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Intravenous Thrombolysis in Acute Myocardial Infarction

Correspondence to: E. Magnus Ohman, MD, FCCP, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715; e-mail: ohman001{at}mc.duke.edu

	Introduction

TOP Introduction Brief History of Reperfusion... Pharmacology of Fibrinolytic... Evaluation of Therapeutic... 1. Fibrinolytic Therapy 2. Adjunctive Treatment With... Recommendations References

 
Fibrinolytic therapy for acute myocardial infarction (MI) has been one of the most potent treatments ever developed for a condition that kills more patients worldwide than any other. This review will focus on approved agents and the randomized trials that have led to their widespread use. The use of adjunctive antithrombotic therapies, such as aspirin and heparin, also will be discussed, but a more complete discussion of these therapies is located in other sections of this supplement. A brief overview of new adjunctive therapies, such as platelet glycoprotein (GP) IIb/IIIa inhibitors and direct thrombin inhibitors, will be provided. This section also will explore how therapeutic success can be evaluated, cost-effectiveness analysis, and complications with this therapy. Finally, we will provide a set of recommendations for the use of fibrinolytic therapy in acute MI based on the published literature.

	Brief History of Reperfusion Therapy for Acute MI

TOP Introduction Brief History of Reperfusion... Pharmacology of Fibrinolytic... Evaluation of Therapeutic... 1. Fibrinolytic Therapy 2. Adjunctive Treatment With... Recommendations References

 
The first description of the use of a prolonged infusion of streptokinase for patients with acute MI appeared in 1958.¹ Several smaller studies followed, but they generally showed no clear therapeutic advantage over standard therapy. When these early trials were combined in a meta-analysis² in the mid-1980s, a significant reduction in mortality was revealed. This observation, coupled with early angiographic observations of reperfusion among patients receiving intracoronary streptokinase,³ ushered in the modern era of reperfusion therapy for acute MI. It was soon recognized that intracoronary fibrinolytic therapy could salvage myocardium and that earlier restoration of patency of the infarct-related artery resulted in better preservation of left ventricular function.^{4 5 6} This discovery led to the transition from intracoronary therapy (with its inherent delay in establishing coronary reperfusion) back to IV therapy.

The use of large clinical trials, which focused on mortality and safety profiles through adequate sample sizes, led to worldwide adoption of IV thrombolysis for acute MI.^{7 8 9 10} Observations from these trials made it possible to define the therapeutic windows and risk/benefit ratios for an array of patient subgroups. The importance of therapy that could be administered rapidly and easily to allow earlier treatment also became evident.¹¹ Continued evaluation of mechanistic components of therapy served as an underpinning for the large mortality trials and led to development of adjunctive therapies to enhance reperfusion rates and safety profiles.¹² Although adjunctive therapies such as aspirin and IV heparin have been found to be important to reduce mortality and to maximize therapeutic efficacy, other approaches to these ends, including direct thrombin inhibition and complete platelet pacification by GP IIb/IIIa inhibitors, remain to be realized. The future of reperfusion therapies, for example, should include strategies compatible with primary angioplasty, which has shown improved mortality over IV thrombolysis in a meta-analysis of 10 small trials¹³ but is limited by a lack of widespread availability and expertise.

	Pharmacology of Fibrinolytic Agents

TOP Introduction Brief History of Reperfusion... Pharmacology of Fibrinolytic... Evaluation of Therapeutic... 1. Fibrinolytic Therapy 2. Adjunctive Treatment With... Recommendations References

 
The term thrombolytic agents really is a misnomer when applied to plasminogen activators. All of these agents convert plasminogen to plasmin that then degrades fibrin, a major structure component of the thrombus; thus, the more correct term is fibrinolytic therapy. The agents can be grouped into direct and indirect plasminogen activators (Table 1 ). The relatively nonspecific agents include streptokinase, anistreplase (anisoylated plasminogen streptokinase activator complex), and urokinase. The newer (or second-generation) plasminogen activators include recombinant tissue-type plasminogen activator (rt-PA) (alteplase or duteplase) and several variants of tissue-type plasminogen activator: reteplase (r-PA), tenecteplase (TNK-tPA), and lanoteplase (n-PA).

Anistreplase
Anistreplase is a modified streptokinase molecule, bound to lys-plasminogen to form an activator complex. Because lys-plasminogen has affinity for fibrin, it was hoped that the complex would be more fibrin specific than streptokinase. The modified streptokinase undergoes activation after deacylation, providing a much longer half-life (approximately 100 min) and allowing single-bolus dosing. The antigenicity and side effects profile of anistreplase are similar to those seen with streptokinase.

Urokinase
This naturally occurring plasminogen activator has been used to treat acute MI for > 30 years.² Urokinase is significantly less antigenic than streptokinase, and, unlike streptokinase, urokinase directly activates plasminogen. Despite its years of use, however, it has not been developed as a standard treatment for acute MI. Although urokinase was used extensively for treating peripheral vascular occlusions, production problems have curtailed its availability.

Saruplase (Prourokinase)
This agent, also known as single-chain urokinase-type plasminogen activator (scu-PA), is a single-chain precursor to urokinase that has little intrinsic enzymatic activity. scu-PA has relative fibrin specificity similar to tissue plasminogen activator (t-PA). The amino-acid sequence of scu-PA resembles that of t-PA, and thus this agent has a very short half-life. Scu-PA circulates bound to a specific inhibitor; under this condition, the catalytic activity of scu-PA is inactivated. In the presence of fibrin, the complex between scu-PA and its specific inhibitor is dissociated and thus scu-PA is able to express its fibrinolytic activity.

rt-PAs
rt-PAs are naturally occurring, serine proteases that are physiologically identical to the naturally occurring endogenous plasminogen activator in humans. In its natural state, t-PA is produced by vascular endothelium. Plasminogen activator inhibitors counteract its effect in humans. The rt-PA molecule was cloned by Pennica and colleagues¹⁴ and is produced by recombinant DNA technology. Two forms have been manufactured commercially. Alteplase is predominantly a single-chain rt-PA molecule. In the mid-1980s, manufacturing began for a predominantly two-chain rt-PA molecule, duteplase. Although these drugs never were compared directly in trials, the latter compound was dropped after large trials failed to show its superiority over streptokinase.

As opposed to streptokinase, alteplase is not antigenic and appears not to be associated with allergic reactions. The fibrin specificity of alteplase is considerably greater than that of streptokinase. Nevertheless, alteplase produces mild fibrinogen depletion. Another theoretical advantage of alteplase over streptokinase is its ability to lyse more highly cross-linked fibrin. This theoretical advantage is more of a consideration among patients who have had symptoms for a longer duration.

r-PA
Truncated forms of rt-PA have been developed; the first was r-PA. This is a single-chain deletion mutant that lacks the finger, epidermal growth factor, and Kringle-1 domains (Fig 1 ).¹⁵ This mutation results in a half-life about twice that of native t-PA, permitting double-bolus therapy of 10 U, 30 min apart. The fibrinogen depletion with r-PA is greater than that with alteplase but less than that with streptokinase. Because the finger domain mediates the high-affinity interaction of rt-PA with fibrin, r-PA has lower affinity for fibrin than rt-PA. No antigenicity has been reported with this compound. Its mode of action otherwise is similar to that of naturally occurring t-PA.

View larger version (49K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Structure of t-PA and mutant forms. Reprinted from Brener and Topol15 with permission.

n-PA
n-PA is another deletion mutant of naturally occurring t-PA. It combines deletions of the finger and epidermal growth factor domains with substitution of the asparagine residue at position 117 with a glycine residue to remove the glycosylation site in the first Kringle domain. It has one of the longest half-lives of the mutant t-PA molecules permitting a single bolus administration. Because it lacks the finger domain, it exhibits lower affinity for fibrin than t-PA.

	Evaluation of Therapeutic Success

TOP Introduction Brief History of Reperfusion... Pharmacology of Fibrinolytic... Evaluation of Therapeutic... 1. Fibrinolytic Therapy 2. Adjunctive Treatment With... Recommendations References

 
The completeness and success of reperfusion therapy have been extensively studied, as measured by angiography and ST-segment resolution on the 12-lead ECG. In addition, the therapeutic risk/benefit ratio has been well established in large mortality trials. The field of thrombolysis developed traditionally; that is, the first studies evaluated a new agent vs a placebo or an established treatment, in trials that tested for superiority. After the first large, placebo-controlled trials showed an unequivocal benefit with fibrinolytic therapy, it became unethical to test newer therapies against placebo therapy. Further, agents that may have shown similar efficacy in superiority trials appeared to have other characteristics that could offer a clinical advantage (such as bolus therapy vs infusion). Thus, a different trial method was developed. This statistical approach, called equivalence testing, is based on the assumption that differences between outcomes with two treatments should be less than a certain predetermined value to be considered equivalent. Recent studies suggest that this threshold should be defined as a < 1% absolute difference in mortality or a relative difference of < 14% between the agents. This threshold is based on the half of the benefit on mortality observed with fibrinolytic therapy over placebo in placebo-controlled trials (a 2% absolute difference in mortality)²⁴ and the full benefit observed with alteplase over streptokinase (1% absolute mortality difference).⁹ To establish equivalence, the 95% confidence intervals (CIs) are calculated based on the absolute difference in mortality rates. A new therapy that has an absolute rate and 95% CI within the 1% is deemed to be of equivalent efficacy to an established therapy. This concept will hold true only if a similar safety profile is observed.

To establish equivalence, a number of different statistical approaches have been taken in randomized clinical trials. There appears not to be any consensus on the exact boundaries to accept. However, it should be recognized that the rationale might differ among different clinical trials depending on what the goal is with the intended therapy. In the International Joint Efficacy Comparison of Thrombolytics (INJECT) trial, in which noninferiority with r-PA was tested against streptokinase, a 1% absolute difference (half of the benefit) in mortality was used as the lower boundary (see section on r-PA), the assumption being that streptokinase is associated with a 2% lower mortality against placebo. However, in a study comparing two different ways of administration of t-PA, a much tighter 95% boundary of 0.4% was used, the assumption being that with similar therapies, half of the benefit that was observed with a bolus plus infusion of t-PA over streptokinase (1%) should be maintained. In this particular case, the observed 95% CI extended to 0.49%, suggesting that the modes of administrations of t-PA were not equivalent (see section on alteplase). Another approach has been to use an odds ratio of < 1.5 (less than a relative 50% increase in mortality) compared with streptokinase (see section on scu-PA).

Angiographic Evaluation
Since the mid-1980s, the angiographic assessment of epicardial coronary flow has been critical in the development of new reperfusion strategies, as seen in Tables 2 3 4 .^{25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75} The angiographic substudy of the Global Utilization of Streptokinase and TPA (alteplase) provided the link between Thrombosis in Myocardial Infarction (TIMI) grade 3 flow (normal antegrade flow) and 30-day survival; Simes and colleagues⁷⁶ showed that the superior survival with alteplase vs streptokinase resulted from the superior epicardial blood flow provided by alteplase. In the 1990s, Gibson and colleagues⁷⁷ moved us beyond a fixation on epicardial coronary flow with the development of concepts such as the corrected TIMI frame count and the myocardial perfusion blush score, which take into consideration both epicardial and microvascular flow. As the field moves toward combining fibrinolytic therapy with antiplatelet therapy, the notion of improved myocardial perfusion through improvement in microcirculatory flow has become an important tenet of reperfusion investigation.

Braunwald and others^78a championed the use of the 12-lead ECG as a way to quantify left ventricular dysfunction after MI. It was not until the mid-1990s, however, that Schroder and colleagues⁷⁹ more completely characterized ST-segment resolution and its relationship to clinical outcomes. Data from five recent randomized trials of almost 6,000 patients, outlining the relationship between ST-segment resolution after fibrinolytic therapy and 30-day mortality, are shown in Table 5 .^{79 80 81 82} Clearly, there is a linear relationship between the degree of ST-segment resolution and later mortality that is highly statistically significant and very relevant clinically, as this is an easily employed bedside technique. Observations from primary angioplasty experiences have confirmed the value of the static ECG as a tool to predict clinical outcomes after reperfusion. While rapid early resolution of ST-segment elevation is better than later resolution, the optimal timing of static ECG tracings is unknown. Furthermore, the ECG undoubtedly provides important information about tissue perfusion and not just epicardial coronary flow; however, how best to incorporate serial tracings into the acute evaluation of these patients requires further investigation.

Mortality and Intracranial Hemorrhage End Points
The large amount of information available from fibrinolytic mortality trials has provided ample opportunity to create outcome models based on patient characteristics. Lee and colleagues⁸⁴ have used the GUSTO-1 trial to provide insight into the predictors of 30-day mortality among patients being treated with fibrinolytic therapy for acute MI (Table 6 ). Certain patient characteristics (age, Killip class, and infarct location) are associated with much higher 30-day mortality.

	1. Fibrinolytic Therapy

TOP Introduction Brief History of Reperfusion... Pharmacology of Fibrinolytic... Evaluation of Therapeutic... 1. Fibrinolytic Therapy 2. Adjunctive Treatment With... Recommendations References

Several trials^{25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42} have reported patency of the infarct-related artery at different time points among patients not receiving fibrinolytic therapy (Table 2) . Most patients did receive aspirin and heparin, although aspirin was not standard therapy for acute MI until the International Study of Infarct Survival (ISIS)-2 trial¹⁰ results were published in 1988.

Several angiographic trials also were undertaken to explore the patency and recanalization rates with IV streptokinase. The first trials explored rates of recanalization. In those studies, patients underwent urgent angiography. If the vessel was occluded (TIMI grade 0 or 1 flow), IV fibrinolytic therapy was given and the rate of opening was established. The delays inherent in this approach, however, suggested adverse effects on left ventricular function, as described. Thus patency trials were developed, wherein patients with acute MI were given fibrinolytic therapy as soon as possible and then underwent angiography, where patency (defined as TIMI grade 2 or 3 flow) was examined. The results for both patency and recanalization trials of streptokinase are shown in Table 3 .^{26 30 34 37 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59} Overall, the angiographic data suggest patency rates with streptokinase of approximately 44% at 60 min and 48% at 90 min. Approximately 2 to 3 h after beginning therapy, patency rates were 72%, achieving a rate of between 75% and 85% at 24 h to 21 days after therapy from a pooled meta-analysis.⁴² These rates are substantially higher than those of control patients (Fig 2 )⁴² but less than those with accelerated alteplase and similar to those with anistreplase or alteplase given > 3 h.

View larger version (23K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Patency rates (TIMI grade 2 or 3 flow) in patients treated with streptokinase, accelerated alteplase, standard-dose alteplase, or anistreplase for acute MI, vs control subjects. Adapted from Granger et al,42 with permission.

A smaller, South American trial (Estudio Multicentrico Estreptoquinasa Republicas de America del Sur)⁹² also was a double-blind, placebo-controlled trial of streptokinase. This study 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 in the 3,568 patients enrolled between 6 h and 24 h (11.2% for streptokinase vs 11.8% for placebo).

Consistent across these trials was that the treatment benefit observed in the first 21 to 42 days was maintained up to 1 year. The Fibrinolytic Therapy Trialists’ Collaborative Group (FTT) combined these and other trials in a meta-analysis.²⁴ The overall benefit was observed among patients with ST-segment elevation or bundle-branch block irrespective of age, sex, BP, heart rate, prior MI, or diabetic status. Furthermore, the treatment benefit was greater the earlier that treatment began. For patients treated within 6 h, the absolute reduction in mortality was 30 lives saved for 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. 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 that occurred within 2 days. Approximately 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 overview thus suggested a treatment benefit for most patients who present with acute MI within 12 h of symptom duration.

Trials of Alteplase
After two small series of patients had been treated with alteplase,^{93 94} the first comparative trial was conducted between alteplase and streptokinase. In the TIMI-1 trial,⁹⁵ 290 patients with acute MI underwent diagnostic coronary angiography and then were treated with either streptokinase or alteplase, in addition to IV heparin. The primary end point, reperfusion of an initially occluded coronary artery after 90 min, was achieved in 62% of alteplase-treated patients compared with 31% of streptokinase-treated patients (p < 0.001; Fig 3 ).^{22 26 95} The patency rate at 90 min, independent of findings on the baseline angiogram, was 70% for alteplase vs 43% for streptokinase (p < 0.001). The European Study Group reported nearly identical results.⁴⁴ Alteplase was then studied in numerous angiographic trials,^{26 31 32 35 36 38 40 42 44 53 54 55 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75} as reviewed by Granger and colleagues (Table 4) .⁹⁶ 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.⁹⁶ Neuhaus and colleagues⁹⁷ developed 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,⁶¹ anistreplase treatment,^{98 99} or streptokinase treatment.¹²

View larger version (37K): [in this window] [in a new window] [Download PPT slide]   Figure 3.. Incidence of TIMI grade 2 or 3 flow 90 min after TNK-tPA or accelerated alteplase treatment in the TIMI-10B trial. Reprinted from Cannon et al,22 with permission.

A total of 41,021 patients were enrolled in GUSTO-1, of which the primary end point was 30-day mortality (Table 10 ).^{9 12} Mortality at 30 days was significantly lower in the accelerated alteplase arm compared with each of the three other arms.⁹ 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 also were reduced in patients treated with alteplase, including less cardiogenic shock, congestive heart failure, and ventricular arrhythmias.

Despite the aggressive regimens of thrombolysis, aspirin, and heparin, intracranial hemorrhage occurred only rarely in GUSTO-1. For each of the streptokinase arms, 0.5% of patients suffered an intracranial hemorrhage compared with 0.7% of patients treated with accelerated alteplase and 0.9% of patients treated with combination fibrinolytic therapy.⁹ To put the results in full perspective, the GUSTO-1 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 benefits of the various fibrinolytic regimens, an angiographic substudy was carried out.¹² Over 2,400 patients were randomized to undergo angiography at 90 min, 180 min, 24 h, or 5 days. At the important, 90-min time point, the alteplase-treated patients had a significantly higher patency rate and a much higher rate of TIMI grade 3 flow, which, as noted above, is associated with the best outcomes (Table 10) .^{9 12} At the other three time points, there were no significant differences among the four fibrinolytic regimens. Thus the benefit of accelerated alteplase was associated with early opening of the infarct-related artery. 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.^{76 102}

TIMI-4: The TIMI-4 trial⁹⁹ was a double-blind trial 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.⁹⁹ 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 double-blind trial confirmed the results found in the GUSTO-1 trial.

The benefits of accelerated alteplase seen in theGUSTO-1 and TIMI-4 trials 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 regimen⁴² 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, subcutaneous heparin, which does not elevate the APTT level until approximately 24 h after the start of treatment. Reocclusion of an open infarct-related artery, which is associated with a threefold increase in mortality, occurs most often during this period. Thus, a subcutaneous heparin regimen cannot prevent this important predictor of poor outcomes.^{103 104}

The benefits of accelerated alteplase and IV heparin, then, are based on the ability to achieve rapid, sustained infarct-artery patency after acute MI. This link between early reperfusion, especially achievement of TIMI grade 3 flow, and improved survival was established in theGUSTO-1 angiographic substudy.^{12 76} Thus, if newer regimens, such as fibrinolytic therapy plus platelet GP IIb/IIIa inhibition,^{105 106} can further improve early reperfusion, further reductions in mortality can be expected.

Double-Bolus Alteplase: Initial interest in a double-bolus regimen of alteplase came from a series of patients to whom two 50-mg boluses of alteplase were given 30 min apart. TIMI grade 3 flow was achieved in 88% of patients, a considerably higher rate than in previous studies.¹⁰⁷ In a later randomized trial,¹⁰⁸ however, 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 trial,¹⁰⁹ 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%). Statistically, double-bolus alteplase was not equivalent to the infusion regimen. Rates of hemorrhagic stroke were 1.12% after double-bolus alteplase compared with 0.81% after accelerated infusion of alteplase (p = 0.23).¹⁰⁹ 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.

Cost-Effectiveness of Alteplase: A formal cost-effectiveness analysis was incorporated into the GUSTO-1 protocol as a substudy to be carried out in the United States and Canada.¹¹⁰ 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.¹¹⁰ The use of alteplase in patients with anterior MI yielded even more favorable cost-effectiveness values but less in inferior infarction and young patients. Thus, the cost-effectiveness of alteplase compared with streptokinase compares favorably with that of other therapies, such as hemodialysis for end-stage renal disease ($35,000 to $50,000 per year of life saved).

Potential Advantages of Bolus Fibrinolytic Agents
Administration of fibrinolytic agents as a bolus has several potential advantages. First, its ease of administration could aid in more rapid treatment of acute MI, which has been shown to improve survival.^{8 111} 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.¹¹² An increased door-to-drug time has recently been shown to relate directly to increased mortality.¹¹³ 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, in that 95% of patients assigned to anistreplase treatment actually received the drug compared with only 89% and 90% of patients in the alteplase and streptokinase groups, respectively.¹⁰¹ Further, in a study by Hilleman and Seyedrondbari,¹¹⁴ patients given double-bolus r-PA therapy received the drug 15 min sooner than did those treated with alteplase infusion.

Second, bolus fibrinolytic may make more feasible the promising strategy of prehospital therapy.^{115 116 117} In an overview of all trials, a 19% reduction in mortality with prehospital treatment compared with standard, hospital-based treatment was observed.¹¹⁵ In a single study,¹¹⁷ using bolus anistreplase treatment, mortality was reduced by > 50% when given before patients arrived at the hospital.

Another potential advantage of bolus fibrinolytic is fewer medication errors, which are associated with adverse outcomes and longer hospital stays in this population.^{118 119 120} With the bolus-plus-infusion regimen for alteplase, for example, there is a surprisingly high percentage of patients with medication errors (an incorrect dose or infusion duration). In GUSTO-1, 12% of the 41,021 patients treated with alteplase or streptokinase infusion had a medication error, although the 30-day mortality was significantly higher in patients with a medication error than in those given the correct dose (for alteplase, 7.7% vs 5.5%; for streptokinase, 11.3% vs 6.4%; both p < 0.001). This observation is limited by the difficulty in adjusting for risk factors for adverse events in this population.¹²¹ In the National Registry of Myocardial Infarction involving > 71,000 patients, patients who received a dose of alteplase > 1.5 mg/kg had a 2.3-fold increase in intracranial hemorrhage, with a multivariate risk ratio of 1.49, suggesting that medication errors with bolus and infusion fibrinolytic therapy may be important.⁸⁸

In the Intravenous n-PA for Treatment of Infarcting Myocardium Early (InTIME)-II trial,¹²² there were more dosing errors in the alteplase group than in the single-bolus n-PA group (7.3% vs 5.7%; p < 0.001). As was seen in GUSTO-1, 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 n-PA. Intracranial hemorrhage also was significantly increased among alteplase-treated patients with medication errors (1.4% vs 0.6% with the correct alteplase dose).¹²² For the double-bolus agent r-PA, the rate of medication errors also has been low; only 1% of patients did not receive the full r-PA dose in one study compared with 4% for alteplase (p = 0.03).¹¹⁴

In summary, these data from several large trials show that (1) bolus fibrinolytic therapy can reduce the rate of medication errors, and (2) medication errors may be associated with increased rates of both mortality and intracranial hemorrhage.

Trials of r-PA
r-PA was one of the first mutant t-PA molecules to undergo extensive clinical testing. Early observations suggested that optimal therapeutic efficacy resulted when r-PA was divided into two boluses (10 U + 10 U) given 30 min apart.¹²³ This was followed by two angiographic trials comparing alteplase with r-PA. The first, the Reteplase Angiographic Phase II International Dose-finding (RAPID)-1 trial, examined three dosing strategies for r-PA (Table 11 ).¹²⁴ These were compared with an infusion of alteplase (100 mg delivered > 3 h). The TIMI grade 3 flow rate at 90 min was 63% with r-PA compared with 49% with alteplase (p < 0.05). A second, larger trial (RAPID-2) compared the best regimen from RAPID-1 with accelerated alteplase.¹²⁵ Once again, r-PA 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 r-PA (10 U + 10 U) compared with 45% for the accelerated alteplase regimen (p < 0.01). The 16% absolute increase in TIMI grade 3 rate with r-PA over accelerated alteplase was less than the 24% increase seen with alteplase over streptokinase in the GUSTO-1 angiographic substudy, but this smaller difference translated into a much larger difference in mortality in the RAPID trials (3.1% for r-PA vs 8.4% for alteplase) in the two RAPID trials.

Trials of TNK-tPA
Clinical testing of TNK-tPA began in the TIMI-10A trial,¹⁶ with 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 given 30 to 50 mg of TNK-tPA than those treated with lower doses (p = 0.032). In TIMI-10B,²² a total of 886 patients were randomized to receive either accelerated alteplase or a 5-s to 10-s bolus of 30 mg or 50 mg of TNK-tPA. The 50-mg dose was discontinued because of increased bleeding and replaced with a 40-mg dose. The 40-mg dose of TNK-tPA produced an incidence of TIMI grade 3 flow at 90 min similar to that with alteplase (Fig 4 )¹²⁷ ; 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]).²² The rate of TIMI grade 2 or 3 flow and TIMI frame counts at 90 min were similar between TNK-tPA and alteplase. At 60 min, there was no difference in the rates of TIMI grade 3 flow or overall patency.

View larger version (33K): [in this window] [in a new window] [Download PPT slide]   Figure 4.. Dosing schedule of weight-adjusted TNK-tPA used in the ASSENT-2 trial. Reprinted with permission from Lancet.127

Safety Results in TIMI-10B: During the first phase of the trial (that is, before the reduction in heparin dosage described below), there were three intracranial hemorrhages among 78 patients (3.8%; 95% CI, 0.8 to 10.8%) treated with the 50-mg dose of TNK-tPA. In the parallel ASSENT-I trial, however, no intracranial hemorrhages occurred at this dose. This dose was dropped 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 TNK-tPA dose in defining the rate of intracranial hemorrhage.

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 after 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 APTT.

The rates of both intracranial hemorrhage and serious bleeding were lower after the protocol amendment, from 2.2 to 0% for the 30-mg dose of TNK-tPA (p = 0.047), and from 2.8 to 1.2% for alteplase (p = 0.29; overall combined p = 0.04).²² The rates of intracranial hemorrhage were similarly and significantly reduced in the overall TNK-tPA experience, combining the TIMI-10B and ASSENT-1 data.¹³⁰ Severe bleeding also decreased with the reduced heparin dosing, from 3 to 0% for the 30-mg dose of TNK-tPA (p = 0.02), and from 8 to 2% for alteplase (p = 0.01; combined, p = 0.001).²² Thus, the subsequent phase-III trial, ASSENT-2, used the lower-dose heparin regimen.

The rate of serious bleeding (noncerebral bleeding requiring transfusion) was lower with TNK-tPA 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 TNK-tPA (p < 0.001) and 1.3% of those treated with 40 mg of TNK-tPA (p < 0.01).¹³¹ Similar low rates were observed in the ASSENT-1 trial.¹³¹ Thus, there was early evidence that the very fibrin-specific agent TNK-tPA might be associated with lower rates of bleeding than alteplase.

ASSENT-I: ASSENT-I was a randomized trial of three doses of TNK-tPA, with its primary goal to determine the rate of intracranial hemorrhage 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 TNK-tPA (n = 1,705), 40 mg of TNK-tPA (n = 1,457), or 50 mg of TNK-tPA (n = 73).¹²⁸ As noted above, the 50-mg dose was discontinued and replaced by 40 mg because of increased bleeding observed in the TIMI-10B study. Intracranial hemorrhage occurred in 0.77% of patients overall: 0.94% in the 30-mg arm and 0.62% in the 40-mg arm. No strokes were found in the 73 patients treated with 50 mg of TNK-tPA. Among patients treated within 6 h of symptom onset, the rates of intracranial hemorrhage were 0.56% with 30 mg of TNK-tPA and 0.58% with 40 mg of TNK-tPA. 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 arms, respectively.

ASSENT-2: TNK-tPA was compared with accelerated alteplase in this large equivalence mortality trial of patients with acute ST-segment elevation MI presenting within 6 h of the onset of chest pain. The study enrolled 16,950 patients worldwide. TNK-tPA was given as a weight-adjusted dose of 0.53 mg/kg given in 5-mg increments, ranging from 30 to 50 mg.¹²⁷

Overall mortality essentially was identical between the two agents: 6.17% for TNK-tPA vs 6.15% for alteplase. This trial was an "equivalence" trial,¹³² and under its prospectively defined criteria, TNK-tPA was shown to be equivalent to alteplase. The relative risk of 30-day mortality was 1.00 for TNK-tPA vs alteplase (90% CI, 0.91 to 1.10; p value for equivalence = 0.028). The equivalence of the agents in reducing mortality was shown in nearly every subgroup tested.

Intriguingly, patients treated > 4 h after symptom onset had improved outcomes compared with such patients treated with alteplase. This benefit may relate to the greater fibrin specificity of TNK-tPA. The first observation of a benefit of greater fibrin specificity in patients treated > 4 h came from the TIMI-1 trial, in that 90-min patency was preserved 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.^{26 95} Similar findings were seen in an analysis of German angiographic fibrinolytic trials.^{133 134} The same pattern favoring the more fibrin-specific agent was seen in the GUSTO-III trial, in that patients treated > 4 h after symptom onset had significantly lower mortality with alteplase compared with r-PA, a less fibrin-specific agent.¹²⁶ 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 its ability to lyse the clot.

Safety Observations: In ASSENT-2, the rates of intracranial hemorrhage were nearly identical for TNK-tPA and alteplase (0.93% and 0.94%, respectively), as were the overall rates of stroke (1.78% and 1.66%).¹²⁷ Of note, patients aged > 75 years showed a trend toward reduced intracranial hemorrhage with TNK-tPA vs alteplase treatment (1.7% vs 2.6%). The group at the highest risk for intracranial hemorrhage was elderly female patients weighing 67 kg,¹³⁵ which has been noted in two previous multivariable analyses.^{88 136} It is encouraging that the rate of intracranial hemorrhage in this high-risk group was only 1.1% after treatment with TNK-tPA compared with 3.0% for those treated with alteplase (multivariate adjusted odds ratio, 0.30; 95% CI, 0.09 to 0.98; p < 0.05).¹³⁵ In all other patients, the intracranial hemorrhage rates were similar between the two groups.

These benefits with regard to intracranial hemorrhage were paralleled by significantly lower rates of major bleeding. In the trial as a whole, the rates of major bleeding were 4.7% for TNK-tPA and 5.9% for alteplase (p = 0.0002).¹²⁷ Overall bleeding likewise occurred in fewer patients treated with TNK-tPA (p = 0.0003).^{127 135} Similarly, the rate of bleeding requiring transfusion was significantly lower with TNK-tPA.

In summary, the single-bolus agent TNK-tPA shows promise based on the data from the ASSENT-2 trial. Mortality with this agent is similar to that with alteplase, and major bleeding is lower. The US Food and Drug Administration recently approved TNK-tPA for use.

Other Fibrinolytic Agents
A number of other fibrinolytic agents have been tested in humans. The agents described in this section are generally not approved for use or are in limited use around the world. However, some of these agents have been extensively tested and some are currently being evaluated.

Urokinase: This agent was one of the first tested fibrinolytic agents in humans. Despite this, it has undergone relatively sparse clinical trials evaluation. A number of smaller angiographic trials were carried out in the 1980s.^{65 70 137 138} These collectively showed angiographic patency and TIMI grade 3 flow rates that in general were superior to streptokinase and similar to those observed with t-PA, particularly when the higher dose of 3 million units was used. Urokinase was tested in a trial of 2,201 patients with a dose of 2 million units of urokinase plus heparin against heparin alone.¹³⁹ At 16 days, the mortality was 8% in the urokinase plus heparin group and 8.3% in the heparin-alone group. This agent therefore offers little clinical advantage over existing agents and is predominantly used for peripheral vascular thrombotic occlusions.

scu-PA: scu-PA is a naturally occurring protein that is produced through recombinant DNA technology. It has a Kringle domain that is homologous to plasminogen and naturally occurring t-PA that makes it relatively fibrin specific. Limited hydrolysis by plasmin converts the molecule to a two-chain urokinase-type plasminogen activator. This agent has undergone limited clinical testing. In an initial angiographic trial, scu-PA was associated with a higher patency rate compared with streptokinase alone (72% vs 48%; p < 0.001) at 60 min after initiation of therapy.⁴³ The effect was only modest at the 90-min angiography (71% vs 64%). An angiographic trial comparing it against 3 h of t-PA was also carried out in 473 patients with acute MI.¹⁴⁰ At 60 min, the patency rates were similar with either regimen (scu-PA, 80%; t-PA, 75%). This was followed by a randomized equivalence trial.¹⁴¹ A total of 3,089 patients were randomized to treatment with either 80 mg of scu-PA or 1.5 million units of streptokinase with IV heparin in both groups.¹⁴² The 30-day mortality rates were 5.7% for scu-PA and 6.7% for streptokinase (absolute difference, 1.01%; 95% CI, - 2.78% to 0.75%). The CIs do not extend to 1%; therefore, a placebo response can be excluded. However, there was a significant higher rate of intracranial hemorrhage with scu-PA (0.9%) compared with streptokinase (0.3%; p = 0.038), calling into question the validity in calling scu-PA equivalent to streptokinase.¹⁴²

n-PA: This is a single-bolus agent that has undergone extensive testing. It is a modified t-PA molecule that has had the fibronectin finger-like and the epidermal growth factor domains deleted. In addition, a point mutation at site 117 has been used. These changes have led to a substantial longer half-life compared with other agents.¹⁴³ It was initially tested in an angiographic trial¹⁴⁴ with doses ranging from 15 to 120 KU/kg in 602 patients with MI. At the highest dose, the patency rate was higher with n-PA compared with accelerated t-PA (83% vs 71%; p < 0.05). There was a trend toward higher TIMI grade 3 flow rates (57% vs 46%, respectively). n-PA was also tested in a large phase-III randomized equivalence trial.¹⁴⁴ A total of 15,078 patients were treated with n-PA using the 120-KU/kg dose vs accelerated t-PA. Overall 30-day mortality was similar between the two agents (n-PA, 6.7% vs t-PA, 6.6%; p < 0.05 for equivalence). However, intracranial hemorrhage was significantly higher with n-PA compared with t-PA (1.13% vs 0.62%; p < 0.003). This agent is not being developed for commercial use.

Staphylokinase: Recombinant staphylokinase is a 136 amino acid single chain that activates plasminogen to plasmin with high fibrin specificity, which has undergone limited testing in humans.¹⁴⁵ In a randomized angiographic trial,¹⁴⁶ 48 patients were allocated to staphylokinase (double bolus of either 10 mg or 20 mg) and had a TIMI grade 3 flow rate of 62% compared with 58% for 52 patients given t-PA. The highest dose (20 mg) had the highest TIMI grade 3 rate (74%). In a further study of 82 patients, a bolus and infusion were tested (15 mg, 30 mg, or 45 mg). The 90-min TIMI grade 3 flow rates showed no evidence of a dose response, with rates from 62% with the lowest dose to 63% with the highest dose.¹⁴⁷

Complications of IV Fibrinolytic Therapy
The main complication of fibrinolytic therapy is bleeding, with the most severe bleeding complication being intracranial hemorrhage. The FTT 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 13 ).²⁴ The excess stroke risk associated with fibrinolytic therapy largely is attributable to the excess risk of intracranial hemorrhage that occurs in the first day after such treatment. In the GUSTO-1 trial of 41,021 patients, 268 patients suffered an intracranial hemorrhage, of whom 160 patients (59.7%) died by 30 days.^{89 148} Clinical predictors of intracranial hemorrhage are shown in Table 7 .⁸⁹ Multivariable predictors of mortality after an intracranial hemorrhage included Glasgow coma scale score, shorter time from fibrinolytic therapy to stroke onset, and total hemorrhage volume,¹⁴⁸ baseline clinical predictors of overall mortality in this population,⁸⁴ of that age of the patient was the most important.

	2. Adjunctive Treatment With Direct Thrombin Inhibitors

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