac arrest, cardiac rupture, and stroke. Similar to the GISSI-1 study, there was clear evidence of time dependency for treatment benefit. Patients treated within 6 h of symptoms had significantly improved survival. While there tended to be benefit for treatment that began within up to 12 h after symptom onset, it was not statistically significant after 4 years of follow-up. Also similar to GISSI-1, the 29 lives per 1,000 patients (95% CI, 20 to 38) treated with streptokinase compared to placebo during days 0 to 35 persisted at 4 years (28 lives per 1,000 patients treated; 95% CI, 14 to 42), and out to 10 years (23 lives per 1,000 treated; 95% CI, 2 to 44).19

Another trial (Estudio Multicentrico Estreptoquinasa Republicas de America del Sur [EMERAS]), also was a blinded, placebo-controlled trial of streptokinase.17 EMERAS was altered to include only patients who presented at least 6 h after but within 24 h of symptom onset, once the ISIS-2 results were reported. Mortality at 35 days did not differ significantly between the streptokinase and placebo groups in the 3,568 patients enrolled between 6 h and 24 h (11.2% for streptokinase vs 11.8% for placebo).

A large number of angiographic trials with streptokinase using IRA patency as a surrogate end point have been performed. Readers are referred to the prior consensus statements for details.14

Tissue plasminogen activator
Early comparative trials.

A number of angiographic trials initially compared patency with tissue plasminogen activator (tPA) over streptokinase. These early trials observed that the 3-h dosing regimen of alteplase resulted in superior patency and TIMI grade 3 flow results at both 60 min and 90 min compared with streptokinase or anistreplase.20Neuhaus and colleagues21developed an “accelerated” 90-min dosing regimen for alteplase, which was found to achieve even higher rates of early reperfusion than did the 3-h regimen of alteplase,22anistreplase treatment,2324 or streptokinase treatment.25Given the importance of rapid reperfusion, a fibrinolytic regimen that achieves a higher rate of early infarct-artery patency would be expected to be associated with lower mortality. However, findings from clinical trials evaluating this association have been inconsistent, and this notion was initially called into question with the disappointing results of the GISSI-2/International Study group and the ISIS-3 trial (Table 4 ).27 The lack of benefit seen in these trials, however, may have been due to the use of subcutaneous (SC) moderate-dose heparin (rather than IV heparin), the use of duteplase as opposed to alteplase, and the lack of an accelerated tPA regimen.

The relationship of early reperfusion and improved survival was strongly supported by the results of the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO)-I trial, which set out to evaluate several promising fibrinolytic regimens.11,25 The reference arms of the trial both used streptokinase, one with SC heparin (12,500 U q12h beginning at 4 h) and one with IV heparin. The third arm was front-loaded (accelerated) alteplase and IV heparin; the fourth arm was combination fibrinolytic therapy, which involved approximately two thirds of the typical doses of alteplase and streptokinase in conjunction with IV heparin. All patients received aspirin, 325 mg/d.

A total of 41,021 patients were enrolled in GUSTO-I, the primary end point of which was 30-day mortality (Table 5 ).11,25 Mortality at 30 days was significantly lower in the accelerated alteplase arm compared with each of the three other arms. The improvement in mortality was present as early as 24 h after treatment began, with alteplase-treated patients having a significantly lower mortality rate. Other major complications, such as cardiogenic shock, congestive heart failure, and ventricular arrhythmias, also were reduced among patients treated with alteplase.

Some physicians have stated that the relative 14% reduction in mortality with alteplase vs streptokinase (an absolute 1% difference considering a baseline risk of approximately 7%) is a small, clinically irrelevant benefit. Thrombolysis itself, however, widely considered to be a revolution in the treatment of acute MI, led to a 25% relative (or approximately 2% absolute) improvement in mortality compared with placebo. In counting the absolute benefit in terms of the number of lives saved, standard fibrinolysis is estimated to save 26 lives per 1,000 patients treated compared with placebo in patients with ST-segment elevation. Treatment with accelerated alteplase and IV heparin saves an additional 10 lives per 1,000 treated, representing a 40% improvement over standard fibrinolytic regimens. Otherwise stated, the use of alteplase instead of streptokinase reduced mortality from 7 to 6 per 100 patients treated.

Despite the aggressive regimens of fibrinolysis, aspirin, and heparin, intracranial hemorrhage was uncommon in GUSTO-I. For each of the streptokinase arms, 0.5% of patients suffered an intracranial hemorrhage (ICH) compared with 0.7% of patients treated with accelerated alteplase and 0.9% of patients treated with combination fibrinolytic therapy. To put the results in full perspective, the GUSTO-I investigators developed the concept of “net clinical benefit,” that is, the avoidance of either death or nonfatal, disabling stroke. When comparing the net clinical benefit among the four regimens, accelerated alteplase still provided a clear benefit compared with the other three regimens. The benefit of accelerated alteplase was seen in nearly every subgroup analyzed, including patients with anterior or inferior MI and in the young and the elderly. The absolute benefit was greater in higher-risk patients, for example, those with anterior MI.

To fully understand the mechanistic benefits of the four different fibrinolytic regimens, an angiographic substudy was carried out.25 More than 2,400 patients were randomized to undergo angiography at 90 min, 180 min, 24 h, or 5 days. At the early 90-min time point, the alteplase-treated patients had a significantly higher patency rate and a much higher rate of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow, which is associated with the best outcomes (Table 5).,11,25 At the other three time points, there were no significant differences between the four fibrinolytic regimens. Thus the benefit of accelerated alteplase was associated with early opening of the IRA. The improved patency at 90 min was associated with improved survival at both 24 h and at 30 days, thus highlighting the benefits of rapid reperfusion.2829

The TIMI-4 trial was a blinded trial24 comparing accelerated alteplase, anistreplase, and their combination. All patients received aspirin and IV heparin. Accelerated alteplase was found to have a 78% patency rate after only 60 min, compared with only 60% for anistreplase or combination fibrinolytic therapy. At 90 min, patency and TIMI grade 3 flow rates both were significantly better in the accelerated alteplase arm. Overall clinical outcomes, using a composite end point and 1-year survival, also were better with alteplase. Thus, this blinded trial confirmed the results found in the GUSTO-I trial.

The benefits of accelerated alteplase seen in the GUSTO-I and TIMI-4 angiographic trials and the superior outcome in GUSTO-I vs the lack of benefit seen in GISSI-2 and ISIS-3 reflects two factors: the alteplase regimen and the heparin dosing. The former trials used the accelerated alteplase regimen, which results in a higher rate of early patency compared with the older, 3-h regimen,20 and early, IV heparin, which improves late infarct-artery patency. In contrast, the GISSI-2 and ISIS-3 trials used the slower infusion of alteplase or duteplase and delayed SC heparin. Reocclusion of an open IRA, often silent, occurs most often in this early time period and is associated with a threefold increase in mortality.3031 Thus, slower infusion of alteplase and delayed heparin administration may account for a lack of benefit.

Cost-effectiveness of alteplase in comparison to streptokinase.

A formal cost-effectiveness analysis was incorporated into the GUSTO-I protocol as a substudy in the United States and Canada.32 At 1 year, alteplase-treated patients had both higher costs ($2,845) and higher survival (an absolute 1.1% higher rate, or 11 more patients surviving per 1,000 patients treated) compared with streptokinase-treated patients. The incremental cost-effectiveness ratio was $32,678 per year of life saved.32 The cost-effectiveness of alteplase was more favorable in patients with anterior MI but less favorable in those with inferior MI and of young age.

Double-bolus alteplase.

Initial interest in a double-bolus regimen of alteplase came from a series of patients in which two 50-mg boluses of alteplase were administered 30 min apart. TIMI grade 3 flow was achieved in 88% of patients, a considerably higher rate than in previous studies.33In a later randomized trial,34however, double-bolus alteplase resulted in TIMI grade 3 flow in only 58% of patients compared with a 66% rate in patients treated with the accelerated, 90-min infusion of alteplase. Further, the Continuous Infusion vs Double-Bolus Administration of Alteplase (COBALT) trial,35 which compared double-bolus vs accelerated infusion dosing of alteplase, was terminated early because of concern about the safety of the double-bolus regimen. Thirty-day mortality tended to be higher in the double-bolus group than in the accelerated-infusion group (7.98% vs 7.53%), and the upper limit of the 95% CI exceeded the prespecified limit for equivalence (0.4% difference). Thus, based on these criteria, double-bolus alteplase was not equivalent to the infusion regimen. Rates of hemorrhagic stroke in the COBALT trial35 were 1.12% after double-bolus alteplase compared with 0.81% after accelerated infusion of alteplase (p = 0.23). Based on these data, double-bolus alteplase is not recommended for general clinical use, and the accelerated, 90-min infusion remains the current standard dosing for alteplase treatment of acute MI.

Bolus fibrinolytic agents

Following the clinical success of alteplase, a number of mutant tPA agents were developed. The structure and properties of these agents have been detailed in the previous consensus document of fibrinolysis.14

Angiographic trials:

Reteplase was one of the first mutant tPA molecules to undergo extensive clinical testing. Early observations suggested that optimal therapeutic efficacy resulted when reteplase was divided into two boluses (10 U plus 10 U) administered 30 min apart.36This was followed by two angiographic trials comparing alteplase with reteplase. The first, the Reteplase Angiographic Phase II International Dose-Finding (RAPID-1) trial37examined three dosing strategies for reteplase (Table 6 ). These regimens were compared with an infusion of alteplase (100 mg delivered over 3 h). The TIMI grade 3 flow rate at 90 min was 63% with reteplase compared with 49% with alteplase (p < 0.05). A second, larger trial, the Reteplase vs Alteplase Patency Investigation During Myocardial Infarction (RAPID-2), compared the best regimen from RAPID-1 with accelerated alteplase.38 Once again, reteplase was found to be superior to accelerated alteplase. When these two trials were combined, the rate of TIMI grade 3 flow at 90 min was 61% for reteplase (10 U plus 10 U) compared with 45% for the accelerated alteplase regimen (p < 0.01). The 16% absolute increase in TIMI grade 3 rate with reteplase over accelerated alteplase was less than the 24% increase seen with alteplase over streptokinase in the GUSTO-I angiographic substudy, but this smaller difference translated into a much larger difference in mortality in RAPID-1 and RAPID-2 (3.1% for reteplase vs 8.4% for alteplase).

Large-scale comparative trials:

The International Joint Efficacy of Comparison of Thrombolytic (INJECT) study39 examined whether double-bolus reteplase was at least equivalent to streptokinase in reducing mortality (Table 7 ). The 35-day mortality rate with reteplase was 9% compared with 9.5% for streptokinase. The 95% CIs for the absolute mortality difference (0.5%; 95% CI, 1.98 to 0.96) did not extend beyond the preset limit for equivalence of 1% higher mortality rate with reteplase compared with streptokinase. Using these preset limits of equivalence, the finding suggested that reteplase is equivalent to streptokinase and therefore superior to placebo. The results served as the basis for US Food and Drug Administration marketing approval for reteplase.

The GUSTO-III study40 compared double-bolus reteplase with accelerated alteplase. This was a superiority trial to test whether the reported 16% increase in TIMI grade 3 flow with reteplase compared with tPA would translate into improved 30-day mortality. A total of 15,059 patients presenting within 6 h of MI symptom onset were enrolled. The primary end point of 30-day mortality was reached in 7.47% of reteplase-treated patients and in 7.24% of alteplase-treated patients (p = 0.6) [Table 7].,40Therefore, reteplase was not superior to alteplase in this study. The 95% CI for the absolute mortality difference of 0.23% ranged from 1.11% in favor of alteplase to 0.66% in favor of reteplase. Using an absolute risk difference of 1% as a cut-off for equivalence (eg, the INJECT trial criteria), these observations did not provide evidence for equivalence of the two agents, because the 95% CI exceeded the 1% difference in favor of alteplase. However, the mortality rates were similar when patients were categorized into subgroups, including by age, infarct location, and enrolling region. There was an interaction between symptom duration and outcomes with reteplase vs alteplase, which was of borderline significance (p = 0.05). The rates of stroke, bleeding, and ICH did not differ significantly. The lack of superiority of reteplase over alteplase in clinical outcome is consistent with the concept that at least a 20% absolute increase in TIMI grade 3 flow incidence is required to substantially improve mortality in acute MI. The 1-year follow-up data of the GUSTO-III trial has also been published.41 The mortality rate for patients treated with tPA was 11.06% (compared to 11.20% with reteplase [p = 0.77]), ie, an absolute mortality difference of 0.14% (95% CI, − 1.21 to 0.93).

Angiographic trials:

Clinical testing of tenecteplase began in the TIMI-10A trial,42with doses ranging from 5 to 50 mg. The trial showed a greater incidence of TIMI grade 3 flow at 90 min (57 to 64%) in patients receiving 30 to 50 mg of tenecteplase than in those treated with lower doses (p = 0.032). In TIMI-10B,43 a total of 886 patients were randomized to receive either accelerated alteplase or a 5- to 10-s bolus of 30 mg or 50 mg of tenecteplase. The 50-mg dose was discontinued due to increased bleeding and replaced with a 40-mg dose. The 40-mg dose of tenecteplase produced an incidence of TIMI grade 3 flow at 90 min similar to that with alteplase (Fig 1 ); the 30-mg dose produced a significantly lower rate (54.6%, p = 0.04 vs alteplase), and the 50-mg dose produced a rate of 65.8% (p = not significant [NS]).,43 At 60 min, there was no difference in the rates of TIMI grade 3 flow or overall patency.

Concept of weight-adjusted dosing:

Both TIMI-10B and the Assessment of the Safety and Efficacy of a New Thrombolytic Agent (ASSENT)-I study (see below) called for prospectively defined, weight-based analyses of efficacy.4345 The rate of TIMI grade 3 flow was 62% to 63% for doses of tenecteplase of approximately 0.5 mg/kg or higher, but was only 51% to 54% at lower doses (p = 0.028 across quintiles). When dose/weight was stratified into tertiles, the coronary flow was improved in patients who received the higher “weight-corrected” dose.45

Safety results in TIMI-10B:

During the first phase of the trial, that is, prior to the reduction in heparin dosage described below, there were three ICHs among 78 patients (3.8%; 95% CI, 0.8 to 10.8%) treated with the 50-mg tenecteplase dose. Although in the parallel ASSENT-I trial no ICHs occurred at this dose, the 50-mg dose was eliminated from further testing in TIMI-10B and, at the same time, the doses of heparin were reduced. Further analysis showed that the concomitant heparin dose could have played a larger role than that of the tenecteplase dose in defining the rate of ICH.

Initially in TIMI-10B and ASSENT-I, heparin dosing was at the discretion of the treating physicians. However, a protocol amendment mandated that patients receive the following dose of heparin: for patients > 67 kg, a 5,000-U bolus and 1,000 U/h infusion; for patients weighing ≤ 67 kg, a 4,000-U bolus and 800 U/h infusion. The amendment also mandated that the heparin dose be adjusted according to the nomogram beginning with the 6-h activated partial thromboplastin time (aPTT).

The rates of both ICH and serious bleeding were reduced after the protocol amendment, from 2.2 to 0% for the 30-mg tenecteplase dose (p = 0.047), and from 2.8 to 1.2% for alteplase (p = 0.29; overall combined p = 0.04).43 The rates of ICH were similarly and significantly reduced in the overall tenecteplase experience combining the TIMI-10B and ASSENT-I data.46 Severe bleeding also decreased with the reduced heparin dosing, from 3 to 0% for tenecteplase, 30 mg (p = 0.02), and from 8 to 2% for alteplase (p = 0.01; combined p = 0.001). Thus, the subsequent phase III trial, ASSENT-II, used the lower-dose heparin regimen.

The rate of serious bleeding (noncerebral bleeding requiring transfusion) was lower with tenecteplase compared with alteplase in TIMI-10B. For alteplase, 7.0% of patients required transfusion compared with 1.0% of patients treated with 30 mg of tenecteplase (p < 0.001) and 1.3% of those treated with 40 mg of tenecteplase (p < 0.01). Similar low rates were observed in the ASSENT-I trial. Thus, there was early evidence that the very fibrin-specific agent tenecteplase might be associated with lower rates of bleeding than alteplase.

Large-scale comparative trials:

ASSENT-I44 was a randomized trial of three doses of tenecteplase, with its primary goal to determine the rate of ICH with each dose, to assist in determining the appropriate dose for a large, phase III trial. A total of 3,235 patients were randomized to receive 30 mg of tenecteplase (n = 1,705), 40 mg of tenecteplase (n = 1,457), or 50 mg of tenecteplase (n = 73).44 ICH occurred in 0.77% of patients overall: 0.94% in the 30-mgstudy arm and 0.62% in the 40-mg study arm. No strokes were found in the 73 patients treated with 50 mg of tenecteplase. Among patients treated within 6 h of symptom onset, the rates of ICH were 0.56% with 30 mg of tenecteplase and 0.58% with 40 mg of tenecteplase. Death, nonfatal stroke, or severe bleeding complications occurred in low proportions of patients: 6.4%, 7.4%, and 2.8%, in the 30-mg, 40-mg, and 50-mg study arms, respectively.

Tenecteplase was compared with accelerated alteplase in ASSENT-II,47 a large trial of patients with acute ST-segment elevation MI presenting within 6 h of chest pain onset, and mortality as primary outcome. The study enrolled 16,950 patients worldwide. Tenecteplase was administered as a weight-adjusted dose of 0.53 mg/kg in 5-mg increments, ranging from 30 to 50 mg.47

Overall mortality was similar between the two agents: 6.17% for tenecteplase vs 6.15% for alteplase. The relative risk of 30-day mortality was 1.00 for tenecteplase vs alteplase (90% CI, 0.91 to 1.10; p value for equivalence, 0.028). This trial was an “equivalence” trial,48 and under its prospectively defined criteria, tenecteplase was shown to be equivalent to alteplase in reducing mortality across nearly all tested subgroups.

Intriguingly, patients treated > 4 h after symptom onset had improved outcomes when treated with tenecteplase (compared to alteplase). This benefit may relate to the greater fibrin specificity of tenecteplase. The first observation of a benefit due to greater fibrin specificity in patients treated > 4 h came from the TIMI-I trial,4950 in which 90-min patency was similar in patients treated with alteplase, whether treated before or after 4 h of symptoms, but patency was significantly worse in patients who received streptokinase after 4 h rather than before. Similar findings came from an analysis of the German angiographic fibrinolytic trials.5152 The same pattern was seen in the GUSTO-III trial,40 in which patients treated > 4 h after symptom onset had lower mortality with alteplase compared with reteplase, a less fibrin-specific agent. The occlusive clot may be more resistant the longer it has been able to mature, and the greater fibrin specificity of a fibrinolytic agent may enhance the ability to lyse the clot.

Safety observations:

In ASSENT-II, the rates of ICH were nearly identical for tenecteplase and alteplase (0.93% and 0.94%, respectively), as were the overall rates of stroke (1.78% and 1.66%). The group at the highest risk for ICH was elderly female patients weighing ≤ 67 kg, which has been noted in two previous multivariable analyses.5354 It is encouraging that the rate of ICH in this high-risk group was only 1.1% after treatment with tenecteplase, compared with 3.0% for those treated with alteplase (multivariable adjusted odds ratio [OR], 0.30; 95% CI, 0.09 to 0.98; p < 0.05). In all other patients, the ICH rates were similar between the two groups.

The benefits with regard to ICH were accompanied by significantly lower rates of major bleeding. In the trial as a whole,47 the rates of major bleeding were 4.7% for tenecteplase and 5.9% for alteplase (p = 0.0002). Overall bleeding likewise occurred in fewer patients treated with tenecteplase (p = 0.0003). Similarly, the rate of bleeding requiring transfusion was significantly lower with tenecteplase.

In summary, the single-bolus agent tenecteplase showed promise based on the data from the ASSENT-II trial. Mortality with this agent was similar to that with alteplase, and major bleeding was lower which led the US Food and Drug Administration to approve tenecteplase for treatment of acute MI. At 1 year follow-up, the mortality rates for alteplase and tenecteplase were 9.1% and 9.2% respectively (RR, 1.01; 95% CI, 0.91 to 1.12).55 The ASSENT-III and ASSENT-III PLUS clinical trials are discussed in the sections on adjunctive therapy with LMWH and GP IIB/IIIa inhibition.

Rationale for the utilization of bolus thrombolytic agents

Despite the lack of clinical benefit over conventional agents, bolus agents have a number of potential treatment advantages that favor their clinical utilization. These benefits are summarized below.

(1) Ease of treatment:

Utilization of bolus fibrinolytic treatment could aid in more rapid treatment of acute MI, which has been shown to improve survival.13 Reducing the time to treatment, particularly the “door-to-drug” time, has been identified as a critical target by the National Heart Attack Alert Program.56 An increased door-to-drug time has been shown to relate directly to increased mortality. The time from “the decision” to “the start of drug” can be reduced if a simple, bolus fibrinolytic agent is available. The advantage of single-bolus therapy in relationship to compliance was established in ISIS-3,27 in which 95% of patients assigned to anistreplase actually received the drug compared with only 89% and 90% of patients in the alteplase and streptokinase groups, respectively. Further, patients administered double-bolus reteplase therapy received the drug 15 min sooner than did those treated with alteplase infusion in a study by Hilleman and colleagues.57

(2) Prehospital treatment:

Time from symptom onset to initial treatment with fibrinolysis has not improved over the last 2 decades.58In an overview5962 of six randomized trials involving 6434 patients, the utilization of a prehospital thrombolysis resulted in significantly earlier treatment of patients, compared to a conventional in-hospital strategy (104 min vs 162 min; p = 0.007). A significant improvement in in-hospital mortality was also evidenced by this approach (OR, 0.83; 95% CI, 0.70 to 0.98). Although the Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction (CAPTIM) trial did not complete planned enrollment; a prehospital thrombolysis strategy compared favorably to primary angioplasty in this study.63Utilization of bolus fibrinolytic therapy enhances the feasibility of this promising strategy. In the Early Retavase-Thrombolysis in Myocardial Infarction 19 study,64 utilization of prehospital reteplase decreased the time to initial treatment by 32 min (compared to conventional in-hospital administration). As a result 49% of patients received initial therapy within 30 min of health-care contact (compared to only 5% in the classically treated group; p < 0.0001).64Similarly, the combination of tenecteplase and enoxaparin utilized as a prehospital strategy enabled 53% of patients to receive reperfusion therapy within 2 h in the ASSENT-3 PLUS trial (see LMWH section).65

(3) Decrease in medication errors:

The ease of administration with bolus fibrinolytic agents can reduce medication errors. These errors have been associated with adverse outcomes and longer hospital stays in this population.6668 A surprisingly high percentage of medication errors (that is, an incorrect dose or infusion duration) have been documented with traditional bolus followed by infusion alteplase therapy. In GUSTO-I, 12% of the 41,021 patients treated with alteplase or streptokinase infusion had a medication error. The 30-day mortality was significantly higher in patients with a medication error than in those receiving the correct dose (for alteplase, 7.7% vs 5.5%; for streptokinase, 11.3% vs 6.4%; both p < 0.001), but the observation is limited by the difficulty in adjusting for risk factors for adverse events in this population. In the National Registry of Myocardial Infarction, > 71,000 patients who received a dose of alteplase > 1.5 mg/kg had a 2.3-fold increase in ICH, with a multivariate risk ratio of 1.49, suggesting that medication errors with bolus and infusion fibrinolytic therapy may be important.

In the Intravenous NPA for Treatment of Infarcting Myocardium Early (InTIME)-II trial,69 there were more dosing errors in the alteplase group than in the single-bolus lanoteplase group (7.3% vs 5.7%, p < 0.001). As was seen in GUSTO-I, mortality was higher among alteplase-treated patients with medication errors vs those receiving the correct alteplase dose (12.5% vs 5.9%, p < 0.001). Interestingly, the same relationship was not seen for weight-adjusted lanoteplase. ICH also was significantly increased among alteplase-treated patients with medication errors (1.4% vs 0.6% with the correct alteplase dose). For the double-bolus agent reteplase, the rate of medication errors also has been low; only 1% of patients did not receive the full reteplase dose in one study, compared with 4% for alteplase (p = 0.03).

Complications of fibrinolytic therapy
The main complication of fibrinolytic therapy is bleeding, with the most dreaded complication being ICH.

The Fibrinolytic Therapy Trialists’ Collaborative Group3 reported, in their overview of nine trials that randomized 58,600 patients, an excess of 3.9 strokes per 1,000 patients treated with fibrinolysis vs placebo (Table 8 ). The excess stroke risk associated with fibrinolytic therapy largely is attributable to the excess risk of ICH. In the GUSTO-I trial of 41,021 patients, 268 patients had an ICH, of whom 160 patients (59.7%) died by 30 days.,70 Clinical predictors of ICH are shown in Table 9 . Multivariable predictors of mortality after an ICH included Glasgow coma scale score, shorter time from fibrinolytic therapy to stroke onset, total hemorrhage volume, and baseline clinical predictors of overall mortality in this population, of which age of the patient was the most important.

The dosage of adjunctive IV UFH, the measured aPTT level, as well as the timing of aPTT monitoring appear to have a strong relationship with the risk of ICH.46,71 Three trials, TIMI-9, GUSTO-II, and TIMI-10, reduced the initial protocol recommended heparin dosage during the course of the study. The results of these trials indicated a decline in the rate of ICH: TIMI-9B (1.87 to 1.07%), GUSTO-IIB (0.92 to 0.71%), and TIMI-10B (2.8 to 1.16%) (Fig 2 ). Recent trials like ASSENT-3,,95 ASSENT-2,47 and InTIME-269 have all used reduced-dose heparin regimens with bolus fibrinolytic drugs. Timing of the aPTT as well as the intensity appears to influence the risk of ICH. Early trials recommended initial aPTT evaluation at 6 h. In contrast, the In-TIME-2 evaluated heparin dose adjustment with 3-h aPTT monitoring. This resulted in the lowest reported ICH rate of 0.64% observed in any megatrial. When this approach was repeated in the ASSENT-3 trial, this heparin-dosing regimen resulted in 0.94% ICH rate (see section on heparin).

Other bleeding.

The Fibrinolytic Therapy Trialists’ Collaborative Group3 defined major bleeding events as those that were considered life-threatening or required blood transfusion. They reported a 1.1% incidence among patients receiving fibrinolytic therapy compared with 0.4% among those receiving placebo, an increase of 7 major bleeds per 1,000 patients so treated. In the most comprehensive report on noncerebral bleeding after fibrinolytic therapy to date, Berkowitz et al72 defined severe bleeding as that causing substantial hemodynamic compromise requiring intervention, and moderate bleeding as that requiring transfusion but without associated hemodynamic compromise.72Table 10 displays bleeding according to treatment assignment in GUSTO-I. The most common cause of bleeding in GUSTO-I was the use of coronary revascularization procedures. The most powerful multivariable predictors of moderate or severe bleeding in GUSTO-I were advanced age, lighter body weight, and female sex (Table 11 ). These variables remained the most potent predictors of bleeding risk even among patients who did not undergo an in-hospital cardiac procedure. That fibrin specificity is associated with bleeding even after adjustment for the aPTT level is suggested by a greater bleeding risk with streptokinase than with alteplase use. More recently, similar observations have been made with tenecteplase that demonstrated a lower bleeding risk compared with alteplase.

Mortality prediction:

The information from fibrinolytic mortality trials has provided ample opportunity to create outcome models based on patient characteristics. Lee and colleagues have used the GUSTO-I trial to provide insight into the predictors of 30-day mortality among patients being treated with fibrinolytic therapy for acute MI (Table 12 ).73Several patient characteristics (age, Killip class, and infarct location) are associated with higher 30-day mortality. Using the InTIME-II trial (n = 14,114) Morrow and colleagues74developed a weighted integer score based on eight clinical factors assessed at the bedside (Fig 3 ). The TIMI risk score showed a > 40-fold increase in mortality with scores ranging from 0 to > 8. These results were validated using data from the TIMI-9 trial. When applied to fibrinolytic patients in a registry setting (National Registry for Myocardial Infarction [NRMI] 3 database, n = 23,960), the TIMI risk score revealed an increasing mortality with increased score (range, 1.1 to 30%; p < 0.001 for trend). The investigators75 calculated the prognostic discriminatory capacity of the TIMI risk score as the area under the receiver operating characteristic curve for prediction of in-hospital mortality, and obtained a value of 0.79 for patients receiving fibrinolytic therapy.

1.1.1. For patients with ischemic symptoms characteristic of acute MI of ≤ 12 h in duration, and ST elevation or left bundle-branch block (of unknown duration) on ECG, we recommend administration of any approved fibrinolytic agent (Grade 1A).

1.1.2. We recommend the use of streptokinase, anistreplase, alteplase, reteplase, or tenecteplase (all Grade 1A).

1.1.3. For patients with symptom duration ≤ 6 h, we recommend the administration of alteplase or tenecteplase over streptokinase (Grade 1A).

1.1.4. For patients with known allergy or sensitivity to streptokinase, we recommend alteplase, reteplase, or tenecteplase (Grade 1A).

1.1.5. For patients with recurrent acute MI, we suggest clinician do not use repeat administration of streptokinase (Grade 2C).

1.1.6. For patients with ischemic symptoms characteristic of acute MI of ≤ 12 h in duration and 12-lead ECG findings consistent with a true posterior MI, we suggest fibrinolytic therapy (Grade 2C).

1.1.7. For high-risk patients with ongoing symptoms characteristic of acute MI or hemodynamic compromise and duration of 12 to 24 h who have ST elevation or left bundle-branch block, we suggest administration of IV fibrinolytic therapy (Grade 2B).

1.1.8. In health-care settings where prehospital administration of fibrinolytic therapy is feasible and primary angioplasty is not available, we recommend prehospital administration of fibrinolytic therapy only (Grade 1A).

1.1.9. For patients with acute MI who are candidates for fibrinolytic therapy, we recommend administration within 30 minutes of arrival to the hospital or first contact with the health-care system (Grade 1A).

1.1.10. In patients with any history of ICH, closed head trauma, or ischemic stroke within past 3 months, we recommend against administration of fibrinolytic therapy (Grade 1C+).

1.2 Clinical experience with fibrinolytic agents not in current clinical use

In order to try and improve on current fibrinolytic agents, a number of new fibrinolytic agents have been developed from the native tPA molecule by either amino-acid point mutation(s), domain depletion or both, hybridization joining a part of one molecule with that of another, and conjugation of a tPA with monoclonal antibodies (Table 2). In addition, non-human plasminogen activators continue in phase II trials, such as pegylated staphylokinase (from Staphylococcus aureus) and vampire bat salivary tPA. Not all of these innovative molecules are likely to move to either phase III outcome trial assessment or product license in this very competitive field without possessing considerable advantages over currently available bolus fibrinolytics.

2.1 Adjunctive treatment with aspirin

All patients with suspected acute coronary syndrome should be considered for aspirin treatment unless they have documented serious allergic reaction, recent severe GI bleeding or suspected ICH. Treatment should be initiated as early as possible, at the time of initial contact with health-care personnel. The benefits of aspirin in this clinical setting are attributed to its inhibition of cyclooxygenase-dependent platelet activation. The dramatic benefit of aspirin administration was established by the landmark ISIS-2 trial (described above).15 Assignment to 162.5 mg of aspirin in this trial (first dose crushed or chewed) resulted in a treatment effect of 25 early lives saved per 1,000 patients treated. Treatment with aspirin also prevented 10 nonfatal reinfarctions and 3 nonfatal strokes per 1,000 patients treated. These effects of aspirin therapy in the trial were uniformly seen in early and late presenters and therapy should be promptly offered in all patients irrespective of presentation delay. The benefit of initial aspirin therapy was sustained long-term in the ISIS-2 trial. Consequently, treatment with aspirin at a dose of 75 to 162 mg should be continued indefinitely. The Antiplatelet Trialists Collaboration7677 reports 40 further deaths, reinfarctions, or strokes prevented per 1,000 patients in the first few years of sustained treatment.

2.1.1. For patients with acute ST elevation MI whether or not they receive fibrinolytic therapy, we recommend aspirin, 160 to 325 mg po, at initial evaluation by health-care personnel followed by indefinite therapy, 75 to 162 mg/d po (both Grade 1A). See chapter by Harrington et al in this Supplement.

2.2 Adjunctive treatment with clopidogrel

Clopidogrel is a thienopyridine derivative that is a potent platelet inhibitor. There are currently little data to suggest the safety and efficacy of clopidogrel administration with concomitant fibrinolytic therapy. It may be considered as an alternative to aspirin in the patient with a serious aspirin allergic reaction or documented aspirin resistance. The empiric loading dose is 300 mg followed by 75 mg/d po in this clinical setting. Two large randomized clinical trials are currently studying the role of clopidogrel with fibrinolytic treatment. Results of these trials will help define the role of clopidogrel in this setting.

2.2.1. In patients who are allergic to aspirin, we suggest administration of clopidogrel with a loading dose of 300 mg and a maintenance dose of 75 mg/d as an alternative therapy to aspirin (Grade 2C).

2.3 Adjunctive treatment with UFH

The theoretical rationale for adjunctive heparin in the setting of concomitant administration of aspirin is not strongly supported by clinical data. Patient receiving streptokinase, anistreplase, or alteplase in the ISIS-3 and GISSI-2 trials received adjunctive subcutaneous heparin treatment or no heparin at all. Treatment with SC heparin, 12,500 IU, was initiated late after clinical presentation (12 h in GISSI-2 and 4 h in ISIS-3). In ISIS-3, an initial reduction in mortality was observed during the period of treatment but the benefit was no longer evident at one month. This benefit was further tempered by an observed increase in hemorrhagic stroke (one to two per 1,000 treated) and excess bleeding (three to five per 1,000 treated). A combined analysis of the two trials suggested the early prevention of five deaths per 1,000 patients assigned heparin during the treatment period (6% vs 7.3%) but no mortality benefit at 35 days or 6 months. An absolute increase in major or severe bleeding of 3.2 ± 0.7% with heparin therapy was also reported. Patients receiving IV UFH with streptokinase in the GUSTO-I trial had similar clinical outcomes of death and reinfarction as the group receiving SC heparin with streptokinase (36% crossover). A tendency to increased rates of bleeding and hemorrhagic stroke with IV UFH were reported.

The evidence for use of heparin with tPA is stronger. Higher rates of angiographic patency were observed in several series, and a direct relationship between measured aPTT and infarct artery patency was observed with tPa.7880 The superiority of front-loaded tPA with UFH over streptokinase in the GUSTO-I trial led to widespread clinical use of the tPA/UFH. In an overview, the addition of IV heparin to tPA resulted in five fewer deaths, three fewer reinfarctions, and one less pulmonary embolism per 1,000 subjects treated. The large trials with t-PA—GUSTO-I, GUSTO-IIb, TIMI 9B, COBALT, and GUSTO-III—all utilized a 5,000-U bolus of adjunctive heparin followed by 1,000 U/h UFH. Newer tPA derivatives have all been tested in combination with UFH; therefore, information regarding its contributory beneficial effects is not available.

Adjunctive heparin use in the setting of fibrinolytic agents appears to have a narrow therapeutic window. Table 13 shows the risk of ICH for patients receiving fibrin-specific agents in major thrombolytic trials. While the baseline risk of ICH varies between individual studies, there appears to be a consistent association between heparin dosing and risk of ICH. The observed rates of ICH for patients receiving SC heparin with tPA in the International Study was 0.4%. In the GUSTO-I trial,25 IV heparin was used in combination with tPA, and an ICH incidence of 0.72% was observed. Higher rates of heparin infusion as well as a higher target aPTT in the GUSTO-IIA and TIMI 9-A studies resulted in a prohibitive increase in ICH. This increase was even more striking with streptokinase, which was associated with a 3% ICH rate. Heparin dosages were subsequently decreased in the TIMI-9B and GUSTO-II B trials. Heparin utilization in recent trials has been guided by a weight adjusted bolus with a target aPTT of 50–70 s. The use of an early 3-h aPTT in the InTIME-II trial resulted in an observed ICH rate of 0.62%. A 60 U/kg bolus (with a maximum dose of 4,000 U) followed by a maintenance infusion of 12U/kg/h (maximum of 1,000 U/h) is adequate with fibrin-specific agents.81These clinical trials involving UFH have used universal therapeutic aPTT ranges—typically 50 to 70 s—regardless of the responsiveness of the thromboplastin reagent in use at the participating institutions. This responsiveness has been shown to have significant variation, similar to that of prothrombin time reagents but tends to correspond to a 0.2 to 0.5 U/mL anti Xa activity.82

Consensus conferences of The College of American Pathologists,83the American College of Chest Physicians,84and other sources,8587 have recommended against these generalization of therapeutic aPTT ranges. There is wide agreement that therapeutic aPTT ranges should be customized for the specific thromboplastin reagent in use. Since clinical trials have failed to do so, evidence-based recommendations for use of UFH for cardiac indications are difficult to make. Our recommendations are based on the aPTT ranges as they are described in published studies. However, institutions that have established therapeutic aPTT ranges in the recommended fashion are encouraged to continue using them. The implementation of a discrepant universal therapeutic range at such an institution may lead to systematic errors in heparin dosing (see chapter by Hirsh et al in this Supplement).

2.3.1. For patients receiving streptokinase, we suggest administration of either IV UFH, 5,000-U bolus, followed by 1,000 U/h for patients > 80 kg, 800 U/h for < 80 kg with a target aPTT of 50 to 75 s (Grade 2C), or SC UFH (12,500 U/12 h for 48 h) [Grade 2A].

2.3.2. For all patients at high risk of systemic or venous thromboembolism (anterior MI, pump failure, previous embolus, atrial fibrillation, or left ventricular thrombus), we recommend administration of IV UFH while receiving streptokinase (Grade 1C+).

2.3.3. For patients receiving alteplase, tenecteplase, or reteplase for fibrinolysis in acute MI, we recommend administration of weight-adjusted heparin (60 U/kg bolus for a maximum of 4,000 U) followed by 12 U/kg/h (1,000 U/h maximum) adjusted to maintain an aPTT of 50 to 75 s for 48 h (Grade 1C).

2.4 Adjunctive treatment with LMWH

The LMWHs have a number of attractive pharmacologic properties compared with UFH (see chapter by Hirsh et al in this Supplement). LMWHs in the context of thrombolysis have been studied in a number of phase 2 studies8894 and two larger exploratory, randomized trials65,95 of ST-segment elevation MI as adjunctive treatment to fibrinolytic therapy (Table 14 ). Coronary angiographic IRA patency following fibrinolysis has been evaluated in three studies with enoxaparin,9294 and one study with dalteparin89 with improved patency (3% to 16% absolute increase in TIMI-29294 and TIMI-3 flow90) and a tendency toward TIMI-3 flow rates8990,9294 (1% to 17% absolute increase when compared to placebo or UFH). ST-segment elevation resolution, suggestive of IRA patency and myocardial tissue level reperfusion, was demonstrated in one study comparing enoxaparin to placebo, but was similar in two studies comparing enoxaparin to UFH94,96 and in one study comparing dalteparin to UFH.89 Lower rates of IRA reocclusion were seen with enoxaparin compared to placebo,92 with a tendency in the same direction when enoxaparin or dalteparin was compared to UFH.90,93

A reduction in left ventricular thrombus formation and arterial thromboembolism was demonstrated in one study with dalteparin as compared to placebo.88 Composite clinical outcomes (including death, reinfarction, and recurrent ischemia) at 30 days were lower in placebo or UFH comparisons with enoxaparin in phase 2 studies.9192,94 While a reduction in reinfarction was seen during the first 7 days of active treatment with dalteparin in one study,90 an increase in the incidence of MI after cessation of dalteparin treatment was subsequently observed in two studies.8990 In these small studies, major bleeding rates were generally similar in the LMWH and UFH groups; a nonsignificant higher rate was seen with enoxaparin as compared to placebo in one study.

The largest trial comparing LMWH to UFH after fibrinolytic therapy completed to date is the ASSENT-3 trial.95 In this open-label trial, patients were randomly assigned to one of three regimens: full-dose tenecteplase and enoxaparin for up to 7 days (n = 2,040), half-dose tenecteplase with weight-adjusted low-dose UFH and a 12-h infusion of the GP IIb/IIIa inhibitor abciximab (n = 2,017), or full-dose tenecteplase with weight-adjusted UFH for 48 h (n = 2,035). The primary exploratory end points were the composites of 30-day mortality, in-hospital reinfarction, or in-hospital refractory ischemia (efficacy end point), and the above end point plus in-hospital ICH or in-hospital major bleeding complications (efficacy plus safety end point). There were significantly fewer efficacy end points in the enoxaparin and abciximab groups than in the UFH group: 11.4% and 11.1% vs 15.4% (RR, 0.74 [95% CI 0.63 to 0.87], p = 0.0002; and RR, 0.72 [95% CI, 0.61 to 0.84], p < 0.0001, respectively). The same was true for the efficacy plus safety end point: 13.7% and 14.2% vs 17.0% (RR, 0.81 [95% CI, 0.70 to 0.93], p = 0.0037; and RR, 0.84 [95% CI, 0.72 to 0.96], p = 0.014, respectively).

There were no significant differences in 30-day mortality, in-hospital ICH, or major bleeding between the enoxaparin and UFH groups, and the 95% CIs around the point estimates were relatively wide given the intermediate sample size of the ASSENT-3 trial. Further, the selected components of the composite end points that were more favorable with enoxaparin as compared to UFH (in-hospital reinfarction and refractory ischemia) were investigator determined and subject to bias because of the open-label design. The duration of antithrombin therapy also differed between the enoxaparin and UFH groups; however, the reduction in the primary efficacy end point was already evident at the end of the UFH infusion (48 h). One year follow-up results demonstrated similar mortality rates among the enoxaparin, abciximab, and UFH groups: 8.2%, 9.4%, and 7.9% (p = 0.2).

The ASSENT-3 PLUS trial65 evaluated the feasibility, efficacy, and safety of prehospital treatment with either tenecteplase plus enoxaparin or tenecteplase plus UFH. The primary efficacy and efficacy-plus-safety end points were identical to those utilized in the main ASSENT-3 trial. Consistent with ASSENT-3, there was a trend toward a lower rate of the composite of 30-day mortality, in-hospital reinfarction, or in-hospital refractory ischemia in the enoxaparin group (14.2% vs 17.4%, p = 0.08). However, the lower rates of reinfarction (3.6% vs 5.9%, p = 0.028) and refractory ischemia (4.4% vs 6.5%, p = 0.067) were offset by a significantly higher rate of ICH (2.2% vs 0.97%, p = 0.048) and a tendency toward more major bleeding (4% vs 2.8%, p = 0.17). The risk for ICH and major bleeding was mainly confined to patients > 75 years old; whether this is due in part to the prehospital administration of fibrinolysis and the initial nonweight-adjusted bolus of enoxaparin therapy, the generally older and higher-risk population included in the trial with presumably reduced renal function (the dose of enoxaparin was not adjusted for in the analysis) remains uncertain.

In summary, despite the promise of LMWH in the small and intermediate-size trials completed thus far, further study is warranted before this treatment can be routinely administered as an alternative to UFH in fibrinolytic-treated, ST-segment elevation patients. The safety concern of enoxaparin among elderly patients will be addressed in the ongoing Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT)-TIMI 25 trial. This blinded, parallel-group study is randomizing approximately 21,000 fibrinolytic-treated patients to receive either enoxaparin or UFH. Patients > 75 years of age will not receive the IV bolus of enoxaparin and will receive only 75% of the SC injection dose. The primary end point is a 30-day composite of all-cause mortality and nonfatal reinfarction; the results of this trial should be awaited before replacing UFH with LMWH in ST-segment elevation MI.

2.4.1. For patients aged ≤ 75 years with preserved renal function (creatinine levels ≤ 2.5 mg/dL in male and ≤ 2.0 mg/dL in female patients), we suggest use of enoxaparin (30-mg bolus IV followed by 1 mg/kg SC q12h) with tenecteplase up to 7 days (Grade 2B).

2.5 Adjunctive therapy with GP IIb/IIIa receptor blockers

Platelet GP IIb/IIIa receptor antagonists have been shown to be effective and safe in reducing the ischemic complications of percutaneous coronary intervention (PCI) and reducing the composite of death or MI among patients presenting with acute coronary syndromes without ST-segment elevation.9798 The success of these agents in these groups of patients has led to a number of investigations combining GP IIb/IIIa receptor blockers with fibrinolytic therapy. Initial trials99102 were performed with full doses of both agents (Table 15 ). These trials uniformly showed improvement in the angiographic or ECG measures of reperfusion, but concerns were raised about bleeding risks with this combination therapy. This concern led to the design of trials104 evaluating the combination of partial-dose fibrinolytic therapy with GP IIb/IIIa inhibition (Table 16 ). The dose-finding phase of the TIMI-14,104 studied 677 patients within 12 h of ST-segment elevation MI. Subjects studied received partial-dose tPA (20 mg, 35 mg, 50 mg, or 65 mg) with abciximab (0.25 mg/kg bolus followed by 0.125 μg/kg/min infusion for 12 h) or abciximab with streptokinase, 0.5, 0.75, 1.25, or 1.5 million units. Heparin, 60 U/kg bolus, followed by 7 U/kg infusion was also simultaneously administered. The streptokinase study arm was discarded due to unacceptable bleeding risk and a dose-confirmation study104 with 211 patients assigned to front-loaded alteplase, with heparin (70 U/kg bolus and 15 U/kg/h) or tPA 50 mg over 60 min with abciximab in addition to either low-dose heparin (60 U/kg bolus, 7 U/kg/h infusion) or very-low-dose heparin (30 U/kg bolus plus 4 U/kg/h infusion). Combination therapy in TIMI-14 resulted in a historical 76% TIMI-3 flow rate at 90 min compared to the 57% seen with standard alteplase treatment with no difference in the overall major bleeding rate (7%). Similarly, the Strategies for Patency Enhancement in the Emergency Department study103 randomized 304 patients to full-dose abciximab alone or abciximab plus reteplase (5 U, 7.5 U, 10 U, 5 U plus 2.5 U, or 5 U plus 5 U). The preferred combination of reteplase (5 U plus 5 U) with abciximab was then compared to standard dosage (10 U plus 10 U) of reteplase in 224 additional patients. In this angiographic trial, TIMI-3 flow rates at 60 to 90 min with half-dose reteplase and abciximab, standard reteplase, and abciximab alone were 62%, 47%, and 27%, respectively. A incidence of 9.2% of severe bleeding complication occurred with the combination treatment compared to 3.3% and 3.7% with reteplase and abciximab, respectively. The increased patency rates observed with combination therapy generated excitement that treatment with these agents would further decrease mortality and prove superior to conventional fibrinolytic therapy.

GUSTO-V105enrolled 16,588 patients in 20 countries between July 1999 and February 2001 within 6 h of ST-segment elevation MI. Patients were randomized in a 1:1 ratio to receive standard-dose reteplase (10 U plus 10 U, 30-min apart) or a combination of abciximab (0.25 mg/kg bolus, 0.125 μg/kg/min infusion—maximum 10 μg/min) for 12 h with half-dose reteplase (5 U plus 5 U, 30 min apart). Patients receiving conventional fibrinolytic received 5,000-U bolus of heparin followed by 1,000 U/h (800 U/h if < 80 kg), while those receiving combination treatment received 60 U/kg (5,000 U maximum) followed by 7 U/kg/h. The primary end point was 30-day mortality, which was similar in both reteplase- and combination-treated patients (5.9% vs 5.6%; OR, 0.95; 95% CI, 0.83 to 1.08; p = 0.43) [Fig 4 ]. There was no difference in the incidence of nonfatal disabling stroke (0.3% vs 0.2%, p = 0.37) or any stroke (0.9% vs 1.0%, p = 0.55) between the two groups. Patient aged > 75 years receiving combination therapy, however, had a doubling of their ICH risk (1.1% vs 2.1%; OR, 1.91; 95% CI, 0.95 to 3.84; p = 0.069), with a significant interaction of treatment by age (p = 0.033). Rates of reinfarction (3.5% vs 2.3%, p < 0.0001) and recurrent ischemia (12.8% vs 11.3%, p < 0.0001) were significantly reduced with combination therapy; and younger patients aged < 75 years, anterior infarctions, and late presenters (> 4 h) appeared to derive greater benefit from combination therapy in prespecified subset analysis. At 1-year follow-up,106 all-cause mortality remained similar in the reteplase-alone and combination-therapy study arms (8.38% vs 8.38%; hazard ratio, 1.00; 95% CI, 0.90 to 1.11; p > 0.99). The initial 30-day trends for a favorable outcome with combination therapy in patients aged ≤ 75 years, and those with anterior infarction, diabetes, or time to treatment > 4 h were less apparent at 12 months. Although the mortality rate for patients who experienced the reinfarction was remarkably high (22.6% vs 8.0% in patients without reinfarction), the 1.2% absolute reduction in reinfarction with combination therapy over standard therapy at 30 days had little impact on 30-day mortality.

The ASSENT-3 study randomized 6,065 patients within 6 h of ST-segment elevation MI to the following: (1) reperfusion therapy with full-dose tenecteplase plus enoxaparin (30-mg IV bolus followed by 1 mg/kg SC q12h for a maximum of 7 days); (2) a combination of half-dose tenecteplase plus abciximab (0.25 mg/kg bolus and 0.125 μ g/kg per min for 12 h) plus weight-adjusted, low-dose heparin (40 U/kg bolus, 7 U/kg/h with a maximum of 800 U/h); or (3) standard therapy with full-dose tenecteplase with weight-adjusted UFH (60 U/kg bolus capped at 4,000 U followed by 12 U/kg/h—maximum of 1,000 U/h).95 The primary end point was an efficacy end point (composite of 30-day mortality, in-hospital reinfarction, or in-hospital refractory ischemia) and the combination of the primary efficacy plus safety (ICH and major bleeding) [Fig 5 ]. Rates of the primary efficacy end point in the groups receiving enoxaparin, combination abciximab, and standard therapy were 11.4%, 11.1%, and 15.4%, respectively (p = 0.0001). Rates of all stroke (1.49% vs 1.52%) as well as ICH (0.94% vs 0.93%) were similar for combination therapy as compared to standard treatment. Total, major, and minor bleeding were all significantly higher with combination treatment, and once again there was no benefit and a tendency toward harm seen in the elderly. In-hospital reinfarction occurred at lower rates in enoxaparin and combination therapy compared with heparin (2.7%, 2.2%, and 4.2%, respectively; p = 0.0009). Thus, GUSTO-V and ASSENT-3 indicate that abciximab combined with half-dose fibrinolytic has a beneficial effect on the end point of reinfarction, with no impact on short (GUSTO-V and ASSENT-3) or long-term mortality (GUSTO-V). In ASSENT-3, major bleeding with combination therapy in the elderly was dramatically higher than with tenecteplase therapy (13.3% vs 4.1%). As a result, the combination regimen should not be utilized in patients aged > 75 years.

Trials with eptifibatide and half-dose fibrinolytic agents have also been performed. Following a dose-confirmation phase, the Integrilin and Low-Dose Thrombolysis in Myocardial Infarction trial107randomized patients to receive double-bolus eptifibatide, 180/90 μg/kg bolus 30 min apart (infusion, 1.33 μg/kg/min) with 50-mg tPA; eptifibatide, 180/90 μ g/kg bolus 10 min apart (infusion, 2 μg/kg/min) with 50-mg tPA; and standard, full-dose, weight-adjusted tPA. Rates of observed TIMI-3 flow at 60 min for the three groups were 42%, 56%, and 40%, respectively. The median TIMI frame count was significantly lower with combination therapy (38 frames vs 33 frames vs 50 frames, respectively; p = 0.02), with similar rates of major bleeding and ICH. Similarly, the Integrilin and Tenecteplase in Acute Myocardial Infarction phase II angiographic trial108 enrolled 438 patients within 6 h of ST-segment elevation MI. The combination of eptifibatide (180 μg/kg bolus, 2 μ g/kg/min followed by 180 μg/kg bolus 10 min later) with half-dosage tenecteplase (0.27 mg/kg) and UFH (60 U/kg, 7 U/kg/h) was selected after the dose-finding phase. In dose confirmation, this regimen had similar TIMI-3 flow (59% vs 49%, p = 0.15), overall patency (85% vs 77%, p = 0.17), and ST-segment resolution (71% vs 61%, p = 0.08) as standard tenecteplase monotherapy (0.53 mg/kg). The rates of ICH observed were 0.6% with combination therapy and 1.7% with standard therapy. A large, clinically powered trial using eptifibatide with fibrinolytic agents has not yet been performed.

2.5.1. We recommend against the combination of standard-dose abciximab and half-dose reteplase or half-dose tenecteplase with low-dose IV UFH over standard-dose reteplase or tenecteplase (Grade 1B).

2.5.2. We suggest clinicians not use the combination of streptokinase and any GP IIb/IIIa inhibitor (Grade 2B).

2.6 Adjunctive therapy with DTIs

DTIs also have undergone extensive evaluation in conjunction with fibrinolytic therapy. The prototypic agent is hirudin, a 65-amino-acid polypeptide derived from the leech Hirudo medicinalis, which acts as a potent, selective thrombin inhibitor compared with heparin (see chapter by Weitz et al on new anticoagulant agents).109Other DTIs have been tested, including bivalirudin,110112 argatroban,113efegatran,114and inogatran.115Potential advantages of hirudin over heparin are that hirudin can inhibit clot-bound thrombin, it is not inhibited by activated platelets,116 and it does not require a cofactor. Thus, it may provide a more stable anticoagulant response.


A metaanalysis117 of five trials with a cumulative enrollment of 9,947 subjects reported a significant reduction in the end point of recurrent MI with DTI, compared to heparin therapy (2.5% vs 3.4%; OR, 0.75; 95% CI, 0.59 to 0.94). However, overall mortality with adjunctive DTI therapy was 4.1% vs 3.9% with heparin (OR, 1.07; 95% CI, 0.88 to 1.31), and the combined end point of death and recurrent MI was not significantly reduced (6.3% vs 6.9%; OR, 0.91; 95% CI, 0.77 to 1.06).

Individual trials.

Individual trials have not shown a dramatic improvement in clinical outcomes with DTIs as adjuncts to fibrinolytic therapy in acute MI. The effects of desirudin (hirudin) with thrombolysis were tested in the TIMI-5, TIMI-6, and TIMI-9, GUSTO-II, Hirudin for the Improvement of Thrombolysis-3, and Hirudin for the Improvement of Thrombolysis-4 trials.118 Hirudin provided a more stable aPTT, which was within the target range almost twice as often. No episodes of thrombocytopenia were reported for hirudin.

In TIMI-5, a lower rate of reinfarction was observed with hirudin than heparin (4.3% vs 11.9% for heparin, p = 0.03) and a trend toward less reocclusion (1.6% vs 6.7%, p = 0.07). In TIMI-6,118a pilot trial (n = 193), hirudin appeared to be as safe as heparin when administered with streptokinase and aspirin to patients with acute MI. Death and nonfatal reinfarction after 6 weeks tended to be lower in the highest doses of hirudin when compared with the lowest dose (5.7% vs 17.6%), but there was little difference in rates of unsatisfactory outcomes (34.3% vs 37.3%) at hospital discharge (death, congestive heart failure, nonfatal reinfarction). In the phase III, TIMI-9B trial, a similar trend toward less reinfarction was noted during hospitalization (2.3% vs 3.4%, p = 0.07), but there was no difference in the primary end point of death, MI, severe congestive heart failure, or shock at 30 days (12.9% for hirudin vs 11.9% for heparin, p = NS). Similarly, the incidence of death or MI did not differ between the two anticoagulants (9.7% vs 9.5% for heparin, p = NS). Hirudin was tested in > 12,000 patients across the spectrum of acute coronary syndromes in the GUSTO-IIb trial.119 There was significantly less reinfarction with hirudin (5.4% vs 6.3% for heparin, p = 0.04), but only a trend toward reduction in death or MI at 30 days (8.9% vs 9.8%, p = 0.06). In patients with ST-segment elevation MI, the incidence of death or MI was slightly lower with hirudin (9.9% vs 11.3%, p = 0.13). There was an intriguing trend toward a greater benefit of hirudin in patients treated with streptokinase vs alteplase in GUSTO-IIb,119 but this was not observed in TIMI-9B.

In the Hirudin for the Improvement of Thrombolysis-3 trial,120excess ICH was observed with lepirudin, a recombinant hirudin, (3.4% vs 0%). In the Hirudin for the Improvement of Thrombolysis-4 trial,121 which enrolled 1,208 patients and used a lower dose of lepirudin, TIMI flow grade 3 was observed in 40.7% in the lepirudin group and in 33.5% in the heparin group (p = 0.16). No differences were seen between lepirudin and heparin in the rate of hemorrhagic stroke (0.2% vs 0.3%), reinfarction (4.6% vs 5.1%), or mortality (6.8% vs 6.4%) at 30 days. Thus, lepirudin in conjunction with streptokinase did not significantly improve reperfusion or clinical outcomes in this study.

Angiographic trials with other DTIs also have been conducted. In a pilot study and the Hirulog Early Reperfusion/Occlusion (HERO) trial,122 a trend toward greater early (90- to 120-min) TIMI grade 3 flow was observed with the higher dose of bivalirudin compared with heparin in patients receiving streptokinase. Testing with other agents found modest or no improvements compared with heparin.

The superior TIMI grade 3 flow achieved with the combination of streptokinase and bivalirudin in the HERO-1 study led to the design and conduct of the HERO-2 trial,123 which randomized 17,073 patients with ST-segment elevation to adjunctive therapy with heparin vs bivalirudin following initial streptokinase treatment. In this trial,123 bivalirudin did not reduce the primary 30-day mortality end point (10.8% vs 10.9%; OR, 0.99; 95% CI, 0.90 to 1.09; p = 0.85). While the rates of severe bleeding (0.7% vs 0.5%; OR, 1.46; 95% CI, 0.98 to 2.19; p = 0.07) and ICH (0.6% vs 0.4%; OR, 1.48; 95% CI, 0.94 to 2.32; p = 0.09) tended to be higher with the use of bivalirudin, it was associated with a lower rate of reinfarction at 96 h (1.6% vs 2.3%; OR, 0.70; p = 0.001).

DTIs should be utilized as an alternative to heparin in the setting of ST-segment elevation MI when HIT is present or suspected (see chapter by Warkentin et al in this Supplement). Given the greater clinical experience, we advocate the use of bivalirudin with streptokinase and hirudin with tPA and tPA derivatives.

2.6.1. For patients with acute ST elevation MI treated with streptokinase, we suggest clinicians do not use bivalirudin routinely (Grade 2A).

2.6.2. For patients with known or suspected HIT who are receiving fibrinolytic therapy, we recommend administration of hirudin with tPA (Grade 1A) and recommend bivalirudin with streptokinase (Grade 2A).