Reperfusion strategies in the emergency treatment of ST-segment elevation myocardial infarction

American Journal of Emergency Medicine (2007) 25, 353 – 366

www.elsevier.com/locate/ajem

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Reperfusion strategies in the emergency treatment of ST-segment elevation myocardial infarctionB W. Frank Peacock MDa,*, Judd E. Hollander MDb, Richard W. Smalling MDc, Michael J. Bresler MDd a

Department of Emergency Medicine, The Cleveland Clinic, Cleveland, OH 44195, USA Department of Emergency Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA c Division of Cardiovascular Medicine, The University of Texas Medical School at Houston and The Memorial Hermann Heart and Vascular Institute, Houston, TX 77225, USA d Department of Surgery, Division of Emergency Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA b

Received 17 May 2006; revised 17 July 2006; accepted 25 July 2006

Abstract Prompt restoration of blood flow is the primary treatment goal in ST-segment elevation myocardial infarction to optimize clinical outcomes. The ED plays a critical role in rapid triage, diagnosis, and management of ST-elevation myocardial infarction, and in the decision about which of the 2 recommended reperfusion options, that is, pharmacologic and mechanical (catheter-based) strategies, to undertake. Guidelines recommend percutaneous coronary intervention (PCI) if the medical contact-to-balloon time can be kept under 90 minutes, and timely administration of fibrinolytics if greater than 90 minutes. Most US hospitals do not have PCI facilities, which means the decision becomes whether to treat with a fibrinolytic agent, transfer, or both, followed by PCI if needed. Whichever reperfusion approach is used, successful treatment depends on the ED having an integrated and efficient protocol that is followed with haste. Protocols should be regularly reviewed to accommodate changes in clinical practice arising from ongoing clinical trials. D 2007 Elsevier Inc. All rights reserved.

1. Introduction The critical goal for the emergency physician in the treatment of ST-segment elevation myocardial infarction (STEMI) is the rapid and effective restoration of blood flow in the infarct-related artery to preserve viable heart muscle. Ischemia resulting from an occluded coronary artery will B Source of support: preparation of this manuscript was supported by PDL BioPharma Inc. * Corresponding author. Tel.: +1 216 445 4546. E-mail address: [email protected] (W.F. Peacock).

0735-6757/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2006.07.013

produce necrosis of the myocardium, beginning within 15 minutes and progressing over 4 to 6 hours or more, depending on the extent of collateral blood flow, any ongoing coronary artery occlusion, and the sensitivity of myocytes to ischemia [1,2]. Thus, the ultimate therapeutic goal is to shorten the total ischemic time as much as possible. A related important secondary goal is to prevent reocclusion of the opened artery [3,4] and to treat immediate complications such as pump failure, shock, and lifethreatening arrhythmias [4]. Blood flow can be restored pharmacologically with fibrinolytic therapy, or mechanically through angioplasty

354 with stent placement. The choice of a reperfusion strategy should be based on numerous factors, including patient eligibility criteria, time since symptom onset, ED capabilities, and availability of cardiac catheterization facilities. As most US hospitals do not have facilities to perform percutaneous coronary intervention (PCI) [5], this will often be a choice between treatment with a fibrinolytic agent, transferring the patient to a PCI-capable hospital, or both. Whichever strategy is chosen, rapid triage, diagnosis, and treatment are essential—studies show that STEMI mortality increases with delays to reperfusion therapy, whether the treatment strategy is fibrinolytic therapy (Fig. 1) or PCI (Fig. 2) [6-10]. Not only does prompt restoration of blood flow to the occluded artery save lives, but it reduces infarct size, minimizes myocardial damage, preserves left ventricular function, and decreases associated morbidity [11]. These findings have led to the concept of the bgolden hourQ; that is, that treatment within the first hour after symptom onset maximizes the benefit of reperfusion therapy. The recommended goal to be achieved in patients with STEMI is a door/medical contact-to-needle time within 30 minutes for fibrinolytic agents and a medical contact-toballoon time within 90 minutes for primary PCI [1,4]. Use of an integrated pharmacoinvasive or facilitated PCI strategy, combining early pharmacologic therapy with immediate or future scheduled catheter-based therapy, is an area of ongoing research. The ED, both in community hospitals and PCI-capable hospitals, plays a pivotal role in the management of STEMI as the patient progresses through the diagnostic processes to the ultimate implementation of a chosen reperfusion strategy. The purpose of this manuscript was to present an overview of currently recommended reperfusion

Fig. 1 Change in mortality associated with time to fibrinolytic treatment [7]. All patients in the ASSET and Late Assessment of Thrombolytic Efficacy (LATE) studies were included because the tabular information available from these trials subdivided by delay was not subdivided by electrocardiogram results. BBB indicates bundle branch block. Adapted with permission from Lancet 1994;343:311-22.

W.F. Peacock et al.

Fig. 2 Change in mortality associated with medical contact-toballoon time [10]. OR indicates odds ratio; CI, confidence interval. Adapted with permission from JAMA 2000;283:2941-47.

strategies in the emergency treatment of STEMI and to discuss appropriate initiation of the first reperfusion therapy in the ED.

2. Diagnosis and initial management of STEMI 2.1. Diagnostic procedures Upon admission to the ED, a patient presenting with symptoms of STEMI, non-STEMI, or a suspected acute coronary syndrome (ACS) should be considered a high priority triage case and subsequently evaluated and treated in accordance with an institution-specific chest pain protocol. The initial triage should include a 12-lead electrocardiogram (ECG) as strong evidence supports that ST-segment elevation identifies those patients likely to benefit from reperfusion therapy. For example, mortality rates are known to increase with the number of ECG leads showing ST elevation, left bundle branch block, or anterior myocardial infarction (MI) [1]. The American College of Cardiology/American Heart Association (ACC/AHA) 2004 guidelines on the care management of acute STEMI recommend that the ECG results should be analyzed by an experienced emergency physician within 10 minutes of patient arrival [1]; these results may also be compared to any prehospital ECG recording that may have been performed in the ambulance. Ideally, 12-lead ECGs performed by paramedics in the field should be transmitted to the receiving institution for immediate confirmation of diagnosis, if possible. A patient history should be performed expeditiously. It is important to ascertain the time of symptom onset; whether the patient has experienced previous episodes of myocardial ischemia, MI, coronary bypass surgery, or PCI; and whether there are any contraindications for treatment [1]. A brief physical examination should also be performed, focusing on

Emergency reperfusion in ST-elevation myocardial infarction identifying potential contraindications to fibrinolysis, such as prior stroke, new neurologic findings that might suggest aortic dissection with carotid artery extension, and severe heart failure, which is an indication for PCI [1]. Registry data indicate that as many as 30% of patients eligible for reperfusion therapy do not receive it [12], and one of the main reasons for this is atypical presentation, that is, no chest pain, but ST-segment elevation on ECG. Therefore, biomarkers of cardiac necrosis are important to ascertain in any patient with suspected acute myocardial infarction. However, reperfusion decisions should not be delayed while waiting for biomarker results, particularly if the patient presents with both continuous chest pain and ST elevation on ECG. For maximum clinical benefit, the emergency physician has a relatively short time-window before initiating a reperfusion strategy. Consequently, the results provided by the 12-lead ECG will be the primary determinant of eligibility for reperfusion therapy, that is, identification of ST-segment elevation on contiguous leads or a new, or apparently new, left bundle branch block. However, additional information derived from other diagnostic procedures may be necessary in some cases to determine the preexistence of complications that may prevent a particular reperfusion strategy from being instituted, such as a recent history of hemorrhagic ulcer, stroke, or head injury, which might preclude the use of fibrinolytic therapy.

3. Overview of emergency STEMI reperfusion treatment options The choice of a reperfusion strategy must be made promptly to protect the myocardium from further potential damage. Initially, the fundamental goal is to keep total ischemic time as short as possible. An institutionally approved reperfusion strategy protocol should be ready for implementation from the time of initial patient contact with the medical system. If paramedics in the field can perform 12-lead ECG and transmit to the receiving institution for confirmation of diagnosis, it may be possible to administer prehospital heparin, antiplatelet, and fibrinolytic therapy. Alternatively, the catheterization laboratory and the interventional cardiology teams can be notified of the patient’s impending arrival, thus shortening time to PCI, if available. A number of clinical factors will determine patient eligibility for a specific reperfusion intervention, including the determination of time-to-needle vs time-to-balloon, assessments based on risk stratification, institutional adherence to risk-stratification protocols, availability of trained staff and interventional cardiology resources, availability of (or ability to provide timely patient transfer to) a 24-hour PCI-capable facility, and the presence of both inclusionary and exclusionary factors that will determine a patient’s eligibility for fibrinolysis [13]. Although the use of coronary artery bypass graft (CABG) for acute reperfusion

355 in STEMI has now been superseded to a great extent by primary PCI and fibrinolysis, urgent or emergency CABG may have a role in the treatment of some patients, such as those with severe multivessel disease, left main coronary artery stenosis, or anatomic features unfavorable for PCI, and those in whom PCI has failed [1]. In addition, patients with mechanical complications such as ventricular septal defect may undergo surgery rather than PCI. However, it should be noted that there is an increased mortality risk associated with urgent/emergency CABG compared with elective surgery [1]. Both the revised practice guidelines released in 2004 by the ACC/AHA Task Force on Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction [1] and the European Society of Cardiology guidelines [14] indicate that PCI is the preferred choice of reperfusion strategies in the management of STEMI, as long as intervention is rapid and performed at centers with a skilled PCI laboratory [1,4]; in addition, the ACC/AHA guidelines recommend that PCI be performed at a facility with cardiac surgery capability [1]. In this context, brapidQ is defined as within 90 minutes of first medical contact. However, it has been estimated that only around 25% of US acute-care hospitals are capable of performing PCI (approximately half of those with catheterization laboratories) [5,15], and even then the facility or required resources may not be available within the desired time frame. When there is potential delay to PCI for a patient presenting up to 3 hours after symptom onset, the emergency physician must decide whether the best course for the patient is to receive a fibrinolytic instead of, or before, PCI. This becomes the blytic decision zoneQ (Fig. 3). For patients presenting more than 3 hours after symptom onset, an invasive strategy is generally preferred [1]. All patients, whether receiving fibrinolysis or undergoing PCI, should receive heparin [1,4,16] to help prevent reocclusion caused by plaque rupture–mediated activation of the coagulation cascade. The ACC/AHA guidelines recommended that unfractionated heparin be given as a bolus of 60 U/kg (up to a maximum of 4000 U) followed by an infusion of 12 U/kg per hour (up to a maximum of 1000 U/h), adjusted to maintain activated partial thromboplastin time at 1.5 to 2.0 times control, in patients receiving reperfusion therapy [1]. Unfractionated heparin is well studied in this situation and is appropriate for any of these patients. However, a reduced dose of unfractionated heparin is recommended for use in fibrinolytic-treated patients and in patients undergoing PCI who receive a glycoprotein (GP) IIb/IIIa inhibitor [1]. There is a less extensive body of evidence regarding low molecular weight heparins in combination with fibrinolytics; however, the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis in Myocardial Infarction 25 study (ExTRACT-TIMI 25) [17] and Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) study [18,19] have shown a clinical benefit (on the composite endpoint of

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W.F. Peacock et al.

Fig. 3 bLytic decision zonesQ for the emergency physician. The shaded boxes indicate the periods of unknown time delays during which a decision must be made about whether or not to administer a fibrinolytic. *ACC/AHA guidelines state that an invasive strategy is generally preferred for patients presenting more than 3 hours after symptom onset [1].

death or nonfatal reinfarction within 30 days, largely due to a reduction in nonfatal reinfarction) with low molecular weight heparins over unfractionated heparin, when used in combination with fibrinolytics. Selective factor Xa inhibition is a novel therapeutic modality that may also have potential in STEMI [1]. Recent data from the Organization for the Assessment of Strategies for Ischemic Syndromes-6 (OASIS-6) study, which compared the factor Xa inhibitor fondaparinux with usual care (placebo or unfractionated heparin, depending on the presence of an indication for treatment with heparin), indicated that fondaparinux provided benefits over usual care in the subgroup of patients who did not receive initial reperfusion therapy or who were also treated with fibrinolytics, but not among patients who underwent primary PCI [20]. In terms of mortality benefit in patients with STEMI, the use of any reperfusion therapy is clearly preferable to no reperfusion therapy at all. It has been shown that reperfusion with fibrinolytic therapy reduces 35-day mortality by 18% [7], with even greater reductions of 25% to 35% when given within 3 hours of symptom onset (Fig. 1). However, the benefit is likely to be even greater than this because these data were derived from early fibrinolytic studies, and even lower mortality rates with fibrinolytics have been reported in more recent clinical trials (discussed in the following section). Thus, it is important to consider the inherent benefits and risks

associated with mechanical (PCI) or pharmacologic (fibrinolytic agent) reperfusion strategies.

4. Primary PCI Compared with fibrinolysis, cardiac catheterization followed by PCI has several advantages: (1) fewer patient exclusions (it is suitable for z90% of patients); (2) significantly higher initial reperfusion rates (TIMI 3 flow range from 70% to 90%); (3) a lower risk of intracranial bleeding; (4) earlier delineation of coronary artery architecture; and (5) risk stratification of patients [1,13,21]. Percutaneous coronary intervention is generally preferred in high-risk patients, such as the elderly (age z75 years) and those with cardiogenic shock, congestive heart failure, or ventricular arrhythmias [1,22], and in those in whom the diagnosis is unclear. To date, there is clinical evidence showing that PCI is associated with a lower risk of nonfatal reinfarction, hemorrhagic stroke, and short-term mortality compared with fibrinolytic therapy [23]. In a meta-analysis of 23 randomized trials enrolling fibrinolytic-eligible patients (n = 7739) with STEMI, primary angioplasty was significantly better at reducing overall short-term mortality vs fibrinolytic therapy (7% vs 9%; P = .0002), nonfatal reinfarction (3% vs 7%; P b .0001), and stroke (1% vs 2%;

Emergency reperfusion in ST-elevation myocardial infarction P = .0004) [23]. However, it is important to note that the positive outcomes in the above meta-analysis were obtained in medical centers with experienced ED staff and prompt medical contact-to-balloon times, where patients would be expected to derive the greatest benefit from PCI. Also, the magnitude of the treatment differences was variable between the studies depending on whether PCI was compared with a fibrin-specific lytic agent (such as reteplase or tenecteplase) or streptokinase, the use of unfractionated heparin as ancillary therapy, as well as other protocol variables [23]. Other aspects of management mandated in clinical trials of fibrinolytics may also have influenced results. For example, patients receiving fibrinolytics in the trial setting may not undergo coronary angiography and, in the event of recurrent MI, may receive repeat treatment with fibrinolytics rather than undergo emergent angiography. In studies comparing transfer for PCI with fibrinolysis, a number of factors tended to favor PCI over fibrinolysis, but might not reflect what is seen in the breal worldQ [24]. These include use of protocols that shortened door-to-balloon times by calling ahead to activate catheterization laboratories and bypassing the ED and coronary care unit; exclusion of patients who were not considered safe for transfer; treatment of patients with recurrent MI after fibrinolysis with repeat fibrinolysis rather than rescue PCI; and exclusion of periprocedural MIs in patients undergoing PCI from composite primary endpoints [24].

4.1. Complications to PCI Complications specific to primary PCI in the treatment of STEMI include (1) adverse reactions to contrast medium; (2) volume loading; (3) problems with arterial access; and (4) technical complications such as coronary artery dissection [1]. Reocclusion occurs in 10% to 15% of patients after percutaneous transluminal coronary angioplasty but in less than 5% after stent implantation. Similarly, the long-term effectiveness of PCI is limited by the occurrence of arterial restenosis, but the incidence has decreased with the advent of stent implantation. Restenosis occurs in 30% to 40% of patients after percutaneous transluminal coronary angioplasty, but decreases to approximately 15% to 20% with stent implantation [1]. Use of drug-eluting stents further reduces the risk of angiographic restenosis, but does not appear to affect mortality, relative to bare metal stents [25]. In addition, when stents are used it is important to continue antiplatelet therapy with clopidogrel, to prevent rethrombosis [1]. Perhaps the biggest disadvantage to the use of PCI is that practical and logistical problems may preclude its use in many cases. As stated previously, it has been estimated that fewer than 25% of acute-care hospitals in the United States have a catheterization laboratory capable of performing PCI; unless rapid transfer is available, the use of PCI would result in unacceptable delays to reperfusion,

357 thus negating its benefit. It has been shown that a prolonged time to PCI is associated with increases in inhospital mortality [9] and long-term (1 and 7 years) mortality [6,9]. A recent analysis of National Registry of Myocardial Infarction data showed that only 37% of patients have a medical contact-to-balloon time within the recommended 90 minutes after presentation and that another 40% do not receive PCI until 2 hours or more after presentation [26]. Furthermore, in those patients who are transferred to a PCI-capable hospital, the median medical contact-to-balloon time in the United States has been shown to be approximately 180 minutes, with only 4.2% of patients actually achieving the reperfusion benchmark of 90 minutes [5]. A recent meta-analysis found that, although increased delay times may be justified for highrisk patients, those with a mortality risk of less than 4% were unlikely to receive any mortality benefit from PCI (compared with fibrinolysis), and PCI may actually be disadvantageous in low-risk patients when immediate fibrinolysis is available [27]. Because for every 10-minute delay in PCI there is a 1% decrease in the mortality difference between PCI and fibrinolytics (Fig. 4) [28], extended medical contact-to-balloon times decrease the relative advantage of PCI and fibrinolytics become the therapy of choice. It should be noted that presentation during off-hours results in substantially longer times to treatment for PCI but not for fibrinolytic therapy; thus, even fewer patients reach recommended medical contact-to-balloon times during these hours [29]. Data from the National Registry of Myocardial Infarction–3/4 registries showed that factors influencing the doorto-balloon time for patients requiring transfer for PCI were the presence of diabetes mellitus, a history of CABG, the presence or absence of chest pain at presentation, the extent

Fig. 4 Absolute risk reduction in 4- to 6-week mortality with primary PCI as a function of PCI-related time delay [28]. Circle sizes reflect the sample sizes of individual studies included in the analysis. Values greater than 0 represent benefit and values less than 0 represent harm (indicating that fibrinolysis is favored). The solid line represents the weighted meta-regression analysis. Reprinted with permission from Am J Cardiol 2003;92:824-6 [28].

358 of primary ECG findings, the duration of symptoms at arrival, the timing of presentation at the initial hospital (regular or off-hours), and facility location (urban or rural) and teaching status (teaching or nonteaching) [5]. Although many of these factors cannot be changed, there are still strategies that can help in minimizing the time to treatment for patients undergoing PCI. Key elements of successful strategies to reduce door-to-balloon times include organizations having an explicit goal of reducing door-to-balloon times, with strong support from senior management and key clinical leaders, and an organizational culture that encourages persistence in overcoming setbacks; focused initiatives to develop innovations to existing standard protocols for treating patients with STEMI, with the flexibility to allow continuous refinement; collaborative, interdisciplinary teams (necessary to achieve important aspects such as rapid acquisition and interpretation of ECG results, ideally before the patient arrives in the ED, with the information transmitted by paramedics, and rapid activation of the catheterization team by ED physicians); and data feedback to monitor progress [30,31]. The level of experience of the catheterization laboratory personnel is an important factor in whether primary PCI is the preferred treatment strategy. The ACC/AHA guidelines for the treatment of STEMI note that an invasive strategy is only preferred when access is available to a skilled PCI laboratory (ie, performed by an individual with experience of N75 PCI procedures per year, and a laboratory performing N200 PCI procedures per year, of which at least 36 are primary PCI for STEMI), with backup surgical capability [1]. Finally, PCI is an expensive treatment option from a health economics perspective, requiring experienced practitioners and costly catheterization laboratory resources [1]. As the key decision maker in the selection of the appropriate reperfusion strategy, the emergency physician must consider the risk/benefit ratio of promptly initiating fibrinolytic therapy or delaying therapy in favor of PCI. In particular, the logistical problems involved in transfer of patients with STEMI may make fibrinolytic reperfusion the better option, while reserving tertiary resources for patients with STEMI in combination with large myocardial infarctions, cardiogenic shock, failed fibrinolysis, or other conditions favoring PCI [27]. Moreover, if the total cumulative delay to PCI will place a patient at risk, the emergency physician may choose to start fibrinolysis, then transfer to the PCI facility. In addition to antithrombin therapy, as described previously, treatment with a GP IIb/IIIa inhibitor should be started before primary PCI [1]. The precise time dependency of this recommendation is unclear, with some recommending early upstream use. Pretreatment of patients undergoing PCI with a loading dose of clopidogrel, to reduce the risk of adverse ischemic events, is recommended in guidelines from the European Society of Cardiology, the American College of Cardiology, the American Heart Association, and the Society for

W.F. Peacock et al. Cardiovascular Angiography and Interventions [1,14,32]. However, it should be noted that the ACC/AHA guidelines recommend delaying initiation of clopidogrel until angiography confirms that emergent CABG is not indicated, as patients undergoing CABG within 5 to 7 days of clopidogrel treatment have an increased bleeding risk, [1] although this issue remains controversial [32].

5. Fibrinolysis Pharmacologic reperfusion with fibrinolytic therapy instituted within 70 minutes from the onset of symptoms can dramatically reduce mortality [1,7,33,34]. Owing to a rapid administration time, fibrinolytics are often the preferred treatment during the bgolden hour.Q In addition, within the first 2 hours between the onset of symptoms and commencement of treatment, fibrinolytics have been shown to reduce mortality by as much as 48% [8]. Gersh et al [35] have suggested that the relationship among time to treatment, mortality, and myocardial salvage may be represented by a curve (Fig. 5), with the greatest benefit and greatest sensitivity to delay during a critical early period of the first 2 to 3 hours after symptom onset. Fibrinolytic therapy is more widely available than PCI and does not need a cardiac interventionalist or catheterization laboratory for administration. Prompt restoration of patency reduces infarct size, minimizes the extent of myocardial

Fig. 5 Hypothetical construct of the relationship among the time from onset of symptoms of acute MI to reperfusion therapy, mortality reduction, and extent of myocardial salvage [35]. The benefit of reperfusion therapy with regard to mortality is greatest in the first 2 to 3 hours after symptom onset, most likely a consequence of myocardial salvage. After this critical early period, the magnitude of the mortality benefit is much reduced, and as the mortality reduction curve flattens, time to reperfusion therapy is less critical. If a treatment strategy is able to move patients back up the curve, a benefit would be expected. The benefit of a shift from point A or B to point C would be substantial, but the benefit of a shift from point A to point B would be small. A treatment strategy that delays therapy during the early critical period, such as patient transfer for PCI, would be harmful (shift from point D to point C or point B). Reprinted with permission from JAMA 2005;293:979-86.

Emergency reperfusion in ST-elevation myocardial infarction damage, preserves left ventricular function, and reduces morbidity [11]. As time to reperfusion plays the key role in improving patient outcomes, a number of studies have assessed the feasibility and efficacy of initiating fibrinolytic therapy before the patient arrives at the hospital. Diagnosis of STEMI through the use of 12-lead ECGs by emergency medical services has enabled the initiation of pharmacologic reperfusion while still in transit to the hospital. Clinical data collected to date have been promising, although additional studies are needed. A meta-analysis of data from prehospital fibrinolysis studies demonstrated a 17% relative reduction in mortality rates with prehospital vs inhospital fibrinolysis [36]. Similarly, data from the Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction (CAPTIM) trial demonstrated that patients randomized less than 2 hours after symptom onset showed a strong trend toward reduced 30-day mortality with prehospital fibrinolysis vs primary PCI ( P = .058; 2.7% vs 5.7%, respectively) [37]. In this regard, a fibrinolytic agent that can be given as bolus injections without the need for weight-based dosing, for example, reteplase, may be particularly well suited for prehospital use. In the Early Retavase-Thrombolysis in Myocardial Infarction 19 ER-TIMI 19 study, 97% of patients receiving prehospital fibrinolysis with reteplase received treatment within 60 minutes of first medical contact; this compares with only 48% among historical controls at the same hospitals who received standard inhospital STEMI treatment [38]. In addition, those patients randomized to prehospital fibrinolysis reached ST resolution more quickly than the inhospital treatment cohort [38]. International studies have suggested that prehospital administration of a fibrinolytic followed by PCI on arrival at a PCI-capable hospital may produce even better outcomes than prehospital fibrinolysis without PCI [39,40]. However, the concept of facilitated PCI (the intentional combination

Table 1

359 of fibrinolytics and PCI) is controversial in light of a recent meta-analysis [41] (see Section 10 below). Some centers in the United States use a strategy of prehospital administration of half-dose fibrinolytic followed by transfer to a PCI-capable hospital. The strategy of initiating fibrinolytic therapy with a half-dose of fibrinolytic, either in the field by emergency medical services professionals or in smaller community hospitals, before transfer for PCI, has shown promise in studies conducted to date [40,42] and is currently being actively investigated in the United States in the Prehospital Administration of Thrombolytic therapy with urgent Culprit Artery Revascularization (PATCAR) trial [43]. It has also been shown that having an integrated protocol that involves cardiology, ED, and paramedic services in patient transfer for PCI can significantly reduce medical contact-to-balloon time [44].

5.1. Overview of current fibrinolytic agents If a fibrinolytic agent is chosen as the most appropriate reperfusion therapy for a patient presenting with STEMI, there are several from which to choose, each agent having its own inherent risks and benefits. The 4 fibrinolytic agents approved in the United States are streptokinase, alteplase (t-PA), reteplase, and tenecteplase [1]. Streptokinase is a nonspecific plasminogen activator, whereas alteplase, reteplase, and tenecteplase are all fibrin-specific agents (Table 1). Choosing a particular agent will depend on numerous factors including hospital formulary preferences, cost, ease of administration (bolus vs infusion), and the possibility of performing subsequent PCI. Based on data from both the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) [46] and Global Use of Strategies to Open Occluded Coronary Arteries (GUSTOIII) [47] trials, accelerated alteplase and reteplase (either agent in combination with intravenous heparin) may provide advantages over streptokinase.

Comparison of key characteristics of approved fibrinolytic agents [1,45,55]

Dose Weight-based dosing Method of administration Antigenic Allergic reactions Fibrin specificity 90-min patency rates, approximate % TIMI grade 3 flow, % Cost per recommended MI dose (US$)c

Streptokinase

Alteplase

Reteplase

Tenecteplase

1.5 MU over 30-60 min No Infusion Yes Yes No 50 32 562.50

Up to 100 mg in 90 min (based on weight)a Yes Bolus + infusion No No Yes 75 54 3404.78

10 U  2 each over 2 min No Double bolus No No Yes 80 60 2872.5

30-50 mg based on weightb Yes Bolus No No Yes 75 63 2917.48 for 50 mg

Modified with permission from J Am Coll Cardiol 2004;44:E1-211. a Bolus 15 mg, infusion 0.75 mg/kg  30 minutes (maximum 50 mg), then 0.5 mg/kg not to exceed 35 mg over the next 60 minutes to an overall maximum of 100 mg. b 30 mg for weight less than 60 kg; 35 mg for 60 to 69 kg; 40 mg for 70 to 79 kg; 45 mg for 80 to 89 kg; 50 mg for 90 kg or more. c Red Book 2005.

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6. Streptokinase Streptokinase has a half-life of 15 to 25 minutes and is administered intravenously over a 60-minute period. The beneficial effect of streptokinase in MI was demonstrated in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-1 (GISSI-1) [48] and Second International Study of Infarct Survival (ISIS-2) [49] trials, which showed a 23% and 30% mortality reduction, respectively, compared to placebo when therapy was given within 3 and 6 hours, respectively, of MI symptom onset. Although commonly used outside of the United States, owing to its immunogenicity and a lack of fibrin specificity, streptokinase is rarely used in the United States [50].

7. Alteplase Alteplase (recombinant t-PA) is a second-generation recombinant protein similar to tissue plasminogen activator (t-PA) occurring naturally in the body. Its mechanism of action is to bind to fibrin in a thrombus and convert entrapped plasminogen to plasmin, thereby initiating local fibrinolysis along with limited systemic proteolysis. Alteplase has a short half-life of 4 to 8 minutes and dosing is dependent on body weight. The currently recommended protocol for the administration of alteplase is the baccelerated regimenQ in which an initial intravenous bolus dose is followed by 90 minutes of intravenous infusion. In the Anglo-Scandinavian Study of Early Thrombolysis (ASSET) [51], alteplase was shown to reduce mortality vs placebo, and in the GUSTO-I trial [46] it demonstrated reduced mortality vs streptokinase. Alteplase achieved patency rates, that is, TIMI 2/3 flow, of up to 81% after 90 minutes of intravenous infusion [52]. Alteplase is cleared exclusively by the liver. Thus, a potential disadvantage is that changes in liver hemodynamics might significantly affect the pharmacokinetics of this agent, reducing clearance and increasing plasma concentration [53]. In addition, administration is complicated by the need for weight estimation and by a regimen that consists of a bolus injection followed by 2 time-dependent infusions over 30- and 60-minute periods. Consequently, alteplase use has declined as newer, more convenient agents have been developed.

8. Reteplase Reteplase is a third-generation recombinant deletion mutant of t-PA and thus also nonimmunogenic. Like alteplase, reteplase is a direct plasminogen activator but was designed to have a longer half-life than alteplase (13-16 minutes); clearance is primarily by the liver and kidney [54]. Reteplase is administered as 2 rapid bolus injections of 10 U each, given 30 minutes apart, and does not require dosage adjustment for body weight.

W.F. Peacock et al. Reteplase was compared with alteplase in the Reteplase vs Alteplase Patency Investigation During Myocardial Infarction (RAPID-2) trial. Reteplase demonstrated superiority to accelerated alteplase at 90 minutes with total patency rates (TIMI 2/3) of 83% vs 73% ( P b .05) and complete perfusion (TIMI 3) rates of 60% vs 45% ( P b .05), respectively [55]. However, in the GUSTO-III trial [47], reteplase did not show superiority to alteplase in terms of 30-day mortality rates (7.5% and 7.2%, respectively). Both reteplase and alteplase were similar in terms of 30-day mortality, hemorrhagic stroke, the combined endpoint of death and stroke, and bleeding complications. Reteplase has the advantage of being administered as simple double bolus injections without the need for weightbased dosing, potentially reducing dosing errors and making it suitable for prehospital and interhospital transfer administration. In addition, being able to withhold administration of the second bolus has benefits from a safety perspective if bleeding occurs or subsequent PCI is required.

9. Tenecteplase Tenecteplase (TNK t-PA) is a recombinant plasminogen activator like alteplase and reteplase. Compared with alteplase and reteplase, tenecteplase has a longer half-life (20-24 minutes) [11]. Tenecteplase is administered as a single bolus injection and dosing is weight based [56]. In the Thrombolysis in Myocardial Infarction-10B (TIMI10B) study, tenecteplase 40 mg achieved similar rates of TIMI 3 flow to front-loaded alteplase at 90 minutes after the start of thrombolysis (62.8% and 62.7%, respectively) [57]. In addition, similar covariate-adjusted 30-day mortality was seen with tenecteplase and front-loaded alteplase (6.18% and 6.15%, respectively) in the Assessment of the Safety and Efficacy of a New Thrombolytic-2 (ASSENT-2) study [58]. With weight-adjusted tenecteplase in ASSENT-2, the rates of intracranial hemorrhage (ICH) and major bleeding were similar to those occurring with alteplase, and rates of noncerebral bleeding complications were lower than with alteplase (26% vs 29%; P = .0003). However, TIMI-10B demonstrated that weight-based dosing is necessary for tenecteplase; rates of intracerebral hemorrhage and serious bleeding showed a dose relationship with tenecteplase and at the highest tenecteplase dose (50 mg) were higher than with alteplase; the tenecteplase 50-mg arm was suspended as a result of the increased bleeding seen in this group. The need for weight-based dosing is a potential disadvantage of tenecteplase, as this can increase the number of dosing errors, although within the clinical trial setting of the ASSENT-2 study more than 96% of patients did receive 95% to 105% of the planned weight-adjusted dose of tenecteplase. However, visual estimations of weight made in the ED have been shown to be grossly inaccurate [59], and inaccurate fibrinolytic dosing is associated with significantly worse outcomes [60].

Emergency reperfusion in ST-elevation myocardial infarction Table 2

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Contraindications and cautions for fibrinolysis in ST-elevation MIa [1]

Absolute contraindications

Relative contraindications

Any prior ICH Known structural cerebral vascular lesion (eg, arteriovenous malformation) Known malignant intracranial neoplasm (primary or metastatic) Ischemic stroke within 3 mo EXCEPT acute ischemic stroke within 3 h Suspected aortic dissection Active bleeding or bleeding diathesis (excluding menses) Significant closed-head or facial trauma within 3 mo History of chronic, severe, poorly controlled hypertension Severe uncontrolled hypertension on presentation (SBP N180 mm Hg or DBP N110 mm Hg)b History of prior ischemic stroke N3 mo, dementia, or known intracranial pathology not covered in contraindications Traumatic or prolonged (N10 min) CPR or major surgery (b3 wk) Recent (within 2-4 wk) internal bleeding Noncompressible vascular punctures For streptokinase, prior exposure (N5 d ago) or prior allergic reaction to this agent Pregnancy Active peptic ulcer Current use of anticoagulants: the higher the INR, the higher the risk of bleeding

SBP indicates systolic blood pressure; DBP, diastolic blood pressure; CPR, cardiopulmonary resuscitation; INR, international normalized ratio. Modified with permission from J Am Coll Cardiol 2004;44:E1-211. a Viewed as advisory for clinical decision making and may not be all-inclusive or definitive. b Could be an absolute contraindication in low-risk patients with MI.

9.1. Complications to fibrinolysis Fibrinolysis is not suitable for some patients with STEMI because of contraindications (Table 2) [1]. In addition, fibrinolytic therapy carries a risk of bleeding and hemorrhage. Although infrequent, the most serious risk is ICH, which is potentially fatal in one half to two thirds of patients [1]. Risk factors for ICH include older age, female sex, black race, previous stroke, systolic blood pressure of 160 mm Hg or higher on admission, lower body weight, and excessive anticoagulation, as well as the actual characteristics of the specific fibrinolytic agent [1]. Furthermore, only 30% to 60% of patients administered a fibrinolytic achieve full angiographic reperfusion (TIMI grade 3 flow) within a 90-minute timeframe (however, increasing to N80% for TIMI grade 2 or 3) [1]. Initial reperfusion with a fibrinolytic agent may also be followed by subsequent reocclusion [3,61]. Another disadvantage of fibrinolysis is that it is less effective than primary PCI at reducing short-term major adverse events, and this disadvantage remains during longterm follow-up [23]. As such, when choosing a reperfusion strategy, primary PCI may be the preferred initial choice in suitable patients except in cases when (1) time delay to PCI would result in undue risk to the patient; (2) facilitated PCI is believed to be the best option; (3) an invasive strategy is contraindicated; or (4) there are vascular access difficulties. However, fibrinolysis does offer the opportunity to achieve early reperfusion in many patients without excluding the option of undergoing rescue PCI for patients in whom fibrinolysis fails. In the Rescue Angioplasty vs Conservative Therapy of Repeat Thrombolysis (REACT) study, after failed fibrinolysis, there was a significant benefit

of rescue PCI compared with both conservative therapy and repeated fibrinolysis on the composite primary endpoint of death, reinfarction, stroke, or severe heart failure within 6 months [62]. A recent meta-analysis also indicated a lower risk of death with rescue PCI vs conservative therapy after failed fibrinolysis [63]. Notably, the rate of major bleeding complications has been shown to be similar with early or late rescue PCI compared with primary PCI [64].

10. Combining fibrinolytic therapy with PCI—facilitated PCI Facilitated PCI, the coupling of initial pharmacologic therapy followed immediately by PCI, is a unified approach to the management of patients with STEMI that has theoretical advantages, but more research is required on its appropriate application. Facilitated PCI can consist of initial full-dose fibrinolysis, half-dose fibrinolysis, a GP IIb/IIIa inhibitor, or a combination of reduced-dose fibrinolytic therapy and a platelet GP IIb/IIIa inhibitor followed immediately by planned PCI [1]. The ACC/AHA STEMI guidelines suggest that facilitated PCI be considered as a reperfusion strategy in higher-risk patients when PCI is not immediately available and bleeding risk is low [1]. Potential limitations include increased risk of bleeding complications, particularly in patients aged 75 years or older, and the added cost of therapy. Less favorable outcomes were seen with facilitated PCI compared with primary PCI in a recent meta-analysis [41]. However, it should be noted that the studies included in the analysis used different clinical endpoints and dosing regimens, and had differences in the time from administra-

362 tion of pretreatment to PCI. The analysis included 9 studies assessing facilitated PCI with a GP IIb/IIIa inhibitor only (abciximab, eptifibatide, or tirofiban), 6 studies assessing a fibrinolytic only (streptokinase, alteplase, or tenecteplase), and 2 studies assessing a GP IIb/IIIa inhibitor/fibrinolytic combination regimen (abciximab with reteplase, or eptifibatide with tenecteplase). Analysis according to type of pretreatment regimen showed that the less favorable outcomes were mainly attributable to use of fibrinolytics alone as pretreatment; in the majority of patients receiving this treatment modality, the fibrinolytic used was tenecteplase (933/1468 patients; 63.6%). Indeed, the Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) tenecteplase study contributed approximately half of the fibrinolytic-treated patients in the meta-analysis. Only 1 included study used a reteplase-based regimen, in combination therapy with abciximab (125 patients; 7.5% of fibrinolytic recipients); this study did not show significant inferiority of facilitated PCI vs primary PCI. In total, fewer than 200 patients who received a combination facilitated PCI regimen were included in the meta-analysis. The recent ASSENT-4 study was initiated to evaluate the efficacy of facilitated PCI with tenecteplase vs PCI alone in patients with acute MI [39]. This study was terminated early (1667 patients enrolled, of a planned 4000) owing to an imbalance in inhospital mortality (mortality in the PCI arm was lower than expected). The incidence of the combined primary endpoint of death, congestive heart failure, or shock at 90 days was significantly higher in the facilitated PCI group than in the primary PCI group, although significant differences were not seen for the individual components of the primary endpoint. Interestingly, when mortality was analyzed separately for prehospital and inhospital fibrinolysis facilitated PCI strategies, the prehospital fibrinolysis facilitated PCI arm demonstrated the lowest mortality rates of all arms, including PCI alone. A number of factors may have contributed to the negative overall findings of ASSENT-4 PCI. Full-dose tenecteplase was used in the facilitated PCI arm, rather than a reduced dose; this may have led to the increased bleeding observed (significantly more inhospital ICH and minor bleeding complications). Patients did not receive an infusion of heparin after bolus administration or an up-front loading dose of clopidogrel, and use of GP IIb/IIIa inhibitors was only permitted for bbailoutQ situations in the facilitated PCI group. In addition, the proportion of patients receiving clopidogrel or ticlopidine after catheterization was significantly lower in the facilitated PCI arm than in the primary PCI arm. Thus, suboptimal concomitant antithrombotic therapy may have contributed to lower infarct artery patency rates and increased rates of early thrombotic complications with facilitated PCI, offsetting the benefits of early reperfusion. Finally, the time interval between administration of tenecteplase and PCI was relatively short for many patients (median, 104 minutes), which may have attenuated or negated the potential benefit of

W.F. Peacock et al. earlier reperfusion with a fibrinolytic; if this time span had been longer, a benefit of the facilitated approach over the primary PCI approach may have been observed. The results of the ADdressing the Value of facilitated ANgioplasty after Combination therapy or Eptifibatide monotherapy in acute Myocardial Infarction (ADVANCE MI) trial, which was also terminated early, owing to slow recruitment (148 patients randomized of a planned 5640), indicated that facilitated PCI with half-dose tenecteplase plus eptifibatide was associated with improved angiographic flow patterns, but also increases in the number of adverse clinical outcomes and bleeding rates, compared to PCI with eptifibatide [65]. Some other studies have suggested potential benefits with a facilitated PCI strategy. The Combined Angioplasty and Pharmacological Intervention vs Thrombolysis Alone in Acute Myocardial Infarction (CAPITAL AMI) study demonstrated that in patients with high-risk STEMI, tenecteplase followed by immediate angioplasty reduced the risk of recurrent ischemic events when compared with tenecteplase alone [66]. In addition, there was no increase in major bleeding complications observed in the facilitated PCI group. In a study conducted by the Leipzig Prehospital Fibrinolysis Group, comparing prehospital combination fibrinolysis (with half-dose reteplase and abciximab, plus aspirin and heparin) followed by either standard care or immediate PCI, the facilitated PCI strategy was associated with a lower infarct size and a higher rate of complete STsegment resolution [40]. Again, the incidence of major bleeding was similar in the 2 groups. Most patients in previous studies of facilitated PCI, such as those captured in the meta-analysis by Keeley et al [41], initially presented to a PCI-capable hospital or had relatively short transfer times, whereas the benefit of facilitated PCI may be for those patients with longer transfer times. Data from a recent study showed that patients transferred to a PCIcapable hospital for facilitated PCI from a distance of 60 to 210 miles had comparable outcomes to patients presenting directly to the same PCI-capable hospital and undergoing primary PCI [42]. The results of future trials, including the Facilitated INtervention with Enhanced reperfusion Speed to Stop Events (FINESSE) [67], Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction, and Trial of Routine ANgioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER AMI) studies, should provide additional details as to the risks and benefits of facilitated PCI. If the results from these trials are encouraging, the benefits of both pharmacologic and mechanical intervention could potentially be expanded to a broader patient population.

11. Other interventions Regardless of which reperfusion strategy a patient will receive, there are a number of routine ED interventions that

Emergency reperfusion in ST-elevation myocardial infarction are believed to have benefit in STEMI. Although aspirin resistance has been described in approximately 10% of patients with suspected coronary syndrome presenting to the ED [68], for most patients, aspirin administration is well recognized to produce a rapid antithrombotic effect in conjunction with almost complete inhibition of thromboxane A2 production. Many patients will have been given aspirin by paramedics before their arrival in the ED. As previously discussed, pretreatment with clopidogrel is recommended for patients undergoing PCI [1,14]. There is also evidence to support the use of clopidogrel, in combination with aspirin, in patients receiving fibrinolytics. The CLARITY-TIMI 28 study recently demonstrated that the addition of clopidogrel (300 mg loading dose then 75 mg once daily) to aspirin further improves the patency rate of the infarct-related artery and reduces ischemic complications in patients with STEMI receiving fibrinolytic therapy [18]. In another large randomized study in patients with acute MI, adding clopidogrel 75 mg daily to aspirin and other standard treatments (such as fibrinolytics) was shown to safely reduce mortality and major vascular events in hospital [69]. Supplemental oxygen may limit ischemic myocardial injury [70] and reduce ST-segment elevation [71]. Nitrate administration reduces preload, and often afterload, thereby decreasing myocardial oxygen demand. Nitrates may also reduce pain by producing vasodilation of coronary arteries and returning coronary flow to more normal levels, thus reducing ischemia [1], although its value in mortality reduction is less clear. Two studies involving approximately 75 000 patients, the ISIS-4 [72] and GISSI-3 [73] trials, failed to show any benefit of nitrate therapy in terms of mortality reduction in patients with suspected acute myocardial infarction. However, these large trials were confounded by frequent prehospital and hospital use of nitroglycerin in the placebo groups. The abrupt cessation of intravenous nitroglycerin has been associated with exacerbation of ischemic changes on the ECG [74], and a gradual reduction in the dose of intravenous nitroglycerin is advisable. Morphine is recommended as an adjunctive analgesic; however, recent literature has questioned the safety of this strategy in patients with non–ST-elevation ACSs [75]. In patients without contraindications, b-blockers reduce myocardial oxygen demand and, by prolonging diastole, may also increase subendocardial perfusion [22]. However, the recent Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) found that, although early administration of the b-blocker metoprolol (intravenously followed by oral administration) to patients admitted to hospital within 24 hours of suspected acute MI reduced the risk of reinfarction and ventricular fibrillation, it was also associated with an increased risk of cardiogenic shock, particularly in patients at high risk of developing shock [76]. Thus, the COMMIT investigators suggested that it may be generally prudent to delay initation of b-blockers until after the patient’s hemodynamic condition has stabilized.

363 The 2004 ACC/AHA STEMI guidelines recommend administration of an angiotensin converting enzyme (ACE) inhibitor within the first 24 hours of STEMI in selected patients (ie, those with anterior infarction, pulmonary congestion, or left ventricular ejection fraction b0.40), in the absence of hypotension or known contraindications to ACE inhibitors, owing to a demonstrated mortality benefit [1]. However, the results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) suggest that ACE inhibitors should not be administered intravenously during this early period; in this study, initial intravenous enalapril followed by oral enalapril starting within 24 hours of MI symptom onset was associated with slightly higher 6-month mortality than placebo, although the difference was not statistically significant [77]. Although there is some evidence for clinical benefit with direct thrombin inhibitors (eg, bivalirudin, hirudin) in ACSs [78,79], none of these agents are currently indicated as first-line therapy in STEMI. The ACC/AHA guidelines note that bivalirudin should only be used as an alternative to heparin in patients with known heparin-induced thrombocytopenia [1]. Although use of GP IIb/IIIa inhibitors is recommended in patients undergoing primary PCI, as noted previously, treatment with GP IIb/IIIa inhibitors alone is not considered a viable reperfusion strategy; however, a combination of abciximab plus halfdose reteplase or tenecteplase may be considered in patients aged less than 75 years with anterior MI location and no risk factors for bleeding, to prevent reinfarction and other complications of STEMI [1].

12. Conclusion The emergency physician plays a critical role in the diagnosis and management of STEMI. Morbidity and mortality benefits obtainable from reperfusion therapy diminish rapidly within the first several hours after symptom onset, which makes a rapid ED response paramount to the success of either pharmacologic or catheter-based reperfusion therapies [80,81]. This need for speed is reflected in the recommendation that medical contact-to-needle time for fibrinolytic therapy be less than 30 minutes and medical contact-to-balloon time for PCI be less than 90 minutes [1]. Consequently, if the patient cannot undergo PCI within the recommended timeframe (either because of the lack of a catheterization laboratory, availability, or transfer times), the emergency physician should consider initiating immediate fibrinolytic therapy. Regardless of the physician’s decision, the STEMI patient’s chance of a good outcome is maximized by excellent communication between the ED and the interventional cardiology team, and by having a multidisciplinary ED team that is fully familiar with institutional treatment protocols, so they can work together to achieve rapid triage, diagnosis, and treatment. The ED team can also play a crucial role in the development of a

364 coordinated prehospital reperfusion protocol, which can further help to reduce the time to treatment in patients with STEMI. The advantage of routinely performing prehospital ECGs which can be remotely interpreted by emergency physicians at the receiving hospital is twofold: (1) The paramedics can administer heparin (60 U/kg, maximum 4000 U), aspirin (162-325 mg, in chewable form), clopidogrel (300 mg), and half-dose fibrinolytic (in eligible patients) to initiate thrombolysis before hospital arrival. (2) Alternatively, the receiving hospital, analogous to a trauma hospital, can activate the catheterization laboratory and interventional team so that the patient can be taken there quickly after arrival at the hospital (greatly reducing medical contact-to-balloon time). Either one of these strategies may contribute to achieving the goal of rapid reperfusion. Preliminary experience from the PATCAR pilot trial has also shown that the combination of these 2 strategies significantly decreases the time from onset of pain to open infarct–related artery. Treatment protocols need to be regularly reviewed and updated, to incorporate changes in care practices that will result from ongoing research, particularly in the areas of the optimal ancillary regimens for PCI and fibrinolysis, and the optimal combination of catheter-based and pharmacological therapy (which may be clarified by the TRANSFER-AMI, FINESSE, and CARESS in AMI studies).

W.F. Peacock et al.

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Acknowledgment Preparation of this manuscript was supported by PDL BioPharma, Inc.

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