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Part I: Pharmacologic Reperfusion
Author: Mary C. Meyer, MD, Emergency Physician, Kaiser Walnut Creek and Richmond, CA.
Peer Reviewers: Charles L. Emerman, MD, Chairman, Department of Emergency Medicine, MetroHealth Medical Center, Cleveland Clinic Foundation, Cleveland, OH; and Steven M. Winograd, MD, FACEP, Attending Physician, Emergency Department, St. Joseph Medical Center, Reading, PA.
In 1980, researchers published a landmark study that demonstrated that transmural myocardial infarction (MI) is caused by occlusive coronary thrombosis.1 Several years later, the first thrombolytic agent, streptokinase, was found to cause a substantial mortality benefit when administered to patients with ST elevation MI (STEMI),2,3 and the era of reperfusion therapy was born. Subsequently, reperfusion therapy accomplished either pharmacologically with fibrinolytics or mechanically with percutaneous coronary intervention (PCI) has become the cornerstone of treatment for STEMI. Current practice guidelines all center on the concept of prompt restoration of epicardial blood flow. The algorithms by which this is accomplished, however, have undergone continuous evolution.
Any of several reperfusion strategies now is acceptable in the acute MI (AMI) patient—the choice among them is complex and still evolving. Traditional treatment algorithms focused on an "either/or" strategy of primary pharmacologic reperfusion in the community hospital or primary PCI in the tertiary care hospital. This choice was felt to be acceptable when the two were considered equivalent reperfusion strategies. The last decade, however, has seen a multitude of trials comparing fibrinolysis with primary PCI, and one overriding concept has emerged: primary PCI is unquestionably superior to primary thrombolysis in the treatment of AMI. Furthermore, although beneficial in reducing the mortality and morbidity associated with AMI, fibrinolysis is not without its complications.
This discovery prompted a new wave of research, all of it dedicated to the pursuit of more rapid and more complete reperfusion. Some 20 trials have been published in the last few years alone, and sorting through the literature can be dizzying. The following article will highlight the major recent developments in AMI reperfusion therapy. It will accent which of the many therapeutic options currently are considered acceptable, and present treatment guidelines for the emergency physician (EP) faced with the patient who presents to the emergency department (ED) with acute STEMI.—The Editor
Epidemiology and Pathogenesis
Approximately 1.5 million cases of STEMI occur yearly in the United States, resulting in 400,000-500,000 deaths per year.4 Mortality ranges from 5% to 50%, depending on patient characteristics, and it has been estimated that half of all patients with STEMI die prior to reaching the hospital, as a result of ventricular arrhythmia.4 This high initial mortality has remained virtually unchanged for 30 years.5
In contrast with community mortality, there has been a profound decrease in hospital mortality during the past five decades. In the 1950s, the in-hospital mortality of STEMI appears to have been approximately 25-30%.6 By the mid-1980s, prior to the thrombolytic era, this number had decreased to 18%—attributed largely to the establishment of coronary care units (CCUs) equipped with defibrillation equipment.7 With the widespread use of fibrinolytics, aspirin, and coronary interventions, the overall one-month mortality rate is now 6-7% in large-scale trials. A recent European Heart Survey suggested that the mortality of patients admitted to European community hospitals was similar: 8.4% at one month.8
The pathogenesis of ST-elevation MI involves a sudden reduction in coronary blood flow, usually caused by atherosclerosis with superimposed thrombosis. It now is understood that coronary occlusion often develops in arteries that have minimal (10-40%) stenosis at baseline.4,9,10 Rather, it is the sudden rupture of a vulnerable plaque and its resulting cascade of inflammatory and thrombotic mediators that causes arterial occlusion. Plaques most vulnerable to rupture have large lipid cores and are inflamed-infiltrated with macrophages.11,12 When a plaque becomes disrupted, the highly thrombogenic subendothelial tissues are exposed. This leads to platelet aggregation and, later, stabilization of the platelet plug once it is crosslinked with fibrin. This thrombotic response is dynamic: Thrombosis and thrombolysis occur simultaneously, often associated with vasospasm; the result is distal embolization of microscopic clot fragments as well as arterial obstruction.13 It is only recently that the importance of distal embolization has been fully appreciated—it causes microvascular obstruction that may prevent successful reperfusion even after the primary infarct-related artery has been opened.13,14
MI, or death of cardiac myocytes, begins to occur after 15-30 minutes of severe ischemia.10 It progresses from the subendocardium to the epicardium due to the greater metabolic demands of the endocardium coupled with lower perfusion and decreased collaterals.10 The presence of ST-elevation MI (previously referred to as transmural) is recognized on an electrocardiogram (ECG) as new ST-segment elevation of greater than 1 mm in two or more contiguous leads, or the presence of a left bundle-branch block not known to be old. Conversely, resolution of this ST-segment elevation has been demonstrated an excellent marker of tissue perfusion—the degree of resolution has been correlated in several studies with both short- and long-term prognosis.15,16 STEMI also is recognized by the elevation of serum biomarkers that indicate acute myocardial ischemia. Of the biomarkers, cardiac troponin is preferred due to its high sensitivity and near absolute specificity. However, since current troponin assays require some time, the EP’s decision to treat STEMI will be based on ECG changes in conjunction with a history consistent with MI.
Fibrinolysis. As noted above, fibrinolytic therapy for the treatment of STEMI began with the discovery that streptokinase offered a clear mortality benefit when compared to placebo.2,3 More than 150,000 patients now have been randomized in trials comparing fibrinolysis with control, or one fibrinolytic with another.2,3,17-19 For patients who can be treated within 12 hours of symptom onset, the evidence for benefit of fibrinolysis is overwhelming. According to the Fibrinolytic Therapy Trialists’ (FTT) Group, for patients who present within six hours of symptom onset, approximately 30 deaths are prevented per 1000 patients treated with fibrinolysis; among patients treated 7-12 hours after symptom onset, the number is 20 deaths prevented per 1000 patients treated.17 Initial concerns about thrombolysis in patients older than 75 years have proved largely unfounded. In a re-analysis of the FTT data, mortality rates in patients older than 75 years presenting with STEMI significantly were reduced by thrombolytic therapy (29.4% vs. 26%, p = 0.03).20
Five fibrinolytic agents currently are approved for the treatment of STEMI.21 These generally can be categorized according to the level of fibrin specificity. Streptokinase and anistreplase are non-specific inhibitors of fibrin, and result in systemic thrombolysis.21 Alteplase (t-PA), tenecteplase (TNK), and reteplase (r-PA) are fibrin-specific and act only on plasminogen already bound to fibrin.6 Early fibrinolytic comparisons demonstrated the superiority of an accelerated t-PA regimen over streptokinase, (10 lives saved per 100 treated with t-PA instead of streptokinase, or a 14% risk reduction, p = 0.001), establishing t-PA as the preferred drug for fibrinolytic therapy.22
Subsequent comparisons between the fibrin-specific agents failed to show significant benefit of one over the other. Accelerated t-PA was compared to r-PA in two trials, and although one study demonstrated a higher rate of TIMI 3 flow with r-PA, no mortality difference was noted in clinical trials.23,24 Similarly, TNK achieved a similar rate of TIMI 3 flow when compared to t-PA, and 30-day mortality was the same (6.17% and 6.15% respectively, p = 0.006).25,26 Hence, although some of the newer thrombolytics may achieve more ease of administration with double or single boluses, their efficacy appears to be the same. Current indications and contraindications for thrombolytic therapy are listed in Table 1.27,28
One overriding concept to emerge from the fibrinolytic trials was the importance of early drug administration.2,24,29-32 Although thrombolyics yielded a mortality advantage up to 12 hours after the onset of symptoms, this benefit was noted to be most impressive when fibrinolytics were administered within six hours of symptom onset, particularly if given in the first hour. When 58,600 patients were analyzed in the FTT trial, thrombolytics in the first hour of symptoms resulted in 65 lives saved per 1000 treated patients; this number was reduced by almost half (37 lives saved/1000 treated patients) in those treated after hour one.17 The finding led to the concept of the "golden hour" in AMI and the American College of Cardiology/American Heart Association (ACC/AHA) recommendation of a "door-to-thrombolytic time" of 30 minutes or less.27
As more data on the efficacy and mechanism of the thrombolytic drugs emerged, so did an understanding that there might be an upper limit, or ceiling, to their actions. It appears that, even in the most successful thrombolytic regimens, 90 minute TIMI 3 flow rates do not exceed 50-60%, and in patients with incomplete perfusion mortality remains high.23,25,33 Thrombolytics are associated with a 5-15% risk of re-occlusion, often resulting in re-infarction.33 As many as 15-20% of patients with STEMI have a direct contraindication to thrombolytic therapy.32 And finally, thrombolysis carries an inherent 1-2% risk of intracranial hemorrhage, usually with catastrophic results.21,33 For these and other reasons, the past five years have seen an increasing focus on adjunctive and alternative therapies to fibrinolysis in the hopes of improved coronary artery recanalization.
Prehospital ECG Transmission and Fibrinolysis
Early in fibrinolytic research it was suggested that the delay between symptom onset and treatment could be improved by moving thrombolytic administration from the CCU to the ED. Although taken for granted now, this concept at the time represented a paradigm shift in management. There now is growing evidence that a second paradigm shift—moving treatment from the ED to the prehospital arena—similarly may be beneficial to the patient. This shift may be relatively simple: Paramedic units might obtain an ECG in the field and alert a receiving hospital to the patient’s imminent arrival. Alternately, paramedics ultimately may be administering thrombolytics in the field.
Technologic advances have made it feasible to obtain 12-lead ECGs in the prehospital setting and transmit them to a base hospital. In two studies, paramedic ECG acquisition had minimal effect on scene-evaluation time (associated with a 1- to 7-minute delay).34,35 It also is evident that prehospital ECG transmission reduces average time to treatment. Although limited by confounding factors, the NRMI-2 data demonstrated reduced door-to-fibrinolysis and door-to-balloon time with prehospital ECG transmission, with an associated mortality benefit.36 Even more impressive were the findings of the Myocardial Infarction Triage and Intervention (MITI) Trial. In this study, the control group received an ECG in the field and treatment upon arrival to the ED; when compared to standard hospital patients not enrolled in the study, control patients were fibrinolysed, on average, 40 minutes earlier (20 minutes vs 60 minutes door-to-thrombolyic, p < 0.001).37 It appears that advance notification that an AMI patient will be arriving hastens hospital triage, similar to the concept underlying the trauma activation system. Prehospital ECGs have been studied only in conjunction with prehospital fibrinolysis, but it is an area that warrants more investigation.38 The small amount of data that exists suggests a real advantage to prehospital ECGs, with improved patient triage.
Before 1993, prehospital fibrinolysis was tested in several small trials outside of North America. The MITI trial was the first large American study to address prehospital thrombolytic administration. The study randomized 360 patients with STEMI to receive either alteplase or placebo and rapid transfer to a receiving ED.37 Investigators found no difference in mortality or a composite outcome of death, stroke, major bleeding, and infarct size, in spite of the fact that thrombolytic administration in the treatment group was significantly faster than the control group (92 vs 120 minutes, p < 0.001).37 The findings were thought to be due, in part, to the rapid fibrinolysis of the control group. As noted above, even the control group received fibrinolysis 40 minutes earlier than AMI patients not enrolled in the study. The MITI study and its lack of significant findings dampened initial enthusiasm for prehospital thrombolysis. The emphasis once again was placed on rapid ED triage and thrombolytic administration.
However, new data suggest that this conclusion may have been premature. A meta-analysis was performed seven years after the MITI study and included six randomized studies involving 6434 patients.38,39 Individually, each of the six trials favored prehospital thrombolysis but failed to show a statistically significant benefit. By contrast, the meta-analysis found that time-to-treatment was reduced by 58 minutes with prehospital fibrinolysis, and this time reduction was associated with a 17% relative risk reduction in hospital mortality (1.7% absolute risk reduction, or one life saved for every 62 patients treated by prehospital rather than in-hospital fibrinolysis).39 Data were insufficient to study 30-day and 60-day mortality. Prehospital fibrinolysis carried no associated risk of inappropriate therapy or compromise of patient safety.
More recently, the Evaluation of the Time Saved by Prehospital Initiation of Reteplase for ST-Elevation Myocardial Infarction (ER-TIMI) 19 trial randomized 945 patients to prehospital or hospital retevase.40 Both endpoints measured were significantly altered by prehospital fibrinolysis. Time from EMS arrival to fibrinolysis averaged 31 minutes in the treatment group, compared with 63 minutes among controls (p < 0.0001).40 Furthermore, although both groups ultimately obtained the same degree of ST resolution on ECG (49.4% complete and 59.95% > 50% ST resolution), this result was achieved 30 minutes earlier in patients treated with prehospital r-PA.40 Rates of intracranial hemorrhage did not differ between the two groups.
Finally, in an intriguing hypothesis, the Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction (CAPTIM) study was designed to evaluate if prehospital fibrinolysis might be a more effective strategy than primary angioplasty in the treatment of AMI.41 The study included 840 AMI patients who received either prehospital alteplase or transfer to a hospital for immediate PCI. Among patients who underwent primary PCI, 6.2% experienced the primary endpoint (composite of death, nonfatal reinfarction, and non-fatal disabling stroke within 30 days) compared to 8.2% in the prehospital fibrinolysis group (p = 0.29).41 Rates of hemorrhagic stroke were similar in the two groups. Of note, there was a nonsignificant but concerning trend toward increased mortality in the PCI group (4.8% vs 3.8%). Also important is the fact that 26% of the patients who received fibrinolytics required rescue angioplasty, and a total of 33% required urgent angioplasty compared with just 4% in the primary PCI group (p < 0.0001).41
The findings of all these studies, and CAPTIM in particular, are intriguing. They suggest that prehospital fibrinolysis certainly is safe, and may even be as effective as primary PCI, with the caveat that fibrinolysis patients frequently will require rescue PCI. Hence, patients who undergo prehospital fibrinolysis often will require transfer to a facility with PCI capabilities. The CAPTIM study does suffer from some limitations; most significantly, the trial enrolled fewer patients than initially planned, resulting in large confidence intervals and reduced statistical power. Nonetheless, it raises an interesting question: Is the combined use of prehospital fibrinolysis with liberal use of rescue PCI a preferential treatment strategy for AMI? An ongoing study—the Prehospital Administration of Thrombolytic Therapy with Urgent Culprit Artery Revascularization (PATCAR)—will help answer this question. The study will examine the effects of prehospital or hospital fibrinolytic administration followed by transfer for acute angiography and stenting.
Current ACC/AHA recommendations endorse prehospital ECG use but are hesitant regarding prehospital fibrinolysis.27 They express concern about the medical and legal implications of this strategy, but suggest that in certain settings prehospital fibrinolysis may be appropriate, especially if a physician is present in the ambulance or transport times are likely to be prolonged.27 Taken together, the research in prehospital ECGs and fibrinolysis is encouraging. In the future, ED physicians should expect to see more incorporation of prehospital care into existing AMI treatment protocols.43
Combined Fibrinolysis and GP IIB/IIIA Inhibitors
An alternate pharmacological reperfusion strategy is lytic therapy in conjunction with a glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist. Platelet inhibition has been a key component of reperfusion therapy since early trials demonstrated the benefit of aspirin in AMI. However, aspirin is a relatively weak antiplatelet drug. In contrast, the GPIIb/IIIa inhibitors block the platelet aggregation phase of acute thrombus formation—the final common pathway by which a platelet plug is formed over a ruptured plaque.21 Although thrombolytics increase TIMI 3 flow in the occluded artery, they also paradoxically increase platelet aggregation.44-46 Hence, the theoretical advantage of combination fibrinolysis-GP IIb/IIIa inhibitor therapy is decreased clot formation and distal embolization. Three GPIIb/IIIa inhibitors currently are available: abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat).44
Early studies of reduced-dose fibrinolysis in combination with a GPIIb/IIIa inhibitor were promising. In TIMI-14, the Strategies for Patency Enhancement in the Emergency Department (SPEED), and the Integrilin and Reduced-Dose of Thrombolytics in AMI (INTRO-AMI) studies, higher rates of TIMI 3 flow were reported in patients who received combination therapy over standard-dose thrombolytics.47-50 In TIMI-14, TIMI 3 flow at 90 minutes significantly was improved in patients who received t-PA and abciximab vs. t-PA alone (77% vs 62%, p = 0.01); the combination of r-PA and abciximab similarly was associated with improved flow, although the difference was not significant (73% vs 70%).47,48 In INTRO-AMI, a combined strategy of t-PA plus eptifibatide achieved significantly higher rates of TIMI flow when compared to t-PA alone.50
Unfortunately, the two trials which examined the impact of combination therapy on clinical endpoints were more disappointing. In GUSTO V, 16,588 patients received reteplase or half-dose reteplase and abciximab.42 At 30 days, the primary endpoint of mortality was no different between the two groups (5.9% vs 5.6%, p = 0.43). Nor did a series of prespecified subgroups (women, elderly, diabetics, anterior MI) have a mortality benefit with combination therapy. The study did note modest reductions in a number of secondary endpoints, including recurrent ischemia, re-infarction, and the need for revascularization.42 These benefits, however, were offset by significantly higher bleeding rates: 1.1% severe bleeding vs. 0.5%, transfusion in 5.7% vs. 4.0%. Most concerning was the increased rate of intracranial hemorrhage that occurred in patients older than 75 years of age (2.1% combination therapy vs 1.1%, p = 0.069). Recently, the GUSTO V investigators published their one-year follow-up results: No mortality benefit was seen between the two groups.51
In the Assessment of the Safety and Efficacy of a New Thrombolytic-III (ASSENT-III) trial, 6095 patients were randomized to tenecteplase and unfractionated heparin, tenecteplase and low molecular weight heparin, or tenecteplase and abciximab.52 The primary outcome was a composite of death, reinfarction, and refractory ischemia. Although the primary endpoint was significantly reduced with combination therapy over tenecteplase plus low-molecular-weight heparin, the frequency of major bleeding and intracranial hemorrhage in the elderly was increased. When a combined efficacy and safety endpoint was evaluated, the tenecteplase-enoxaparin arm appeared to be the most attractive option due to lower rates of bleeding.52
So where do these studies leave us? Frankly, the role of combination therapy is not clear—there are some benefits but they come at the cost of increased bleeding rates. This has diminished much of the excitement over combination therapy, and most institutions have not implemented the strategy in their STEMI practices.44-46 In particular, ASSENT-III suggested that fibrinolysis plus low-molecular-weight heparin provides similar clinical outcomes to combination therapy but without the bleeding complications. Combination therapy also is unlikely to be competitive with a primary PCI strategy.45 Fibrinolysis plus GP IIb/IIIa inhibitors should not be used in patients older than 75 years of age due to increased intracranial hemorrhage rates.
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