Thrombolytics and Myocardial Infarction

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1 REVIEW Thrombolytics and Myocardial Infarction Vijayalakshmi Kunadian 1 & C. Michael Gibson 2 1 Cardiothoracic Division, The James Cook University Hospital, Middlesbrough, UK 2 Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Keywords Acute myocardial infarction; Streptokinase; Thrombolysis. Correspondence C. Michael Gibson, M.S., M.D., Beth Israel Deaconess Hospital, 1 Pilgrim Way, Boston MA 02115, USA. Tel.: ; Fax: ; mgibson@perfuse.org SUMMARY Coronary artery disease is the single leading cause of death in the United States. Occlusion of the coronary artery was identified to be the cause of myocardial infarction almost a century ago. Following a series of investigations, streptokinase was discovered and demonstrated to be beneficial for the treatment of patients with acute myocardial infarction in terms of reducing short- and long-term mortality. Newer agents including tissue plasminogen activators such as alteplase, reteplase, tenecteplase were developed subsequently. In the present era, thrombolytic therapy and primary percutaneous coronary intervention has revolutionized the way patients with acute myocardial infarction are managed resulting in significant reduction in cardiovascular death. This article provides an overview of the various thrombolytic agents utilized in the management of patients with acute myocardial infarction. doi: /j x Introduction Acute myocardial infarction (AMI) occurs approximately in 1.1 million Americans each year, of which 460,000 cases are fatal. About half of those deaths occur within 1 h of the start of symptoms and before the patient reaches the hospital (source NHLBI) [1]. Nearly a century ago, in 1912, Herrick described complete obliteration of the proximal segment of the left anterior descending artery with a red thrombus as the cause of AMI in a 55-yearold man during an autopsy examination [2]. In 1958, Fletcher first reported the use of thrombolytic therapy for the management of AMI [3]. Subsequently several small trials reported the benefit of streptokinase (SK) in the management of patients with AMI [4 8]. Newer agents including tissue plasminogen activators (TPA) such as alteplase, reteplase, tenecteplase (TNK) were developed subsequently. In the present era, thrombolytic therapy and primary percutaneous coronary intervention (PPCI) has revolutionized the way patients with AMI are managed resulting in significant reduction in cardiovascular mortality [9,10]. The objective of both treatment strategies is to provide a rapid, complete, and sustained restoration of blood flow in the infarct-related coronary artery (IRA) [11,12]. The goal of this article is to provide an overview of the various thrombolytic agents utilized in the management of patients with AMI. History of Thrombolytic Agents SK In 1933, Dr. William Tillett discovered SK through sheer chance when he observed that streptococci agglutinated plasma but not serum. He inferred that fibrinogen contained in the plasma and not in the serum resulted in the agglutination of streptococci as fibrinogen gets absorbed onto the surface of streptococci. He further concluded that any plasma containing streptococci would not clot and this laid the foundation for thrombolysis in various settings [13 16]. Christensen and MacLeod coined the term streptokinase in 1945 [17]. SK was originally utilized in the treatment of patients with tuberculous hemorrhagic pleural effusions and tuberculous meningitis [18,19]. In the setting of AMI, SK produced by various species of streptococci can bind and activate human plasminogen into plasmin that results in fibrinolysis. Although several small studies [5 8] demonstrated the beneficial effects of SK in terms of reducing 30-day and 1-year mortality, the GISSI (Grupo de Análisis de la Cardiopatíá Isquémica Aguda-1) and the ISIS (International Study of Infarct Survival-2) trials firmly established the efficacy of intravenous SK in the management of patients with AMI. In the GISSI trial, at 21 days there was 18% reduction in overall hospital mortality following the administration of SK compared with the control group (10.7% vs. 13% in the controls, P = , relative risk [RR] 0.81). The extent of the beneficial effect appeared to be related to the time of onset of chest pain to SK infusion (RR 0.74, 0.80, c 2010 Blackwell Publishing Ltd Cardiovascular Therapeutics 30 (2012) e81 e88 e81

2 Thrombolytics and Myocardial Infarction V. Kunadian and C.M. Gibson 0.87, and 1.19 for the 0 3, 3 6, 6 9, and 9 12 hour subgroups) [20]. Likewise in the ISIS-2 trial, patients with AMI randomized to SK and aspirin compared with neither treatment resulted in significant reduction not only in death (8% vs. 13.2%), but also stroke (0.6% vs. 1.1%) and reinfarction (1.8% vs. 2.9%) [21]. The early survival benefit obtained with SK and aspirin persisted up to 10 years during follow-up [22]. Comparison of SK with TPA Newer thrombolytic agents have been developed in order to provide longer half-life to enable bolus administration, fibrin specificity, and to be resistant to natural inhibitors such as plasminogen activator inhibitor-1 (PAI-1). Newer agents and their properties are displayed in Table 1. Following the breakthrough discovery of SK in the treatment of patients with AMI and the emergence of novel agents, the attention shifted to determine which thrombolytic agent was the best. The GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries), GISSI-2 [23], and ISIS-3 [24] investigators compared intravenous SK and TPA in the treatment of AMI. The GISSI-2 trial consisting of 12,490 patients demonstrated that SK and TPA were equally safe and effective in AMI [23] and did not demonstrate specific differences between the two thrombolytic agents (TPA vs. SK) with regards to the combined endpoint of death and severe left ventricular damage (23.1% vs. SK 22.5%; RR 1.04, 95% confidence interval [Cl] ). Although major bleed was significantly higher in SK and heparin-treated patients (TPA 0.5% vs. SK 1.0%, RR 0.57, 95% Cl ), the overall incidence of stroke was similar in all treatment groups [23]. Similar findings were established in the ISIS-3 trial consisting of 41,299 patients with suspected AMI who were randomized between SK, TPA, or anisoylated plasminogen-sk activator complex (APSAC). There was no significant difference in mortality (10.6% SK vs. 10.5% APSAC) and reinfarction (3.47% SK vs. 3.55% APSAC) among all randomized patients at 35 days. APSAC was associated with a slight excess of strokes immediately following the administration of the drug (1.04% SK vs. 1.26% APSAC; P = 0.08), which was primarily due to cerebral hemorrhage (0.24% SK vs. 0.55% APSAC, P < ) [24]. Although no significant difference was observed between SK and TPA in GISSI-2 and ISIS-3, the GUSTO trial demonstrated that an accelerated regimen of TPA (administration of TPA over a period of 90 min, with two-thirds of the dose given in the first 30 min instead of the conventional period of 3 h) resulted in significant reductions in death and disabling strokes among patients with AMI. Accelerated TPA group resulted in 14% reduction in mortality at 30 days compared with the SK strategies. There was slight excess of hemorrhagic stroke for accelerated TPA (P = 0.03) when compared with the SK strategies. However, the combined endpoint of death or disabling stroke was significantly lower in the accelerated TPA group than in the SK only groups (6.9% vs. 7.8%, P = 0.006) [11]. Other Agents Alteplase (rtpa) Alteplase is a serine protease found on endothelial cells. It is manufactured from recombinant biotechnology and referred to as recombinant TPA (rtpa) which catalyses the conversion of plasminogen to plasmin. In addition to the GUSTO trial, other trials have demonstrated that the accelerated alteplase infusion regimen administered over a 90-minute period to be the preferred treatment strategy when compared with a double dose alteplase therapy due to slightly increased rate of intracranial bleeding in the latter group (1.12% vs. 0.81%) [25]. The phase I TIMI (thrombolysis in myocardial infarction) trial demonstrated that the administration of rtpa in patients with AMI resulted in reperfusion in twice as many occluded infarct-related arteries compared with SK during the first 90 min of initiation of treatment [12,26]. Reteplase Reteplase is a recombinant nonglycosylated form of human TPA produced in Escherichia coli and has a longer half-life of min. Reteplase binds fibrin and has the ability to penetrate into thrombi. Reteplase has been compared with accelerated alteplase infusion regimen and was demonstrated to offer no significant benefit in terms of reduction in 30-day mortality among patients with AMI [27]. Likewise, reteplase in combination with Table 1 Comparison of different thrombolytic agents Agent Molecular weight (D) Plasma half life (min) Fibrin specificity Plasminogen activation Antigenicity Dose Streptokinase Indirect + 1.5MIU/60min Mutants of native tissue plasminogen activator Tenecteplase Direct 0.5 mg/kg bolus Alteplase Direct 100 mg/90 min Reteplase Direct 2 10 IU boluses 30 min apart Lanoteplase Direct 120 IU/kg bolus Recombinant single-chain urokinase plasminogen activator Saruplase ± Direct 80 mg/60 min Staphylokinase Indirect mg/30 min IU, international units; M, million. e82 Cardiovascular Therapeutics 30 (2012) e81 e88 c 2010 Blackwell Publishing Ltd

3 V. Kunadian and C.M. Gibson Thrombolytics and Myocardial Infarction abciximab did not provide significant benefit in terms of 30-day survival [28,29]. However a double dose reteplase ( MU) utilized in the RAPID trial resulted in complete, rapid and sustained thrombolysis of IRA at 90 min and 5 14 day (63% vs. 49%, P = 0.019; and 88% vs. 71%, P < 0.001) compared with alteplase and improved regional and global left ventricular function at discharge. Global ejection fraction and regional wall motion in the reteplase group were superior to those of the TPA group at hospital discharge (53 ± 1.3% vs. 49 ± 1.3%, P = 0.034) [30]. The RAPID II trial further confirmed the advantage of reteplase over accelerated alteplase in achieving higher rates of early reperfusion in the IRA and fewer acute coronary interventions [31]. The improved IRA patency rates demonstrated in the RAPID trials did not however translate into improved clinical outcomes in the INJECT (International Joint Efficacy Comparison of Thrombolytics.) trial which demonstrated no significant difference between reteplase and SK in reducing 35-day mortality [32]. Tenecteplase TNK is a 527 amino acid glycoprotein that is developed by introducing modifications to the complementary DNA for natural human TPA. It binds to fibrin and selectively converts thrombusbound plasminogen to plasmin, which degrades the fibrin matrix of the thrombus. TNK has a higher fibrin specificity and greater resistance to inactivation by its endogenous inhibitor (PAI-1) compared to native TPA [33]. A single bolus TNK was demonstrated to be fibrin specific and was associated with increased IRA patency rates (64% TIMI 3 flow with 50 mg bolus dose) in the TIMI 10A trial [34]. In the TIMI 10B trial, TNK-tPA (40 mg) and alteplase produced similar rates of TIMI grade 3 flow at 90 min (62.8% vs. 62.7%, respectively, P = NS) [35]. Subsequently the ASSENT 1 trial (Assessment of the Safety and Efficacy of a New Treatment) demonstrated that the safety profile of TNK was comparable to alteplase [36]. The efficacy and safety profile of single bolus TNK translated into improved mortality rates comparable to alteplase (6.18% for TNK and 6.15% for alteplase) in the ASSENT-2 trial. Rates of intracranial hemorrhage (ICH) were comparable (0.93% for TNK and 0.94% for alteplase), but fewer noncerebral bleeding complications (26.43% vs %, P = ) and less need for blood transfusion (4.25% vs. 5.49%, P = ) were seen with TNK. The rate of death or nonfatal stroke at 30 days was comparable between TNK and alteplase (7.11% vs. 7.04%, RR 1.01 [95% CI ]) [37]. Furthermore, the ASSENT 3 trial demonstrated that the addition of enoxaparin or abciximab to TNK reduced ischemic complications. There were significantly fewer efficacy endpoints (composite of 30-day mortality, in-hospital reinfarction, and recurrent ischemia) in the enoxaparin and abciximab groups than in the unfractionated heparin group [38]. Despite the differences observed between the thrombolytic agents in individual studies, a subsequent meta-analysis however did not demonstrate significant differences between the various thrombolytic agents in reducing mortality [39]. Lanoteplase Lanoteplase (npa) is a variant of TPA with greater fibrinolytic activity and slower clearance from the plasma [40]. The InTIME (Intravenous NPA for the Treatment of Infarcting Myocardium Early) investigators demonstrated that the administration of npa resulted in equivalent thrombolytic efficacy to alteplase in terms of its impact on 6-month survival (mortality: alteplase 8.8% vs. npa 8.7%). However, npa was associated with an increased risk of hemorrhagic strokes (alteplase 0.64% vs. npa 1.12%, P = 0.004) [41]. Saruplase Saruplase or prourokinase (scupa) is a naturally occurring glycoprotein that is converted by plasmin into urokinase and seems to have intrinsic plasminogen activating potential. It is produced by recombinant technology in E. coli. Saruplase was compared with SK in the PRIMI and COMPASS (Comparison Trial of Saruplase and Streptokinase) trials. The 5-year results of the PRIMI trial demonstrated that the mortality rate was comparable between saruplase and SK (20.8% vs. 16.9%) and slight benefit favoring SK in terms of reduction in reinfarction rates compared with the saruplase group (10.8% vs. 19%) [42]. Likewise, in the COMPASS (Comparison Trial of Saruplase and streptokinase) trial the 30-day mortality rates were comparable between saruplase and SK (5.7% vs. 6.7%, P < 0.01 for equivalence) and hemorrhagic strokes occurred more frequently with saruplase (0.9% vs. 0.3%) [43]. Alteplase was compared with saruplase in the SESAM (Study in Europe with Saruplase and Alteplase in Myocardial Infarction) trial, which demonstrated that saruplase was as effective as alteplase in early coronary artery patency rates, reocclusion rates, and complication rates [44]. Thus, although the mortality rates were comparable between saruplase and other agents, saruplase was overcome by other adverse events such as increased reinfarction rates and hemorrhagic strokes limiting its applicability as a preferred agent. Staphylokinase Staphylokinase is a 136 amino-acid protein produced by certain strains of staphylococcus aureus and has a unique mechanism of fibrin selectivity. Recombinant staphylokinase (STAR) has been demonstrated to provide beneficial effects among patients with AMI. The STAR trial, a multicenter randomized open trial was designed to assess the thrombolytic efficacy, safety, and fibrin specificity of STAR compared with accelerated alteplase. The TIMI flow grade 3 at 90 min was achieved in 62% of STAR patients versus 58% of rtpa patients (risk ratio 1.1, 95% CI 0.76 to 1.5). Higher dose resulted in greater TIMI 3 flow compared with a lower dose (50% with 10 mg STAR vs. 74% with 20 mg STAR). STAR therapy was not associated with increased mortality or electric, hemorrhagic, mechanical, or allergic complications. However among patients who were administered STAR, there was an occurrence of antibody-mediated STAR-neutralizing activity from the second week following treatment [45]. The pegulated staphylokinase (PEG-Sak) was evaluated in the CAPTORS II trial (Collaborative Angiographic Patency Trial Of Recombinant Staphylokinase) which demonstrated that PEG-Sak at doses of mg/kg resulted in TIMI 3 flow rates in 33%, whereas the TIMI 3 flow was 41% at the highest PEG-Sak dose studied (0.05 mg/kg). c 2010 Blackwell Publishing Ltd Cardiovascular Therapeutics 30 (2012) e81 e88 e83

4 Thrombolytics and Myocardial Infarction V. Kunadian and C.M. Gibson Table 2 Contraindications to thrombolysis Absolute contraindications to thrombolysis Head trauma or brain surgery within 6 months Any previous history of hemorrhagic stroke History of stroke, dementia, or central nervous system damage within 1year Known intracranial malignancy Suspected aortic dissection Internal bleeding within 6 weeks Active bleeding and known bleeding disorder Major surgery, trauma, or bleeding within 6 weeks Traumatic cardiopulmonary resuscitation within 3 weeks Relative contraindication to thrombolysis Oral anticoagulant therapy Acute pancreatitis Active peptic ulceration Pregnancy or within 1 week postpartum Dementia Transient ischemic attack within 6 months Infective endocarditis Active cavitating pulmonary tuberculosis Advanced liver disease Intracranial thrombus Uncontrolled hypertension (systolic blood pressure >180 mm Hg, diastolic blood pressure >110 mmhg) Prior streptokinase use presenting later [50]. Boersma and colleagues evaluated the relation between treatment delay and short-term mortality (up to 35 days) using tabulated data from all randomized trials that compared fibrinolytic therapy with placebo or control (study period ). In this study, greater benefit was observed among patients who received fibrinolytic therapy at 0 1-h time interval from symptom onset (65 [SD 14], 37 [9], 26 [6] and 29 [5] lives saved/1000 treated patients in the 0 1, 1 2, 2 3, and 3 6 hour intervals, respectively). Furthermore the proportional mortality reduction was significantly higher among individuals treated within 2 h compared to those treated later (44% vs. 20%, P = 0.001). In the GUSTO-1 trial, female, elderly, and diabetic patients were associated with longer presentation and treatment delays. Newby and colleagues evaluated the relations of baseline characteristics to three prospectively defined time variables: symptom onset to treatment, symptom onset to hospital arrival (presentation delay), and hospital arrival to treatment (treatment delay). Previous infarction or bypass surgery was an additional risk factor for treatment delay. Patients who received thrombolysis within 2 h of symptom onset had lower overall mortality (<2 h,5.5%;>4 h, 9.0%). Longer presentation and treatment delays were both associated with increased mortality rate (presentation delay <1 h, 5.6% and >4 h, 8.6%; treatment delay <1 h,5.4%,and>90 min, 8.1%). The incidence of recurrent ischemia and reinfarction decreased as the time to treatment increased with elevated rates of shock, heart failure, and stroke [51]. This was comparable to that found following the administration of rtpa (41%) [46]. Limitations of Thrombolysis Contraindications to Thrombolysis Although the use of fibrinolytic therapy was associated with significant reduction in mortality, it was soon demonstrated to be overcome by a number of limitations. An analysis from the TIMI- 9 registry demonstrated that 10.3% of patients have contraindications to thrombolysis, which consisted of prior stroke or transient ischemic attack, recent cardiopulmonary resuscitation, trauma, surgery, recent bleeding, persistent hypertension, and significant illness [47] (Table 2). Timing of Thrombolytic Treatment The benefit of fibrinolytic therapy decreases as time progresses following the onset of symptoms. Prehospital administration of thrombolysis was beneficial if administered within 70 min in terms of reduction in the composite score of death, stroke, serious bleed, and infarct size (P = 0.009) [48]. A meta-analysis by Morrison and colleagues demonstrated that prehospital thrombolysis resulted in significant decrease in time to thrombolysis and all-cause mortality [49]. Further studies suggest that significant mortality reduction is demonstrated among patients treated with fibrinolytic therapy within the first 2 h of symptom onset compared to those Cerebrovascular Events Stroke remains a catastrophic complication following fibrinolytic therapy. The Fibrinolysis Therapy Trialists (FTT) collaborators analysis demonstrated that thrombolysis was associated with an increase in stroke rate compared to control patients (1.2% vs. 0.8%, P < ) [9]. An analysis from the GUSTO-1 study demonstrated that the overall incidence of stroke following fibrinolytic therapy was 1.4% (95% of stroke occurred within 5 days). Combination treatment with SK and TPA was associated with significantly more stroke than SK alone (1.64% vs. 1.19%, P < 0.007). Of these, among 41% of cases the stroke was fatal. ICH occurred in 0.46% of cases who received SK and 0.88% of cases who received combination therapy (P < 0.001) [52]. Another analysis demonstrated a slight increase in ICH among patients receiving TPA (0.95%) [53]. Patency of Infarct Arteries In addition to the above limitations, early patency of the infarctrelated arteries is not demonstrated in all patients treated with fibrinolytic therapy. Angiography following fibrinolytic therapy demonstrates that TIMI flow grade 3 is achieved in only 40 60% of cases. In an analysis from the GUSTO trial, the patency of infarct artery (TIMI flow grade 2/3) at 90 min was achieved in 81% of cases in the accelerated TPA group compared to only 54% in the SK group (P < 0.001). Normal flow (TFG 3) was achieved in 54% of patients who received TPA compared to 40% among those who received the other treatments (SK + subcutaneous heparin, SK + intravenous heparin, combination SK, TPA, and heparin) e84 Cardiovascular Therapeutics 30 (2012) e81 e88 c 2010 Blackwell Publishing Ltd

5 V. Kunadian and C.M. Gibson Thrombolytics and Myocardial Infarction [11]. The mortality at 30 days was significantly increased among those who had reduced flow compared to those who had normal flow (8.9% vs. 4.4%, P = 0.009). Reinfarction and Recurrent Ischemia Thrombolysis is also overcome by frequent occurrence of recurrent ischemia, reocclusion of the infarct artery (reocclusion within 5 7 days occurred in % cases in the GUSTO analysis), and reinfarction. Reinfarction occurred in 4.3% of cases following thrombolysis at a median of 3.8 days after thrombolysis. The 30-day mortality was increased among those who had reinfarction compared to those who did not have reinfarction (11.3% vs. 3.5%, P < 0.001). The mortality from 30 days to 1 year was also significantly increased among those who had reinfarction (4.7% vs. 3.2%, P < 0.001) [54]. Age Several studies have demonstrated that short-term and long-term mortality increases with age. In the GUSTO-1 subanalysis, there was not only an increase in 30-day mortality with age (3.0% [<65 years], 9.5% [65 74 years], 19.6% [75 85 years], and 30.3% [>85 years]), there was also an increase in stroke, cardiogenic shock, bleeding, and reinfarction. Accelerated TPA was associated with fewer combined death or disabling stroke in all but the oldest patients, who showed a weak trend toward a lower incidence with SK plus subcutaneous heparin [odds ratio 1.13; 95% CI ]. Likewise, accelerated TPA treatment resulted in lower 1-year mortality in all but the oldest patients (47% TPA vs. 40.3% SK) [55]. Weaver and colleagues demonstrated that 28% of patients hospitalized for AMI were 75 years of age and only 5% of patients were administered a systemic thrombolytic agent. There was an increase in mortality rates with increasing age (<2% in patients 55 years, 4.6% in those years, 12.3% in those years and 17.8% in those 75 years of age) [56]. While elderly patients are at highest risk, the relative and absolute risk reductions associated with fibrinolytic administration in these patients are quite favorable. Infarct Size and Site The extent of myocardial injury appears to be more relevant than the site in determining in-hospital mortality and efficacy of thrombolytic therapy. Mauri and colleagues evaluated the impact of infarct site and infarct extent on in-hospital outcome and efficacy of thrombolytic therapy in the GISSI trial [57]. Patients were divided into two groups based on the standard 12-lead electrocardiogram site pattern (anterior, inferior, lateral, and multiple locations) and the extent of ST segment elevation (small, modest, large, and extensive infarct in 2 9 leads). SK significantly reduced mortality only in anterior and multiple site infarcts. There was a progressive increase in the mortality rate based on infarct size (6.5% in small infarcts to 9.6% in modest, 14.3% in large and 21.7% in extensive). Utility of Thrombolytic Therapy in the Present Era Early Transfer to a PCI Center to Improve Thrombolytic Outcomes Although primary PCI for AMI is now the accepted treatment strategy, several centers continue to utilize thrombolytic therapy as PPCI facilities are not readily available locally. A discussion on facilitated PCI is beyond the scope of this article. However the benefits of early transfer to improve thrombolytic outcomes are presented in this section. Recently several studies have determined the benefit of early transfer to a PPCI center following the administration of fibrinolytic agents. The CARESS-in-AMI (Combined Abciximab Reteplase Stent Study in AMI) study determined whether early transfer for PCI following pharmacotherapy administration improves outcomes compared to a conservative watchful waiting approach among STEMI patients with anticipated delay in primary PCI due to their presentation to a non-pci center [58]. Six hundred patients in this study were pretreated with aspirin, heparin, half-dose reteplase, and abciximab. Subsequently patients were randomized to either immediate transfer for PCI or transfer only in case of failed reperfusion or clinical deterioration. This study demonstrated that there was significant benefit in terms of reduction in 30-day mortality with the immediate transfer strategy (4.4% vs. 10.7%, P = 0.004) without any differences in the bleeding events. Subsequently, the TRANSFER AMI (Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in AMI) demonstrated that early transfer of patients presenting to non-pci centers within 6 h of thrombolysis in the setting of an AMI for PCI resulted in fewer ischemic complications compared with standard treatment (including rescue PCI, if required, or delayed angiography) [59,60]. The primary endpoint consisting of the composite of death, reinfarction, recurrent ischemia, new or worsening congestive heart failure, or cardiogenic shock within 30 days was significantly reduced in routine early PCI group compared with the standard treatment group (11% vs. 17.2%, P = 0.004) with no significant difference in the incidence of major bleed [59]. A meta-analysis (not including TRANSFER-AMI trial) demonstrated significant reduction in 30-day (to 1 year) mortality (odds ratio [OR] 0.55, 95% CI ) and reinfarction (OR 0.53, 95% CI ) with early transfer for PCI following thrombolysis compared with ischemia-guided management with no difference in the risk of stroke (OR 1.31, 95% CI ) or major bleeding (OR 1.41, 95% CI ) [61]. More recently, the NORDISTEMI trial (NORwegian study on DIstrict treatment of ST-elevation myocardial infarction) demonstrated that the composite of death, reinfarction, stroke, or new ischemia at 12 months was significantly reduced in the early invasive group (immediate transfer following thrombolysis) compared with the conservative group (transfer only for failed reperfusion or clinical deterioration) (6% vs. 16%, hazard ratio: 0.36, 95% CI 0.16 to 0.81, P = 0.01). There were no significant differences in bleeding or infarct size observed among patients treated with thrombolysis and clopidogrel in areas with long transfer delays to PCI centers [62,63]. c 2010 Blackwell Publishing Ltd Cardiovascular Therapeutics 30 (2012) e81 e88 e85

6 Thrombolytics and Myocardial Infarction V. Kunadian and C.M. Gibson Intracoronary (IC) Thrombolytic Therapy Rentrop first reported IC administration of SK in the management of patients with AMI [64]. The efficacy of IC fibrinolytic therapy was studied among patients undergoing primary PCI. It has been demonstrated that SK inhibits red-cell aggregation and reduces platelet aggregation in vitro. It has also been demonstrated histopathologically, in an open-chest model of anterior descending artery occlusion and reperfusion, that SK results in improved perfusion of the microvasculature in severely ischemic myocardium following restoration of coronary flow [65,66]. In a small study by Sezer and coworkers, the IC SK (250 ku of IC SK over 3 min) was associated with significantly better coronary flow reserve, index of microvascular resistance, collateral flow index, mean coronary wedge pressure, and diastolic deceleration time compared to the control group 2 days following the procedure [67]. However, improvement in these physiological parameters did not translate into improvements in left ventricular size and function at 6 months. It should be noted that the study was underpowered to ascertain differences in clinical events or LV function at 6 months. Likewise, IC TNK is a safe, well tolerated, and effective treatment for the management of thrombotic complications in high-risk complex PCI. Kelly and coworkers demonstrated that TNK-supported PCI significantly improved the no reflow phenomenon among high-risk PCI patients [68]. Abbas and coworkers studied IC TPA in the setting of recanalization for chronic total occlusion among patients with progressive symptoms in whom prior PCI attempts failed. This study demonstrated that administration of fibrin-specific fibrinolytics was associated with a high success rate of recanalization of chronically occluded arteries with tapering morphology [69]. Recommendations Based on the evidence so far, the 2009 ACC/AHA focused update for the management of patients with acute ST elevation myocardial infarction classifies patients into those presenting to PPCI centers and non-ppci centers. Those presenting to PPCI centers should be offered primary PCI (Class I recommendation) and for those presenting to non-pci centers, it is reasonable for high-risk patients who receive fibrinolytic therapy as primary reperfusion therapy to be transferred as soon as possible to a PCI-capable facility where PCI can be performed either when needed or as a pharmacoinvasive strategy (Class IIa recommendation, Level of Evidence: B) [70]. Conclusion Thrombolytic therapy has revolutionized the way patients with AMI were managed in the 20th century. It is needless to say that in the 21st century, PPCI is the best treatment strategy for the management of AMI. However, primary PCI is not readily available to all patients. In this setting, thrombolytic therapy followed by immediate referral for coronary angiography with a view to percutaneous coronary intervention is the recommended treatment option. IC thrombolytic therapy might be beneficial during PPCI. Take Home Message Thrombolytic therapy remained the mainstay of treatment for patients with AMI. However, PPCI is now the established treatment strategy for the management of AMI. Patients who present to a PCI center should be offered this treatment without significant door-balloon time delays. Among patients who present to a non- PPCI center, thrombolysis with immediate transfer to a PCI center should be considered. Author Contributions Dr. Kunadian contributed to the construction of the manuscript. Dr. Gibson carried out review and appraisal of the manuscript. Conflict of Interest Dr. Kunadian reports no conflict of interest. Dr. Gibson has received research and grant support from the Genentech, Inc. References 1. Morbidity and Mortality: 2009 Chart Book on Cardiovascular, Lung and Blood disease Ref Type: Internet Communication. 2. Kerrick J. Coronary obstruction. JAMA 1912;59: Fletcher AP, Alkjaersign N, Smyrniotis FE, Sherry S. The treatment of patients suffering from early myocardial infarction with massive and prolonged streptokinase therapy. Trans Assoc Am Physicians 1958;71: Yusuf S, Collins R, Peto R, et al. Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: Overview of results on mortality, reinfarction and side-effects from 33 randomized controlled trials. Eur Heart J 1985;6: Koren G, Weiss AT, Hasin Y, et al. Prevention of myocardial damage in acute myocardial ischemia by early treatment with intravenous streptokinase. NEngl JMed1985;313: Lew AS, Laramee P, Cercek B, Rodriguez L, Shah PK, Ganz W. The effects of the rate of intravenous infusion of streptokinase and the duration of symptoms on the time interval to reperfusion in patients with acute myocardial infarction. Circulation 1985;72: Simoons ML, Serruys PW, van den BM, et al. Improved survival after early thrombolysis in acute myocardial infarction. A randomised trial by the Interuniversity Cardiology Institute in The Netherlands. Lancet 1985;2: Hillis LD, Borer J, Braunwald E, et al. High dose intravenous streptokinase for acute myocardial infarction: Preliminary results of a multicenter trial. JAmColl Cardiol 1985;6: Fibrinolytic Therapy Trialists (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: Collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994;343: Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003;361: The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. NEnglJMed 1993;329: Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987;76: e86 Cardiovascular Therapeutics 30 (2012) e81 e88 c 2010 Blackwell Publishing Ltd

7 V. Kunadian and C.M. Gibson Thrombolytics and Myocardial Infarction 13. Garner RL, Tillett WS. Biochemical studies on the fibrinolytic activity of hemolytic streptococci: II. Nature of the reaction. JExpMed1934;60: Garner RL, Tillett WS. Biochemical studies on the fibrinolytic activity of hemolytic streptococci: I. Isolation and characterization of fibrinolysin. JExp Med 1934;60: Tillett WS, Edwards LB, Garner RL. Fibrinolytic activity of hemolytic streptococci. The development of resistance to fibrinolysis following acute hemolytic streptococcus infections. J Clin Invest 1934;13: Tillett WS, Garner RL. The fibrinolytic activity of hemolytic streptococci. JExp Med 1933;58: Christensen LR, Macleod CM. A proteolytic enzyme of serum: Characterization, activation and reaction with inhibitors. J Gen Physiol 1945;28: Sherry S, Tillett WS, Read CT. The use of streptokinase-streptodornase in the treatment of hemothorax. J Thorac Surg 1950;20: Cathie IA. Streptomycin-streptokinase treatment of tuberculous meningitis. Lancet 1949;1: Gruppo Italiano per lo Studio della Streptochinasi nell Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1: ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2: Baigent C, Collins R, Appleby P, et al.; for The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. BMJ 1998;316: Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto Miocardico. GISSI-2: A factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction. Lancet 1990;336: ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: A randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet 1992;339: The Continuous Infusion versus Double-Bolus Administration of Alteplase (COBALT) Investigators. A comparison of continuous infusion of alteplase with double-bolus administration for acute myocardial infarction. NEnglJMed 1997;337: TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. NEnglJMed1985;312: The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. NEnglJMed1997;337: Topol EJ. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: The GUSTO V randomised trial. Lancet 2001;357: Lincoff AM, Califf RM, Van de WF, et al. Mortality at 1 year with combination platelet glycoprotein IIb/IIIa inhibition and reduced-dose fibrinolytic therapy vs conventional fibrinolytic therapy for acute myocardial infarction: GUSTO V randomized trial. JAMA 2002;288: Smalling RW, Bode C, Kalbfleisch J, et al.; for the RAPID Investigators. More rapid, complete, and stable coronary thrombolysis with bolus administration of reteplase compared with alteplase infusion in acute myocardial infarction. Circulation 1995;91: Bode C, Smalling RW, Berg G, et al.; for The RAPID II Investigators. Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. Circulation 1996;94: Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): Trial to investigate equivalence. International Joint Efficacy Comparison of Thrombolytics. Lancet 1995;346: Keyt BA, Paoni NF, Refino CJ, et al. A faster-acting and more potent form of tissue plasminogen activator. Proc Natl Acad Sci USA 1994;91: Cannon CP, McCabe CH, Gibson CM, et al. TNK-tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A dose-ranging trial. Circulation 1997;95: Cannon CP, Gibson CM, McCabe CH, et al.; for the Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: Results of the TIMI 10B trial. Circulation 1998;98: Van de WF, Cannon CP, Luyten A, et al. Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: The ASSENT-1 trial. The ASSENT-1 Investigators. Am Heart J 1999;137: Van de WF, Adgey J, Ardissino D, et al. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: The ASSENT-2 double-blind randomised trial. Lancet 1999;354: Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: The ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358: Dundar Y, Hill R, Dickson R, Walley T. Comparative efficacy of thrombolytics in acute myocardial infarction: A systematic review. QJM 2003;96: Llevadot J, Guigliano RP. Pharmacology and clinical trial results of lanoteplase in acute myocardial infarction. Expert Opin Investig Drugs 2000;9: Intravenous NPA for the treatment of infarcting myocardium early: InTIME-II, a double-blind comparison of single-bolus lanoteplase vs accelerated alteplase for the treatment of patients with acute myocardial infarction. Eur Heart J 2000;21: Spiecker M, Windeler J, Vermeer F, et al. Thrombolysis with saruplase versus streptokinase in acute myocardial infarctionfive-year results of the PRIMI trial. Am Heart J 1999;138(3 Pt 1): Tebbe U, Michels R, Adgey J, et al.; for the Comparison Trial of Saruplase and Streptokinase (COMASS) Investigators. Randomized, double-blind study comparing saruplase with streptokinase therapy in acute myocardial infarction: The COMPASS Equivalence Trial. J Am Coll Cardiol 1998;31: Bar FW, Meyer J, Vermeer F, et al. Comparison of saruplase and alteplase in acute myocardial infarction. SESAM Study Group. The Study in Europe with Saruplase and Alteplase in Myocardial Infarction. Am J Cardiol 1997;79: Vanderschueren S, Barrios L, Kerdsinchai P, et al.; for The STAR Trial Group. A randomized trial of recombinant staphylokinase versus alteplase for coronary artery patency in acute myocardial infarction. Circulation 1995;92: Armstrong PW, Burton J, Pakola S, et al. Collaborative angiographic patency trial of recombinant staphylokinase (CAPTORS II). Am Heart J 2003;146: Cannon CP, Bahit M, Haugland JM, et al. Under-utilization of evidence based medications in acute ST elevation myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI 9) registry. Crit Pathways Cardiol 2002;1: Weaver WD, Cerqueira M, Hallstrom AP, et al. Prehospital-initiated vs hospital-initiated thrombolytic therapy. The Myocardial Infarction Triage and Intervention Trial. JAMA 1993;270: Morrison LJ, Verbeek PR, McDonald AC, Sawadsky BV, Cook DJ. Mortality and prehospital thrombolysis for acute myocardial infarction: A meta-analysis. JAMA 2000;283: Boersma E, Maas AC, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: Reappraisal of the golden hour. Lancet 1996;348: Newby LK, Rutsch WR, Califf RM, et al.; for the GUSTO-1 Investigators. Time from symptom onset to treatment and outcomes after thrombolytic therapy. J Am Coll Cardiol 1996;27: Gore JM, Granger CB, Simoons ML, et al. Stroke after thrombolysis. Mortality and functional outcomes in the GUSTO-I trial. Global use of strategies to open occluded coronary arteries. Circulation 1995;92: c 2010 Blackwell Publishing Ltd Cardiovascular Therapeutics 30 (2012) e81 e88 e87

8 Thrombolytics and Myocardial Infarction V. Kunadian and C.M. Gibson 53. Gurwitz JH, Gore JM, Goldberg RJ, et al. Risk for intracranial hemorrhage after tissue plasminogen activator treatment for acute myocardial infarction. Participants in the National Registry of Myocardial Infarction 2. Ann Intern Med 1998;129: Hudson MP, Granger CB, Topol EJ, et al. Early reinfarction after fibrinolysis: Experience from the global utilization of streptokinase and tissue plasminogen activator (alteplase) for occluded coronary arteries (GUSTO I) and global use of strategies to open occluded coronary arteries (GUSTO III) trials. Circulation 2001;104: White HD, Barbash GI, Califf RM, et al. Age and outcome with contemporary thrombolytic therapy. Results from the GUSTO-I trial. Global Utilization of Streptokinase and TPA for Occluded coronary arteries trial. Circulation 1996;94: Weaver WD, Litwin PE, Martin JS, et al.; for The MITI Project Group. Effect of age on use of thrombolytic therapy and mortality in acute myocardial infarction. J Am Coll Cardiol 1991;18: Mauri F, Gasparini M, Barbonaglia L, et al. Prognostic significance of the extent of myocardial injury in acute myocardial infarction treated by streptokinase (the GISSI trial). Am J Cardiol 1989;63: Di Mario C, Dudek D, Piscione F, et al. Immediate angioplasty versus standard therapy with rescue angioplasty after thrombolysis in the Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI): An open, prospective, randomised, multicentre trial. Lancet 2008;371: Cantor WJ, Fitchett D, Borgundvaag B, et al. Routine early angioplasty after fibrinolysis for acute myocardial infarction. NEnglJMed2009;360: Cantor WJ, Fitchett D, Borgundvaag B, et al. Rationale and design of the Trial of Routine Angioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI). Am Heart J 2008;155: Wijeysundera HC, You JJ, Nallamothu BK, Krumholz HM, Cantor WJ, Ko DT. An early invasive strategy versus ischemia-guided management after fibrinolytic therapy for ST-segment elevation myocardial infarction: A meta-analysis of contemporary randomized controlled trials. Am Heart J 2008;156: Bohmer E, Hoffmann P, Abdelnoor M, Arnesen H, Halvorsen S. Efficacy and safety of immediate angioplasty versus ischemia-guided management after thrombolysis in acute myocardial infarction in areas with very long transfer distances results of the NORDISTEMI (NORwegian study on DIstrict treatment of ST-elevation myocardial infarction). J Am Coll Cardiol 2010;55: Bohmer E, Arnesen H, Abdelnoor M, Mangschau A, Hoffmann P, Halvorsen S. The NORwegian study on DIstrict treatment of ST-elevation myocardial infarction (NORDISTEMI). Scand Cardiovasc J 2007;41: Rentrop KP, Blanke H, Karsch KR, et al. Acute myocardial infarction: Intracoronary application of nitroglycerin and streptokinase. Clin Cardiol 1979;2: Ben-Ami R, Sheinman G, Yedgar S, et al. Thrombolytic therapy reduces red blood cell aggregation in plasma without affecting intrinsic aggregability. Thromb Res 2002;105: Woo KS, Armiger LC, White HD, Norris RM. Can streptokinase produce beneficial effects additional to coronary recanalization? Quantitative microvascular analysis of critically injured reperfused myocardium. Microvasc Res 2000;60: Sezer M, Oflaz H, Goren T, et al. Intracoronary streptokinase after primary percutaneous coronary intervention. NEnglJMed2007;356: Kelly RV, Crouch E, Krumnacher H, Cohen MG, Stouffer GA. Safety of adjunctive intracoronary thrombolytic therapy during complex percutaneous coronary intervention: Initial experience with intracoronary tenecteplase. Catheter Cardiovasc Interv 2005;66: Abbas AE, Brewington SD, Dixon SR, Boura JA, Grines CL, O Neill WW. Intracoronary fibrin-specific thrombolytic infusion facilitates percutaneous recanalization of chronic total occlusion. J Am Coll Cardiol 2005;46: Kushner FG, Hand M, Smith SC, Jr., et al focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;54: e88 Cardiovascular Therapeutics 30 (2012) e81 e88 c 2010 Blackwell Publishing Ltd