Introduction
A ST-segment myocardial infarction (STEMI) is caused by the occlusion of a major epicardial coronary artery and is generally triggered by rupture of a vulnerable plaque, with subsequent formation of an occlusive thrombus. Rapid restoration of coronary blood flow is essential in preventing myocardial necrosis, and early reperfusion of the infarct-related artery limits infarct size and improves outcome (see also Chapter 13 ). Therefore, achieving the shortest possible delay between symptom onset and reperfusion is one of the most critical factors in the management of STEMI (see Chapter 5 ). Effective reperfusion of the infarct-related artery can be achieved by mechanical reperfusion, using primary percutaneous coronary intervention (PCI) (see Chapter 17 ) or by pharmacological reperfusion using fibrinolytic agents. Unfortunately, only a minority of hospitals worldwide have immediate access to a catheterization facility. Moreover, hospitals with a catheterization laboratory often do not offer primary PCI during nonoffice hours. In contrast, fibrinolysis is universally available without the need for advanced logistics ( Table 15-1 ). Thus, despite the impressive benefit and increasing use of primary PCI (see Figure 13-4 ), fibrinolysis remains the only option for reperfusion for many STEMI patients worldwide. In the past few decades, remarkable progress has been made in improving fibrinolytic therapies, in identifying patients who benefit from this treatment, and in identifying patients at risk of bleeding. In addition, in the past several years, studies have provided answers on to how to fit fibrinolytic therapy into contemporary hospital networks, especially when and how to plan angiography and PCI in successfully reperfused patients after fibrinolysis (see Chapter 14 ).
| Fibrinolysis | Primary PCI |
|---|---|
| Advantages | |
| Universally available | More efficient reperfusion and better outcome |
| Independent of physician’s experience and can be used by trained paramedics | Less risk of reinfarction or residual ischemia |
| Can be administered in prehospital setting or community hospitals | Less risk of systemic and intracranial hemorrhage |
| Disadvantages | |
| Higher risk of systemic and intracranial bleeding | Dependent of experience of team and on availability of 24/7 facilities |
| Reperfusion in 60% of patients | PCI-related time delays can be long |
| Not efficient in patients presenting late | |
A Brief Historical Overview
Sudden thrombotic occlusion of an epicardial coronary artery was identified as the trigger for MI by James Herrick as early as 1912, but this pathophysiological mechanism was largely ignored in subsequent decades. In a postmortem study in the 1960s of 176 “fresh” infarctions, Kagan and colleagues found evidence of a thrombotic coronary occlusion in only 87 patients, versus a “nonthrombotic” occlusion in an additional 43 patients. Interest in thrombolysis for MI did not accelerate until more than a decade later in 1980, after DeWood and colleagues provided strong angiographic evidence of a total occlusion in STEMI patients who presented early after onset of symptoms.
Pharmacological reperfusion for patients with an MI was investigated as early as the 1950s by Fletcher and colleagues. In the 1960s and 1970s, several studies of intravenous and intracoronary thrombolytic therapy showed conflicting results, mainly because of small sample sizes, and different treatment protocols and endpoint analyses. In addition, bleeding risk was often deemed to be unacceptably high. Nevertheless, a pivotal European trial in 1971, coordinated by Verstraete (n = 764), demonstrated a significant benefit of intravenous streptokinase versus heparin with respect to in-hospital mortality (18.5% vs. 26.3%; P = .011) in STEMI patients. In 1981, a pilot trial by Markis and colleagues with nine patients treated with an intracoronary infusion of streptokinase showed that local lytic therapy had the potential of salvaging jeopardized myocardium, especially in early presenters. Another trial, the Western Washington study (n = 250), also demonstrated an almost threefold reduction in 30-day mortality among patients treated with intracoronary streptokinase, a benefit that persisted at 1-year follow-up. Because of the logistic challenges associated with intracoronary administration and the lack of a perceived benefit of intracoronary versus systemic administration, later studies used simpler intravenous dosing schemes. A meta-analysis from 1985 that included 33 trials confirmed a significant beneficial effect of thrombolytic agents on outcome. The era of fibrinolysis in STEMI had finally dawned. In 1986, the first large-scale trial to show a significant reduction in mortality with a fibrinolytic agent was the landmark Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardio (GISSI-1) trial (see the section on Clinical Trials of Streptokinase ).
Role of Fibrinolysis in Contemporary Care
Is fibrinolysis still relevant in the 21st century, now that guidelines and advocacy groups unequivocally recommend primary PCI (PPCI) as the preferred reperfusion strategy? Compared with fibrinolysis, PPCI achieves higher patency rates and is associated with fewer intracranial bleeding complications (see Chapter 17 ). PPCI also immediately deals with the underlying lesion or ruptured plaque, and easily gauges the extent of coronary disease ( Table 15-1 ). In aggregate, PPCI is better than lytic therapy in terms of outcome, but only if it can be done within 120 minutes after first medical contact by an experienced catheterization team (see Chapter 5 and Chapter 14 ). Achieving such rapid implementation of PPCI is not possible in a considerable proportion of STEMI patients worldwide, depending on geography and the healthcare organization. As a consequence, fibrinolysis remains an important option for many patients. For example, in the contemporary international long-tErm follow-uP of anti-thrombotic management patterns In acute CORonary syndrome patients (EPICOR) registry, fibrinolytic agents were used in 14% to 33% of STEMI patients, depending on the region. Also, in the most recent European survey, the rate of fibrinolysis varied greatly among the 37 participating countries, from being almost nonexistent in the Czech Republic to more than 80% (300 per 1 million inhabitants) of patients who received reperfusion therapy in the Ukraine ( Figure 15-1 ).
It is clear that in remote or sparsely populated areas, fibrinolysis is often the only option to expedite reperfusion. Structural and unexpected interhospital transfer delays are often underestimated in urban areas as well. Once a STEMI patient is committed to be sent to a PPCI-capable center, but unanticipated delays occur, an opportunity for early reperfusion is lost. Such patients are likely to have benefited from early fibrinolysis in the absence of contraindications. Transfer-related delays in PPCI are common, and as door-to-balloon delays increase, the outcome advantage of PPCI over fibrinolysis clearly diminishes (see Chapter 14 ). In a large American registry (n = 115,316), only one-half of the STEMI patients referred for PPCI achieved the guideline-recommended first door-to-balloon time of less than 120 minutes. More specifically, less than half of the patients with an estimated transfer delay greater than 30 minutes were treated within 120 minutes. In contrast, only half of the STEMI patients with an estimated drive time exceeding 60 minutes were treated with fibrinolysis. In essence, although efforts to reduce transfer times and optimize STEMI networks for prompt referral are obviously needed, a substantial proportion of patients with STEMI might still benefit from lytic therapy. For example, in a recent systematic registry performed in Belgium (a small country with a high density of catheterization laboratories), the shift of fibrinolytic therapy in non–PCI-capable hospitals to referring for PPCI has resulted in longer overall treatment delays and no change in overall outcome. In most STEMI networks, fibrinolysis is not isolated from PCI. The optimal combination of fibrinolysis and PCI (rescue or planned) is still being investigated, and is the subject of a separate chapter (see Chapter 14 ). In addition, interest in local intracoronary administration of lytics has attracted renewed interest, especially as an alternative for PPCI patients with a large thrombotic burden. For these reasons, fibrinolysis in well-established networks is still relevant today.
How Do Fibrinolytic Agents Work?
The goal of administering a fibrinolytic agent is to dissolve the clot that impedes blood flow in a coronary artery. This dissolution of thrombus is achieved pharmacologically by activating the fibrinolytic system. Fibrinolytic agents convert the inactive proenzyme plasminogen to its active state, plasmin ( Figure 15-2 ). Plasmin then degrades fibrin, a major constituent of thrombi, to soluble fibrin-degradation products, ultimately resulting in clot dissolution. Fibrinolytic agents are traditionally categorized as fibrin-selective versus nonselective agents, depending on whether they lyse clots in the absence of systemic plasminogen activation ( Table 15-2 ).
| Nonfibrin-specific Agents | Fibrin-Specific Agents |
|---|---|
| Streptokinase | Alteplase and derivatives |
| Saruplase | Reteplase |
| APSAC (anistreplase) | Tenecteplase Lanoteplase Amediplase Monteplase Pametiplase |
| Staphylokinase |
Streptokinase, anistreplase, and urokinase are nonfibrin-selective fibrinolytic agents, and indiscriminately activate both circulating and clot-bound plasminogen to plasmin. This activity not only causes local dissolution of a thrombus, but also causes systemic degradation of circulating fibrinogen. In contrast, alteplase and its derivatives, as well as staphylokinase, digest clot-bound fibrinogen relatively selectively and tend not to deplete systemic coagulation factors as much as streptokinase. Fibrin-selective drugs are more efficient in dissolving thrombi. However, the selective nature of fibrin-specific lytic agents does have some unwanted side effects; their lack of systemic fibrinogen depletion might increase the risk of rethrombosis and reocclusion (see Chapter 23 ). Subsequent derivatives of alteplase have been aimed at providing more practical bolus delivery at the same time as potential improvements in the risk–benefit balance caused by the enhanced fibrin specificity of some derivatives.
Several circulating factors suppress the activation of plasminogen, most notably plasminogen activator inhibitor (PAI)-1 (see Figure 15-2 ). Active plasmin is inhibited by α 2 -antiplasmin. Resistance or lack of resistance to PAI-1 partially characterizes the potency of the different fibrinolytic agents. Consequently, PAI-1 is a major determinant of the resistance of platelet-rich thrombi to lysis by fibrinolytic agents.
Specific Fibrinolytic Agents
Streptokinase
Streptokinase is a nonfibrinogen-specific fibrinolytic agent that indirectly activates plasminogen ( Tables 15-3 and 15-4 ). Streptokinase is a single-chain, 414-amino acid long protein that resembles serine proteases, but it does not have enzymatic activity on its own. Plasminogen is activated after forming a complex with streptokinase, exposing its active site, which catalyzes the conversion to plasmin. This complex is more resistant against inactivation by α 2 -antiplasmin than free-circulating plasmin.
| Fibrin Specificity | Half-Life (min) | PAI-1 Resistance | |
|---|---|---|---|
| Streptokinase | − | 18–23 | − |
| APSAC | − | 40–90 | − |
| Alteplase | ↑ | 3–4 | − |
| Reteplase | ↓ | 15–18 | − |
| Tenecteplase | ↑↑ | 20–24 | ↑ |
| Lanoteplase | ↓ | 30–45 | ↑ |
| Pametiplase | ↑ | 30–47 | − |
| Monteplase | ↑ | 23 | ↑ |
| Staphylokinase (PEG) | ↑↑↑ | 13 | − |
| Streptokinase |
| 1.5 million IU/1 h |
| Alteplase |
| 15-mg bolus |
| 90-min infusion |
|
| Reteplase |
| Initial 10 U bolus, followed by second 10 U bolus 30 min later |
| Tenecteplase |
Weight-adjusted single bolus:
|
| Half-dose if age >75 yrs ∗ |
In STEMI, 1.5 million units of streptokinase is usually given in a 1-hour infusion. However, because of its lack of fibrin specificity, streptokinase generates active plasmin in the circulation and induces a systemic lytic state, when α 2 -antiplasmin becomes exhausted. Circulating fibrinogen levels decrease well below 20% of baseline within the first 60 minutes after infusion. As a consequence, additional anticoagulants are not always recommended in combination with streptokinase or other nonfibrin-specific fibrinolytics (see Chapter 18 ). Whether there is a benefit in adding intravenous heparin is still a matter of debate.
Because streptokinase is produced by hemolytic streptococci, patients who receive streptokinase invariably develop antistreptococcal antibodies. This immunological reaction often causes fever, but would also completely neutralize a new dose of streptokinase in the first 3 months after administration, effectively precluding early re-administration. In some patients, high neutralizing antibody titres persist for years after their treatment. In addition, preexisting anti-streptokinase antibodies are relatively common and can impede reperfusion after treatment with streptokinase in patients with acute MI. However, hypotension, a frequent but often transient side effect of streptokinase, is more likely the result of bradykinin release than being caused by an acute allergic reaction.
Clinical Trials of Streptokinase
In the GISSI-1 study, 11,806 patients with STEMI presenting within 12 hours of symptom onset were randomized to either intravenous streptokinase or control therapy. In-hospital mortality was 10.7% in patients treated with intravenous streptokinase versus 13.1% in control patients, indicating 23 lives saved per 1000 patients treated. This benefit in mortality was preserved after 1- and 10-year follow-up ( Figure 15-3 ). Another landmark trial, ISIS-2 (Second International Study of Infarct Survival), clearly showed a benefit of adding aspirin to streptokinase; 17,187 patients received 1.5-MU streptokinase, 160-mg/day aspirin for 1 month, both treatments, or neither. Treatment with aspirin or streptokinase alone resulted in a significant reduction in mortality (23% and 24%, respectively), with a much greater benefit with a combined administration. Aspirin significantly reduced nonfatal reinfarction and was not associated with any significant increase in intracranial hemorrhages (ICHs) (see Chapter 19 ). The reinfarction rate was higher when streptokinase was used alone, an effect that was abolished when aspirin was added.
Tissue-Type Plasminogen Activator
Recombinant tissue-type plasminogen activator (rt-PA; alteplase) is a single-chain, tissue-type plasminogen activator molecule, manufactured by recombinant DNA technology (see Tables 15-3 and 15-4 ). Alteplase is a relatively weak plasminogen activator in the absence of fibrin. However, the presence of fibrin at the surface of a clot considerably boosts alteplase’s activation rate of plasminogen by forming a ternary complex. As a consequence, it has considerably greater fibrin specificity than streptokinase, but it induces mild systemic fibrinogen depletion. Plasmin formed at the surface of fibrin is also more resistant to inactivation by α 2 -antiplasmin. The effectiveness of alteplase is also offset to some extent by PAI-1. Alteplase requires a continuous intravenous infusion because of its short half-life. It also needs concomitant anticoagulant therapy, because fibrin-specific agents increase the risk of reocclusion by a factor of two in the absence of a generalized systemic lytic state.
Clinical Trials of Tissue-Plasminogen Activator
The initial experience with alteplase in STEMI patients confirmed its thrombolytic potency and its fibrin specificity. Before settling on the current front-loaded dosing, a variety of alteplase dosing schemes were tested in several studies. In one of the first large-scale study with alteplase, the ASSET (Anglo-Scandinavian Study of Early Thrombolysis) trial in 1988, an unusually long administration of alteplase was used. This first trial showed a 26% mortality reduction compared with placebo, despite the absence of aspirin in this study. Alteplase, given in a 3-hour dosing regimen, was subsequently shown to achieve significantly better patency scores than streptokinase, although in two large-scale trials, ISIS-3 (n = 41,299, with duteplase) and GISSI-2–International (n = 12,490, with alteplase), a similar tPA regimen resulted in the same mortality rates as streptokinase.
The question which of the two, streptokinase or alteplase, is the most effective in terms of mortality reduction was finally settled in 1993 in the first Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial. In this trial, which included more than 40,000 patients, a shorter 90-minute dosing regimen of alteplase was used and was shown to achieve higher patency rates than the 3-hour scheme. Thirty-day mortality was 6.3% in patients who received alteplase and intravenous heparin compared with 7.4% in patients treated with streptokinase and intravenous heparin ( P = .001), which was driven by a significantly higher Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 at 90 minutes (54% vs. 32%, with streptokinase). Early reocclusion was not uncommon in the era before systematic planned angiography and angioplasty after lytic therapy (see Chapter 23 ), in part because of the paradoxical procoagulant and platelet-activating side effects of fibrinolytic agents, and was associated with a high 30-day mortality—12% compared with 1.1% in patients with early and persistently patent coronary arteries. In the end, GUSTO-1 convincingly settled the discussion whether successful early vessel patency associated with fibrinolysis, as observed in the earlier phase II studies, directly translated into improved outcome, often referred to as the “open artery theory,” or whether fibrinolysis improved outcome by mechanisms other than early coronary reperfusion. The 30-day mortality differences between the four fibrinolytic strategies compared in the main GUSTO-I trial (all 41,021 patients) were predicted accurately from differences in the 90-minute TIMI grade 3 flow rates in the angiographic substudy. This close match between mortality differences predicted from early patency data and actual mortality supported the paradigm that early, complete, and sustained epicardial coronary artery reperfusion is an essential mechanism underlying the life-saving potential of fibrinolytic therapy.
Reteplase
After the identification of the molecular structure of tissue plasminogen activator, several attempts were made at improving its properties by targeted mutations and deletions (see Tables 15-3 and 15-4 ). In general, these efforts focused on improving fibrin specificity and resistance to PAI-1, and especially on prolonging its half-life. Reteplase, a second-generation thrombolytic agent, was a first attempt to improve on the shortcomings of alteplase. It is a mutant of alteplase in which the finger, the kringle-1 domain, and epidermal growth factor domains are removed. This results in a decreased plasma clearance with a longer half-life than alteplase (see Table 15-3 ), allowing administration as bolus injection. However, the removal of the finger domain diminishes fibrin specificity, although inactivation by PAI-1 remains similar to alteplase.
Clinical Trials of Reteplase
In two open-label randomized pilot trials, different doses of reteplase were evaluated in patients with acute MI. In two studies (Reteplase [r-PA] vs Alteplase Patency Investigation During Acute Myocardial Infarction [RAPID] I and II) patients treated with two boluses of 10 U reteplase, given 30 minutes apart, had significantly higher rates of TIMI grade 3 flow compared with patients treated with either the 3-hour or front-loaded infusion of alteplase ( Figure 15-4 ). Encouraged by these favorable early patency rates, reteplase was evaluated in two large outcome trials. In the double-blind International Joint Efficacy Comparison of Thrombolytics (INJECT) trial, 6010 patients with acute MI within 12 hours of symptom onset were randomized to either double-bolus reteplase (10 U), given 30 minutes apart, or streptokinase. INJECT did not find any difference in 35-day mortality between double-bolus reteplase and streptokinase. The percentage of patients with complete ST-segment resolution was significantly higher with reteplase in a substudy of INJECT, but this did not translate into improved outcome. In the GUSTO-III trial, which was designed as a superiority trial, 15,059 patients were randomized to double-bolus reteplase or front-loaded alteplase. Like the INJECT study, mortality at 30 days was again similar for both treatment arms (7.47% vs. 7.24%), as was the incidence of hemorrhagic stroke (0.91% vs. 0.93%) or other major bleeding complications. Similar mortality rates were maintained for both treatment groups at 1-year follow-up (see Figure 15-3 ) and remained consistent among various subgroups, including older adults and patients presenting early after symptom onset. Thus, higher patency rates at 90 minutes with reteplase did not translate into lower short- or intermediate-term mortality rates. This discordance between initial patency and outcomes might be explained in part by increased platelet activation and surface receptor expression, and subsequent reocclusion, with reteplase compared with alteplase. Reteplase is still available and in clinical use today.
