CARDIOLOGY/CLINICAL POLICY Clinical Policy: Emergency Department Management of Patients Needing Reperfusion Therapy for Acute ST-Segment Elevation

From the American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Reperfusion Therapy for Acute ST-Segment Elevation Myocardial Infarction: Susan B. Promes, MD, MBA (Subcommittee Chair) Jonathan M. Glauser, MD, MBA Michael D. Smith, MD, MBA Sam S. Torbati, MD Michael D. Brown, MD, MSc (Committee Chair)

Members of the American College of Emergency Physicians Clinical Policies Committee (Oversight Committee):

Michael D. Brown, MD, MSc (Chair 2014-2017) Michael D. Smith, MD, MBA Richard Byyny, MD, MSc (Methodologist) Molly E. W. Thiessen, MD Deborah B. Diercks, MD, MSc Christian A. Tomaszewski, MD, MS, MBA Seth R. Gemme, MD Jonathan H. Valente, MD Charles J. Gerardo, MD, MHS Stephen P. Wall, MD, MSc, MAEd (Methodologist) Steven A. Godwin, MD Stephen J. Wolf, MD Sigrid A. Hahn, MD, MPH Stephen V. Cantrill, MD (Liaison with Quality and Patient Benjamin W. Hatten, MD, MPH Safety Committee) Jason S. Haukoos, MD, MSc (Methodologist) Jon Mark Hirshon, MD, MPH, PhD (Board Liaison 2016- Graham S. Ingalsbe, MD (EMRA Representative 2015-2017) 2017) Amy Kaji, MD, MPH, PhD (Methodologist) Rhonda R. Whitson, RHIA, Staff Liaison, Clinical Policies Heemun Kwok, MD, MS (Methodologist) Committee and Subcommittee Revising the Reperfusion Bruce M. Lo, MD, MBA, RDMS Therapy for Acute Myocardial Infarction Clinical Policy Sharon E. Mace, MD Travis Schulz, MLS, AHIP, Staff Liaison, Clinical Policies Devorah J. Nazarian, MD Committee Jean A. Proehl, RN, MN, CEN, CPEN (ENA Representative 2015-2017) Approved by the ACEP Board of Directors June 28, 2017 Susan B. Promes, MD, MBA Kaushal H. Shah, MD Richard D. Shih, MD Endorsed by the Emergency Nurses Association Scott M. Silvers, MD August 22, 2017

Policy statements and clinical policies are the official policies of the American College of Emergency Physicians and, as such, are not subject to the same peer review process as articles appearing in the journal. Policy statements and clinical policies of ACEP do not necessarily reflect the policies and beliefs of Annals of Emergency Medicine and its editors.

0196-0644/$-see front matter Copyright © 2017 by the American College of Emergency Physicians. https://doi.org/10.1016/j.annemergmed.2017.09.035

724 Annals of Emergency Medicine Volume 70, no. 5 : November 2017 Clinical Policy

[Ann Emerg Med. 2017;70:724-739.] perform the intervention. What are the sources of these delays? What are the indications for fibrinolytic therapy in the age of PCI? These questions are critical for emergency ABSTRACT physicians who practice in rural and remote locations Ischemic disease is the leading cause of in the without immediate access to PCI centers. Aside from the world. More than half a million patients present to immediate outcomes for reperfusion and death, data on emergency departments across the United States each year long-term functional outcomes are critical to determine the with ST-segment elevation myocardial infarctions.1 Timely impact these interventions ultimately have on patient lives. reperfusion is critical to saving myocardium at risk. Finally, the role of pain relief—in particular, opioid use—is Multiple studies have been conducted that demonstrate discussed in light of newer research that raises some that improved care processes are linked to improved concern over long-term outcomes in chest pain patients survival in patients having an acute myocardial infarction. treated with opioids. This clinical policy from the American College of This clinical policy addresses 3 issues that are relevant to Emergency Physicians addresses key issues in reperfusion practicing emergency physicians. The first 2 questions for patients with acute ST-segment elevation myocardial address whether there is a benefit to giving fibrinolytic infarction. A writing subcommittee conducted a systematic therapy to STEMI patients when PCI will be delayed and review of the literature to derive evidence-based whether transfer to a PCI-capable facility for the STEMI recommendations to answer the following clinical patient decreases the incidence of major adverse cardiac questions: (1) In adult patients having an ST-segment events (MACE). The clinical heterogeneity among the elevation myocardial infarction, are there patients for research studies investigating these topics make whom treatment with fibrinolytic therapy decreases the interpretation of the results challenging. For example, there incidence of major adverse cardiac events when is no standard definition of MACE. MACE may include percutaneous coronary intervention is delayed? (2) In adult such endpoints as death, , , and patients having an ST-segment elevation myocardial congestive heart failure, but not all studies use the same infarction, does transfer to a percutaneous coronary endpoints. Definitions for MACE will be identified in the intervention center decrease the incidence of major adverse policy as appropriate for clarity. In addition, there is no cardiac events? (3) In adult patients undergoing reperfusion uniformity on timing metrics. The final critical question therapy, should opioids be avoided to prevent adverse examines the safety of opioid use in this population. outcomes? Evidence was graded and recommendations This is a revision of the 2006 American College of were made based on the strength of the available data. Emergency Physicians (ACEP) clinical policy on reperfusion therapy in emergency department (ED) INTRODUCTION patients with suspected acute myocardial infarction (MI).3 Although timely percutaneous coronary intervention (PCI) has become the standard treatment for ST-segment elevation myocardial infarction (STEMI), the fact remains METHODOLOGY that only a minority of hospitals in the United States are This clinical policy is based on a systematic review with capable of performing this intervention on site, and even critical analysis of the medical literature meeting the fewer can provide 24-hour access to the intervention. inclusion criteria. Searches of MEDLINE, MEDLINE When a patient presents with STEMI, national guidelines InProcess, Cochrane, EMBASE, and Scopus databases were recommend a first medical-contact-to-device time of less performed. All searches were limited to human studies than 90 minutes for individuals presenting to a PCI- published in English. Specific key words/phrases, years used capable site and less than 120 minutes from first medical- in the searches, dates of searches, and study selection are contact-to-device time for those who need to be transferred identified under each critical question. In addition, relevant to a PCI-capable hospital.2 Although very few patients are articles from the bibliographies of included studies and treated solely with fibrinolytic therapy without an more recent articles identified by committee members and angiographic assessment of their coronary arteries, the time- reviewers were included. dependent nature of getting the patient to a PCI center This policy is a product of the ACEP clinical policy requires knowledge of how delays affect clinical outcomes. development process, including internal and external Systems have been developed for rapid out-of-hospital review, and is based on the existing literature; when triage to PCI-capable centers and for rapid interhospital literature was not available, consensus of Clinical Policies transfer from a noncapable PCI facility to one that can Committee members was used and noted as such in the

Volume 70, no. 5 : November 2017 Annals of Emergency Medicine 725 Clinical Policy recommendation (ie, consensus recommendation). Review question for which it is being considered. As such, it was comments were received from emergency physicians, possible for a single article to receive a different Class of cardiologists, individual members of the American College Evidence rating when addressing a different critical of Cardiology Foundation/American Heart Association, a question. Question-specific Classes of Evidence grading patient representative, and members of ACEP’s Medical- may be found in the Evidentiary Table included at the end Legal Committee. Comments were received during a 60- of this policy. day open-comment period, with notices of the comment period sent in an e-mail to ACEP members, published in EM Today, and posted on the ACEP Web site. The Translation of Classes of Evidence to responses were used to further refine and enhance this Recommendation Levels clinical policy; however, responses do not imply Based on the strength of evidence grading for each endorsement. Clinical policies are scheduled for revision critical question (ie, Evidentiary Table), the subcommittee every 3 years; however, interim reviews are conducted when drafted the recommendations and the supporting text technology, methodology, or the practice environment synthesizing the evidence using the following guidelines: fi Level A recommendations. Generally accepted changes signi cantly. ACEP was the funding source for this fl clinical policy. principles for patient care that re ect a high degree of clinical certainty (eg, based on evidence from one or more Class of Evidence I or multiple Class of Evidence II Assessment of Classes of Evidence studies). Two methodologists independently graded and assigned Level B recommendations. Recommendations for a preliminary Class of Evidence for all articles used in the patient care that may identify a particular strategy or range formulation of this clinical policy. Class of Evidence is of strategies that reflect moderate clinical certainty (eg, delineated whereby an article with design 1 represents the based on evidence from one or more Class of Evidence II strongest study design and subsequent design classes (ie, studies or strong consensus of Class of Evidence III design 2 and design 3) represent respectively weaker study studies). designs for therapeutic, diagnostic, or prognostic studies, or Level C recommendations. Recommendations for meta-analyses (Appendix A). Articles are then graded on patient care that are based on evidence from Class of dimensions related to the study’s methodological features, Evidence III studies or, in the absence of any adequate such as randomization processes, blinding, allocation published literature, based on expert consensus. In concealment, methods of data collection, outcome instances in which consensus recommendations are made, measures and their assessment, selection and “consensus” is placed in parentheses at the end of the misclassification biases, sample size, generalizability, data recommendation. management, analyses, congruence of results and The recommendations and evidence synthesis were then conclusions, and conflicts of interest. Using a reviewed and revised by the Clinical Policies Committee, predetermined process combining the study’s design, which was informed by additional evidence or context methodological quality, and applicability to the critical gained from reviewers. question, articles received a Class of Evidence grade. An There are certain circumstances in which the adjudication process involving discussion with the original recommendations stemming from a body of evidence methodologist graders and at least one additional should not be rated as highly as the individual studies on methodologist was then used to address any discordance in which they are based. Factors such as heterogeneity of original grading, resulting in a final Class of Evidence results, uncertainty about effect magnitude, and assignment (ie, Class I, Class II, Class III, or Class X) publication bias, among others, might lead to a (Appendix B). Articles identified with fatal flaws or downgrading of recommendations. ultimately determined to not be applicable to the critical When possible, clinically oriented statistics (eg, question received a Class of Evidence grade “X” and were likelihood ratios, number needed to treat) are presented to not used in formulating recommendations for this policy. help the reader better understand how the results may be However, content in these articles may have been used to applied to the individual patient (Appendix C). formulate the background and to inform expert consensus This policy is not intended to be a complete manual on in the absence of robust evidence. Grading was done with the evaluation and management of patients with STEMI respect to the specific critical questions; thus, the Class of but rather a focused examination of critical issues that have Evidence for any one study may vary according to the particular relevance to the current practice of emergency

726 Annals of Emergency Medicine Volume 70, no. 5 : November 2017 Clinical Policy medicine. Potential benefits and harms of implementing appropriate time frame necessary to achieve optimal recommendations are briefly summarized within each outcomes. critical question. Key words/phrases for literature searches: STEMI, It is the goal of the Clinical Policies Committee to myocardial infarction, , balloon, coronary, provide an evidence-based recommendation when the percutaneous coronary intervention, adverse effects, medical literature provides enough quality information to mortality, fibrinolytic agents, thrombolytic therapy, answer a critical question. When the medical literature does recombinant proteins, antithrombins, platelet aggregation not contain adequate empirical data to answer a critical inhibitors, risk assessment, risk factors, time factors, question, the members of the Clinical Policies Committee survival rate, survival analysis, treatment outcome, adverse believe that it is equally important to alert emergency cardiac, delay, transportation of patients, patient transfer, physicians to this fact. health services accessibility, emergency medical services, This clinical policy is not intended to represent a legal myocardial reperfusion, time-to-treatment, pharmaco- standard of care for emergency physicians. invasive therapy, facilitated PCI, and variations and Recommendations offered in this policy are not intended to combinations of the key words/phrases. Searches included represent the only diagnostic or management options January 1, 2006 to search dates of January 12, 2016, available to the emergency physician. ACEP recognizes the January 29, 2016, February 9, 2016, February 24, 2016, importance of the individual physician’s judgment and and January 10, 2017. patient preferences. This guideline provides clinical Study Selection: Two hundred thirty-four articles were strategies for which medical literature exists to answer the identified in the search. Forty-three articles were selected critical questions addressed in this policy. from the search results for further review, with 6 Class III Scope of Application. This guideline is intended for studies included for this critical question. health care providers working in EDs. Many hospitals in the United States with inpatient beds Inclusion Criteria. This guideline is intended for adult do not have a cardiac catheterization laboratory with direct patients presenting to the ED with suspected acute access to PCI. Although PCI as a revascularization STEMI. procedure is desirable within 90 minutes of first medical Exclusion Criteria. This guideline is not intended for contact, this time frame is impossible to achieve in such pediatric patients, pregnant patients, or patients with facilities. Quality initiatives have demonstrated time benefit contraindications to fibrinolytic treatment. to coordination of out-of-hospital performance and transmission of ECG data with emergency care and with CRITICAL QUESTIONS response of catheterization laboratory personnel and fi 1. In adult patients having a STEMI, are there patients interventional cardiology. There are barriers to ef cient for whom treatment with fibrinolytic therapy transfer, including the availability of on-call specialists and decreases the incidence of MACE when PCI is impediments to transportation, such as inclement weather; delayed? therefore, time to PCI will vary between health systems and Patient Management Recommendations individual situations. Level A recommendations. None specified. With the rise of freestanding emergency centers from Level B recommendations. Fibrinolytics may be which any patient sustaining an MI must be transferred administered to patients when door-to-balloon (D2B) time for care, and with the closure of rural hospitals, it is is anticipated to exceed 120 minutes. expected that the number of patients with chest pain and STEMI presenting to non-PCI-capable facilities will Level C recommendations. A dose reduction should be fi considered when administering fibrinolytics to patients increase. Given the availability of brinolytic therapy to aged 75 years or older. any practitioner of emergency care, it is important to define a time frame during which these patients will Potential Benefit of Implementing the derive benefit from fibrinolysis as initial therapy for Recommendations: The use of fibrinolytics when D2B STEMI. time is delayed may result in better long-term outcomes Rather than using fibrinolytics, multiple studies favor with a decrease in MACE. PCI with a D2B time of less than 120 minutes, including Potential Harm of Implementing the transfer time.4-11 It is not always feasible to achieve PCI in Recommendations: Time estimates are challenging to less than 120 minutes even at PCI-capable hospitals; obtain in the context of an emergency, therefore patients therefore, fibrinolytics followed by PCI may be considered may not receive the recommended therapy within the in select circumstances. There is variation in the dosing of

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fibrinolytics before transfer for PCI, namely full-dose versus who were transferred from a zone 1 hospital (<60 miles reduced dose. away) underwent primary PCI as the reperfusion method. A Class III study by Vora et al12 consisting of a registry Patients transferred from zone 2 hospitals (60 miles away) of 22,481 patients (Acute Coronary Treatment and received , , unfractionated , a b- Intervention Outcomes Network Registry) indicated that blocker, and reduced-dose fibrinolytic, most frequently when estimated interhospital drive time exceeded 30 with comparable outcomes in stroke, major minutes, only 42.6% of transferred patients achieved the bleeding, 30-day mortality, and reinfarction. The authors’ first D2B time of less than 120 minutes. Among 15,437 conclusions were that an argument should be made for patients eligible for full-dose fibrinolysis or PCI with fibrinolytic therapy if there is inclement weather or for a estimated transfer drive times of 30 to 120 minutes, 34.3% 60-mile transport cutoff if there is no inclement weather.16 received fibrinolysis (median door-to-needle time of 34 Finally, in a Class III study,17 STEMI patients who minutes). Median transfer time was 49 minutes. Patients presented within 3 hours of symptom onset and could not treated with fibrinolysis versus PCI had no significant receive PCI within 1 hour were randomized in the out-of- mortality difference (3.7% versus 3.9%; odds ratio 1.1; hospital setting to either transport for primary PCI or 95% confidence interval [CI] 0.9 to 1.4), but had higher treatment with full-dose tenecteplase plus clopidogrel and bleeding risk, which included a decrease in hemoglobin enoxaparin before transfer to a PCI-capable hospital. The level (4 g/dL), or , or RBC primary endpoints were a composite of death, shock, transfusion (10.7% versus 9.5%; odds ratio 1.2; 95% CI congestive heart failure, or reinfarction within 30 days. 1.0 to 1.3). The mortality rates took into consideration Emergency was required in 36% of the multiple confounders such as transfer times, presence of tenecteplase group and the remainder underwent heart failure, shock, and within-hospital clustering. A Class angiography at a median 17 hours after randomization. In III study13 from Canada measured the primary endpoint, this study, the composite endpoint was similar regardless of which was the composite of death, whether the patient received fibrinolytic therapy or primary within 30 days, new or worsening heart failure, PCI (12.4% versus 14.3%, respectively). There was a reinfarction, recurrent ischemia, or new or worsening higher incidence of intracranial hemorrhage in patients who congestive heart failure within 30 days in all patients who received fibrinolytic therapy. This increase was mitigated by received full-dose fibrinolysis. Five hundred thirty-seven the use of half-dose tenecteplase in patients older than 75 patients were randomly assigned to be immediately years.17 transferred for PCI within 6 hours after fibrinolytics. Five In summary, use of fibrinolytics is recommended when, hundred twenty-two patients were randomized to standard by physician judgment, the D2B time will exceed 120 fibrinolytic therapy without PCI, but 182 patients (39.9%) minutes for any reason. When fibrinolytics are used in received urgent catheterization (rescue PCI), with stents patients older than 75 years, consideration should be given implanted in 98.3%. The immediate transfer for PCI to using half-dose to mitigate the potential for bleeding group had better primary endpoints (11% versus 17.2%). complications. However, no patients received PCI within 90 minutes.13 A 2008 Class III report14 of 2,869 STEMI patients treated at 5 high-volume centers demonstrated significantly Future Research lower mortality with reduced dose fibrinolysis followed by There may be a subset of patients who benefit from urgent PCI compared with primary PCI. Mean time to fibrinolysis before PCI depending on, for example, age or PCI was 253 minutes, whereas mean time to fibrinolysis anatomic location of the infarction, as well as time to PCI. was 54 minutes. A Class III randomized study15 of a total It is unknown whether a given time limit for, say, a 45- of 2,452 patients suggested a mortality benefit to reduced- year-old man with an inferior MI applies to a 77-year-old dose plus abciximab as opposed to abciximab woman with an anterior MI. It may be that the benefitof alone, or placebo, followed by expedited primary PCI when PCI over fibrinolysis is most pronounced in high-risk PCI delays of greater than 1 hour were anticipated. Data in patients: those with anterior MI or with hemodynamic a Class III study16 from Minnesota attempted to address compromise. reperfusion options in STEMI patients with expected Transport time to a PCI-capable institution is frequently delays to a PCI-capable hospital. More than 2,600 not known with any precision and may be underestimated consecutive STEMI patients from 31 referral hospitals were by receiving PCI centers. If timing is really important, ways entered into a registry, as well as 600 who presented to the to accurately estimate transfer times must be identified. PCI center. Patients who presented to the PCI hospital or How accurate is any assessment of time given weather and

728 Annals of Emergency Medicine Volume 70, no. 5 : November 2017 Clinical Policy transport conditions? This question should be answered choosing between these 2 therapies and is now centered on before any hard and fast guidelines are developed on PCI the expedited treatment of patients with PCI and the versus fibrinolysis. Emergency physicians should know the construction of systems and networks to facilitate this, framework within which they are working. Any including interhospital transfer. The introduction of recommendations must be predicated on a realistic estimate STEMI care programs has reduced mortality.18 This raises of time to transport and time to intervention. the question of which patients benefit the most from Many studies, especially those from overseas, have rushing to the PCI-capable institution and what those disparate endpoints, such as stroke, recurrent ischemia, benefits are. The American Heart Association guidelines reinfarction, death, cardiogenic shock, congestive heart recommend transfer of patients with STEMI to a PCI failure, and readmissions. Although this policy looked at center even if they have received fibrinolytic therapy.19 MACE, future research should explore functional status There is literature in regard to the out-of-hospital (functional capacity or ejection fraction) and survival. activation of catheterization laboratories and the timing ’ 2. In adult patients having a STEMI, does transfer to a effects of emergency medical services selection of the PCI center decrease the incidence of MACE? receiving facility. However, the question was framed from the perspective of a community emergency physician who Patient Management Recommendations needs to make critical decisions about transferring a Level A recommendations. None specified. STEMI patient who presents to a non-PCI-capable Level B recommendations. To decrease the incidence of hospital. MACE, patients with STEMI should be transferred to a According to a Class II study by Widimsky et al,20 the PCI-capable hospital as soon as possible. treatment of STEMI with PCI has a mortality and MACE Level C recommendations. None specified. advantage over fibrinolytic administration alone and that Potential Benefit of Implementing the treatment is time dependent. This study was a randomized Recommendations: Patients who receive timely PCI may controlled trial in the Czech Republic that compared experience better outcomes with a decrease in MACE. fibrinolysis at a community hospital not capable of PCI Potential Harm of Implementing the (421 patients) versus interhospital transfer (429 patients) Recommendations: Patients may decompensate en route to for PCI. Pain onset to randomization was similar in both the PCI facility resulting in poor outcomes. groups. Transfer time was 48 minutes (SD 20), and D2B Key words/phrases for literature searches: ST-elevation once arrived at a PCI capable center was 26 minutes (SD myocardial infarction, myocardial infarction, percutaneous 11). Inclusion criteria for this study were that patient coronary intervention, thrombolytic therapy, PCI transport to a PCI facility was feasible within 30 minutes of center, time factors, time-to-treatment, treatment enrollment and the distance to the PCI center was less than outcomes, patient transfer, survival rate, survival rates, 120 km (approximately 75 miles). Clinical outcomes risk, timing, complications, adverse effects, delayed measured were 30-day and 5-year death, MI, stroke, and intervention, emergency medical services, hospital, and revascularization. The incidence of MACE was lower in the variations and combinations of the key words/phrases; transfer for PCI group for both 30-day (24% in the Searches included January 1, 2006, to search dates of fibrinolytic group versus 14% in the PCI group; difference January 12, 2016, January 29, 2016, and February 10% [95% CI 4% to 15%]; number needed to treat 10) 24, 2016. and 5-year MACE (53% in the fibrinolytic group versus Study Selection: Two hundred two articles were 40% in the PCI group; difference 13% [95% CI 6% to identified in the search. Forty-five articles were selected 20%]; number needed to treat 8), respectively.20 from the search results for further review, with 1 Class II A Class III study by Wöhrle et al21 compared the and 1 Class III study included for this critical question. outcomes of STEMI patients who presented to a PCI There are many articles and guidelines published on this center versus patients who presented to a non-PCI center topic. Given the rigorous methodological process to answer and were transferred to a PCI-capable hospital and found this specific critical question, 2 studies were used to inform no significant difference in MACE at 30 days and 1 year. the final recommendation. Many articles were eliminated There was a total delay (symptom-to-balloon inflation) of because they were indirectly or not applicable. There has 67 minutes because of transfer to a PCI facility in this been a significant paradigm shift in the treatment of acute study. The actual time from symptom onset to a PCI- coronary syndrome (ACS) worldwide during the past few capable facility for transferred patients was 195 versus 116 decades. Previously, treatment choices included PCI and minutes for patients who presented directly to a PCI fibrinolytic therapy. The literature has shifted away from hospital.

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Transfer to PCI-capable hospitals can result in delays Potential Benefit of Implementing the to D2B time. How long can a patient wait before PCI Recommendations: Opioids offer relief to chest pain loses its advantage over fibrinolytics? Patients show patients by reducing discomfort and helping them relax favorable outcomes when they receive PCI for STEMI. The during a highly stressful medical event. goal is to begin transfer from a non-PCI-capable hospital Potential Harm of Implementing the once a STEMI is identified with a goal of total time from Recommendations: Opioids can potentially result in less first medical contact to intervention of less than 120 salvageable myocardium if administered to patients having minutes.19 an MI. In summary, best outcomes will likely be met by Key words/phrases for literature searches: opioids, developing systems in which STEMI is identified early opiates, analgesics, fentanyl, morphine, hydromorphone, in the out-of-hospital process and the patient is drug interactions, age factors, adenosine, piperazines, transported directly to a PCI-capable facility. For patients platelet aggregation, thiophenes, acute coronary syndrome, who develop STEMI after ED presentation in the suspected acute coronary syndrome, myocardial infarction, non-PCI-capable hospital, systems can be constructed reperfusion therapy, percutaneous coronary intervention, to expedite transfer to a PCI-capable facility. Therefore, angioplasty, thrombolytics, fibrinolytics, harm, risk, the recommendation is to transfer patients with STEMI adverse, treatment outcome, patient risk, and variations to a PCI-capable facility to decrease the incidence of and combinations of the key words/phrases; Searches MACE. included January 1, 2006, to search dates of January 12, 2016, January 29, 2016, and February 24, 2016. Future Research Study Selection: Twenty-five articles were identified in No studies exist to determine the exact interval after the search. Nine articles were selected from the search symptom onset when the benefits of emergent transfer results for further review, with 1 Class III study included dissipate. Current literature cited as support for transfers as for this critical question. best practice are based on observational studies with little In the absence of a history of hypersensitivity, judicious uniformity with respect to measured outcomes or the use of opioids has generally been considered safe in patient populations. The development of standardized hemodynamically stable patients with suspected ACS. metrics, definitions, and outcomes would allow comparison Largely based on expert opinion, current guidelines from of studies and robust meta-analyses. For example, what the American College of Cardiology/American Heart 2 22 does first medical contact mean? Does it mean the time Association and European Society of Cardiology when a patient is cared for by out-of-hospital providers or recommend intravenous morphine as the drug of choice to by the first hospital contact point? Standardized prospective relieve pain and anxiety and warn against the use of trials using well-designed integrated network protocols in nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclo- the United States or abroad may be the best setting for oxygenase (COX)-2 inhibitors due to increased risk for future prospective trials needed to provide a high degree of MACE associated with their use in patients with STEMI clinical certainty while avoiding ethical concerns in and non–ST-segment elevation ACS. The American randomizing patients to different treatment arms. Better College of Cardiology/American Heart Association recently delineation of the expected delay that would lead to reduced the level of recommendation for morphine fibrinolytic administration, as well as the optimal dose of administration in non-STEMI chest pain and unstable 23 fibrinolytics, would be useful to the referring emergency angina patients to a Class IIb recommendation. physician. As background, a retrospective cardiac magnetic resonance study of STEMI patients reperfused by PCI 3. In adult patients undergoing reperfusion therapy, showed that patients who received intravenous morphine should opioids be avoided to prevent adverse displayed larger infarct size, larger extent of microvascular outcomes? obstruction and less salvageable myocardium compared Patient Management Recommendations with those who did not.24 Evidence arguing against the Level A recommendations. None specified. routine use of opioids for patients with ACS who are Level B recommendations. None specified. undergoing reperfusion therapy comes from studies aimed Level C recommendations. Because safety has not been at evaluating the pharmacokinetic and pharmacodynamics established, clinical judgment should be used in deciding of P2Y12 receptor inhibitors (such as prasugrel and whether to provide or withhold morphine in patients ticagrelor).25 A recent retrospective study26 and a 2016 undergoing reperfusion therapy. prospectively designed study27 demonstrate delayed

730 Annals of Emergency Medicine Volume 70, no. 5 : November 2017 Clinical Policy absorption and activity of P2Y12 receptor inhibitors and Relevant industry relationships: There were no their metabolites in patients receiving morphine compared relevant industry relationships disclosed by the with those who did not. Impaired gastrointestinal subcommittee members for this topic. absorption is the suspected cause of the underlying Relevant industry relationships are those relationships mechanism of morphine’s effect. Although provocative, the with companies associated with products or services that last 4 studies24-27 cited received Class of Evidence grade significantly impact the specific aspect of disease “X” because they lacked the methodological design to addressed in the critical question. definitively address the clinical question. The traditional support for use of opioids in patients with ACS undergoing reperfusion therapy has been challenged in REFERENCES 1. Ward MJ, Kripalani S, Zhu Y, et al. Incidence of emergency department recent years, with studies suggesting that morphine may visits for ST-elevation myocardial infarction in a recent six-year period actually be harmful in this population; given that clinicians in the United States. Am J Cardiol. 2015;115:167-170. often cannot predict which chest pain patients will be 2. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of undergoing reperfusion therapy, the routine use of morphine the American College of Cardiology Foundation/American Heart to treat chest pain has been called into question. Initial Association Task Force on Practice Guidelines. J Am Coll Cardiol. concerns for potential harmful effects of morphine were 2013;61:e78-e140. raised as a result of registry data revealing higher rates of 3. Fesmire FM, Brady WJ, Hahn S, et al. American College of Emergency Physicians. Clinical policy: indications for reperfusion therapy in adverse clinical outcomes in non-STEMI ACS patients emergency department patients with suspected acute myocardial treated with clopidogrel who received intravenous morphine infarction. Ann Emerg Med. 2006;48:358-383. compared with those who did not. Using a propensity-score- 4. Aplin R, Tiede D, Lovitz C, et al. A regional system for delivery of primary percutaneous coronary intervention in ST-elevation myocardial matching method, the use of morphine was associated with infarction: STEMI–St. Cloud. J Invasive Cardiol. 2009;21:639-644. increased inhospital mortality (odds ratio 1.5; 95% CI 1.3 to 5. Pinto DS, Kirtane AJ, Nallamothu BK, et al. Hospital delays in 1.6), and the increased risk of death in patients persisted reperfusion for ST-elevation myocardial infarction. Implications 28 when selecting a reperfusion strategy. Circulation. across all risk groups in a study by Meine et al (Class III). 2006;114:2019-2025. Taken together, these data show that a therapeutic 6. Pinto DS, Frederick PD, Chakrabarti AK, et al. Benefit of transferring dilemma exists between the traditional beliefs in ST-segment–elevation myocardial infarction patients for percutaneous morphine’s beneficial effects for non-STEMI ACS patients coronary intervention compared with administration of onsite fi fibrinolytic declines as delays increase. Circulation. versus the recently identi ed potential harmful effects when 2011;124:2512-2521. morphine is used in the context of reperfusion therapy. 7. Beri A, Printz M, Hassan A, et al. versus primary Therefore, physicians should be aware of this theoretical percutaneous intervention in ST-elevation myocardial infarction with long interhospital transfer distances. Clin Cardiol. treatment dilemma and understand the lack of evidence to 2010;33:162-167. recommend for or against the use of opiates in STEMI 8. Bohmer E, Hoffmann P, Abdelnoor M, et al. Efficacy and safety of patients. Physicians are left with making case-by-case immediate angioplasty versus ischemia-guided management after in acute myocardial infarction in areas with very long decisions until further data helps delineate a stronger transfer distances. Results of the NORDISTEMI (NORwegian study on recommendation. DIstrict treatment of ST-Elevation Myocardial Infarction). J Am Coll Cardiol. 2010;55:102-110. 9. Manari A, Ortolani P, Guastaroba P, et al. Clinical impact of an inter- Future Research hospital transfer strategy in patients with ST-elevation myocardial Adequately powered prospective trials are needed to infarction undergoing primary angioplasty: the Emilia-Romagna ST- segment elevation acute myocardial infarction network. Eur Heart J. support or refute and quantify a potential negative clinical 2008;29:1834-1842. effect of opioids on patient outcomes for patients 10. Nielsen PH, Maeng M, Busk M, et al. Primary angioplasty versus undergoing revascularization. If the causal effect is real, the fibrinolysis in acute myocardial infarction. Circulation. 2010;121:1484-1491. detailed underlying mechanism of the interaction requires 11. Stenestrand U, Lindback J, Wallentin L; for the RIKS-HIA Registry. further study because it may apply only to morphine and Long-term outcome of primary percutaneous coronary intervention vs not to other opioids, such as those that are ultrashort- prehospital and in-hospital thrombolysis for patients with ST-elevation myocardial infarction. JAMA. 2006;296:1749-1756. lasting. If the effect is mostly related to gastrointestinal 12. Vora AN, Holmes DN, Rokos I, et al. Fibrinolysis use among patients absorption, then intravenous preparations of P2Y12 requiring interhospital transfer for ST-segment elevation myocardial inhibitors may provide alternatives to oral routes for infarction care. A report from the US National Cardiovascular Data patients who benefit most from opioids such as those with Registry. JAMA Intern Med. 2015;175:207-215. 13. Cantor WJ, Fitchett D, Borgundvaag B, et al. Routine early angioplasty severe pain or those with ongoing pain and anticipated long after fibrinolysis for acute myocardial infarction. N Engl J Med. travel times from non-PCI to PCI centers. 2009;360:2705-2718.

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14. Denktas AE, Athar H, Henry TD, et al. Reduced-dose fibrinolytic 22. StegPG,JamesSK,AtarD,etal;fortheTaskForceonthe acceleration of ST-segment elevation myocardial infarction treatment Management of ST-Segment Elevation Acute Myocardial Infarction coupled with urgent percutaneous coronary intervention compared to of the European Society of Cardiology. ESC guidelines for the primary percutaneous coronary intervention alone. Results of the management of acute myocardial infarction in patients AMICO (Alliance for Myocardial Infarction Care Optimization) Registry. presenting with ST-segment elevation. Eur Heart J.2012;33: JACC Cardiovasc Interv. 2008;1:504-510. 2569-2619. 15. Ellis SG, Tendera M, de Belder MA, et al. 1-Year survival in a 23. Amsterdam EA, Wenger NK, Brindis RG, et al; ACC/AHA Task Force randomized trial of facilitated reperfusion. Results from the FINESSE Members; Society for Cardiovascular Angiography and Interventions (Facilitated Intervention With Enhanced Reperfusion Speed to Stop and the Society of Thoracic Surgeons. 2014 ACC/AHA guideline for the Events) Trial. J Am Coll Cardiol Intv. 2009;2:909-916. management of patients with non–ST-elevation acute coronary 16. Larson DM, Duval S, Sharkey SW, et al. Safety and efficacy of a syndromes: executive summary: a report of the American College of pharmaco-invasive reperfusion strategy in rural ST-elevation Cardiology/American Heart Association Task Force on Practice myocardial infarction patients with expected delays due to long- Guidelines. Circulation. 2014;130:2354-2394. distance transfers. Eur Heart J. 2012;33:1232-1240. 24. de Waha S, Eitel I, Desch S, et al. Intravenous morphine administration 17. Armstrong PW, Gershlick AH, Goldstein P, et al. Fibrinolysis or primary and reperfusion success in ST-elevation myocardial infarction: insights PCI in ST-segment elevation myocardial infarction. N Engl J Med. from cardiac magnetic resonance imaging. Clin Res Cardiol. 2013;368:1379-1387. 2015;104:727-734. 18. Blankenship JC, Scott TD, Skelding KA, et al. Door-to-balloon times 25. Parodi G, Valenti R, Bellandi B, et al. Comparison of prasugrel and under 90 min can be routinely achieved for patients transferred for ST- ticagrelor loading doses in ST-segment elevation myocardial infarction segment elevation myocardial infarction percutaneous coronary patients. J Am Coll Cardiol. 2013;61:1601-1606. intervention in a rural setting. J Am Coll Cardiol. 2011;57:272-279. 26. Parodi G, Bellandi B, Xanthopoulou I, et al. Morphine is associated with 19. O’Connor RE, Al Ali AS, Brady WJ, et al. Part 9: acute coronary a delayed activity of oral antiplatelet agents in patients with ST- syndromes: 2015 American Heart Association guidelines update for elevation acute myocardial infarction undergoing primary cardiopulmonary resuscitation and emergency cardiovascular care. percutaneous coronary intervention. Circ Cardiovasc Interv. Circulation. 2015;132:S483-S500. 2015;8:e001593. 20. Widimsky P, Bilkova D, Penicka M, et al. Long-term outcomes of patients 27. Kubica J, Adamski P, Ostrowska M, et al. Morphine delays and with acute myocardial infarction presenting to hospitals without attenuates ticagrelor exposure and action in patients with myocardial catheterization laboratory and randomized to immediate thrombolysis or infarction: the randomized, double-blind, placebo-controlled interhospital transport for primary percutaneous coronary intervention. Five IMPRESSION trial. Eur Heart J. 2016;37:245-252. years’ follow-up of the PRAGUE-2 trial. Eur Heart J. 2007;28:679-684. 28. Meine TJ, Roe MT, Chen AY, et al; for the CRUSADE Investigators. 21. Wöhrle J, Desaga M, Metzger C, et al. Impact of transfer for primary Association of intravenous morphine use and outcomes in acute percutaneous coronary intervention on survival and clinical outcomes coronary syndromes: results from the CRUSADE quality improvement (from the HORIZONS-AMI Trial). Am J Cardiol. 2010;106:1218-1224. initiative. Am Heart J. 2005;149:1043-1049.

Annals’ Impact Factor

Impact Factor score, one of many metrics of a journal’sinfluence, is a measure of the frequency with which the average article in a journal has been cited over a given period of time. Annals’ Impact Factor rose to an all-time high this year, to 5.352.

732 Annals of Emergency Medicine Volume 70, no. 5 : November 2017 Clinical Policy

Appendix A. Literature classification schema.* Design/Class Therapy† Diagnosis‡ Prognosis§ 1 Randomized, controlled trial or Prospective cohort using a criterion standard or Population prospective cohort or meta-analysis of randomized trials meta-analysis of prospective studies meta-analysis of prospective studies

2 Nonrandomized trial Retrospective observational Retrospective cohort Case control

3 Case series Case series Case series

*Some designs (eg, surveys) will not fit this schema and should be assessed individually. †Objective is to measure therapeutic efficacy comparing interventions. ‡Objective is to determine the sensitivity and specificity of diagnostic tests. §Objective is to predict outcome, including mortality and morbidity.

Appendix B. Approach to downgrading strength of evidence. Design/Class Downgrading 123 None I II III 1 level II III X 2 levels III X X Fatally flawed X X X

Appendix C. Likelihood ratios and number needed to treat.* LR (D)LR(–) 1.0 1.0 Does not change pretest probability 1–5 0.5–1 Minimally changes pretest probability 10 0.1 May be diagnostic if the result is concordant with pretest probability 20 0.05 Usually diagnostic 100 0.01 Almost always diagnostic even in the setting of low or high pretest probability

LR, likelihood ratio. *Number needed to treat (NNT): number of patients who need to be treated to achieve 1 additional good outcome; NNT¼1/absolute risk reduction100, where absolute risk reduction is the risk difference between 2 event rates (ie, experimental and control groups).

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of Evidentiary Table. mrec eiieVolume Medicine Emergency Study & Year Class of Setting & Study Methods & Outcome Results Limitations & Comments Published Evidence Design Measures Vora et al12 III Secondary analysis 1,771 STEMI referring 22,481 patients with STEMI eligible for Generalizable; MACE not (2015) of ACTION centers to 366 STEMI fibrinolysis or PCI; specifically evaluated registry, the largest receiving centers; no significant mortality benefit between ongoing quality outcomes: inhospital fibrinolysis vs PCI (3.7% vs 3.9%; improvement mortality and major OR=1.1; 95% CI 0.9 to 1.4), but had a registry of AMI in bleeding higher bleeding risk (10.7% vs 9.5%; the U.S.; OR=1.2; 95% CI 1.0 to 1.3) objective to assess the association of estimated interhospital drive times with reperfusion strategy selection (fibrinolysis vs primary PCI) Cantor et al13 III Randomized Random allocation of N=1,059; 522 to fibrinolytic group, 537 to Unblinded; concern that patients (2009) clinical trial fibrinolytic fibrinolytic+transfer group; 89% of in intervention group were (TRANSFER-AMI therapy+rescue or fibrinolytic+rescue or delayed PCI ultimately cared for more Trial); 52 sites in delayed PCI vs underwent PCI, median 33 h after aggressively; early PCI was not Canada fibrinolytic randomization; 99% of early: no attempts made within therapy+immediate fibrinolytic+immediate transfer for PCI 90 min transfer to another underwent PCI, median 3 h after hospital for PCI within 6 randomization;17.2% of those with h of fibrinolysis; all fibrinolysis+rescue or delayed PCI met patients received aspirin, outcome vs 11% of those with heparin or enoxaparin, fibrinolysis+immediate transfer and PCI and fibrinolysis met outcome (RR=0.6; 95% CI 0.5 to 0.9, (tenecteplase); P=.004) outcome: MACE at 30 0 o : 5 no. 70, days (death, reinfarction, cardiogenic shock, or new or worsening heart failure) November 2017 Volume 0 o : 5 no. 70, November

2017 Evidentiary Table (continued). Study & Year Class of Setting & Study Methods & Outcome Results Limitations & Comments Published Evidence Design Measures Denktas et al14 III Secondary analysis Local protocols dictated N=2,869; 1,200 fibrinolysis+PCI, 1,669 Use of stepwise logistic (2008) of registry data use of aspirin, heparin, PCI; significant differences in baseline regression; no blinding; from multiple clopidogrel, and low- characteristics between study groups; protocols were locally dependent centers in the US; molecular-weight mean time to PCI was 253 min; mean time objective to heparin; multivariable to fibrinolysis was 54 min; evaluate reduced- analyses used to adjust mortality significantly lower with dose out-of- for differences between fibrinolysis+PCI vs PCI alone; however, hospital groups; primary outcome: fibrinolysis+PCI was not a significant fibrinolysis for mortality at 30 days; predictor of any outcome after adjusting STEMI patients secondary outcomes: for age, creatinine level, hyperlipidemia, followed by PCI vs death, reinfarction, and diabetes mellitus PCI alone stroke, PCI, and shock Ellis et al15 III Randomized Random allocation to N=2,452; no significant differences in Outstanding follow-up rates (2009) clinical trial reduced-dose mortality among the 3 groups (6.3%, (≈98%) in all groups; (FINESSE Trial); reteplase+abciximab, 7.4%, and 7.0%; P=NS) excluded patients <60 y with objective to abciximab alone, or inferior MI because they were evaluate 12-mo placebo, followed by considered low risk; outcomes of expedited PCI; outcome: blinded, placebo controlled; facilitated PCI 1-y mortality MACE not considered; (prespecified secondary primary endpoint underpowered endpoint of principal because principal study stopped

Annals study) early of mrec Medicine Emergency lnclPolicy Clinical 735 lnclPolicy Clinical 736 Annals of mrec eiieVolume Medicine Emergency

Evidentiary Table (continued). Study & Year Class of Setting & Study Methods & Outcome Results Limitations & Comments Published Evidence Design Measures Larson et al16 III Prospective data Standardized protocol N=2,634; 600 received primary PCI; Although methodologically (2012) collection for across all hospitals; all excellent balance between propensity- limited by use of a data registry, STEMI registry; patients received aspirin, score-matched groups; no significant this may also incur strength in 31 centers in clopidogrel, difference between groups in regard to terms of pragmatic evaluation; Minnesota; unfractionated heparin, stroke, major bleeding, 30-day mortality no new data about optimal objective to and β-blocker; or reinfarction anticipated transfer time, but evaluate safety and multivariable statistical presents argument for efficacy of half- methods, including use of fibrinolysis first if inclement dose propensity score weather, transfer using 60-mile fibrinolysis+transfer matching to compare cutoff if no inclement weather for immediate PCI groups (distance and weather vs primary PCI considerations) 0 o : 5 no. 70, November 2017 Volume 0 o : 5 no. 70,

Evidentiary Table (continued).

November Study & Year Class of Setting & Study Methods & Outcome Results Limitations & Comments Published Evidence Design Measures Armstrong et III Open-label, Patients were randomized N=1,915 patients, 1,892 of whom Open label; study sponsored by al17 (2013) prospective, if they presented within 3 underwent randomization; after loss to Boehringer Ingelheim; baseline 2017 multicenter, h of symptom onset and follow-up and withdrawal of consent there imbalance in the number who randomized trial an ST-segment elevation were 944 patients in the fibrinolysis group had previous PCI with 6.4% in from 99 sites in 15 on ECG but could not and 948 in the PCI group; 36% of the the fibrinolytic group and 8.8% countries receive PCI within 1 h patients randomized to the fibrinolysis in the primary PCI group; 36% after first medical group required rescue PCI; the composite of patients in the fibrinolysis contact; the treatment endpoint occurred in 12.4% of the group underwent rescue PCI group received fibrinolysis group and 14.3% of the fibrinolytic therapy and primary PCI group; RR=0.86 (95% CI the PCI within 24 h, and 0.68 to 1.09); the total number of the control group was small but statistically greater in the received PCI alone; in the fibrinolysis group at 1.6% vs 0.5% mainly event that there was not driven by the rate of hemorrhagic stroke at ST-segment resolution of 1.0% compared with 0.3%; there was no at least 50% in the difference in nonintracranial major fibrinolytic group, they bleeding received PCI; primary endpoint was a 30-day composite of death from any cause, shock, congestive heart failure, or reinfarction; after enrollment of 21% of the anticipated final study population, the Annals fibrinolytic dose was reduced by half for of patients >75 y secondary mrec Medicine Emergency to increased intracranial hemorrhage rate lnclPolicy Clinical 737 lnclPolicy Clinical 738 Annals of mrec eiieVolume Medicine Emergency

Evidentiary Table (continued). Study & Year Class of Setting & Study Methods & Outcome Results Limitations & Comments Published Evidence Design Measures Widimsky et II PRAGUE-2 trial Fibrinolysis at a 421 in fibrinolytic group and 429 in PCI group Open label; outcome defined al20 (2007) with 5-y follow- community hospital not transported to nearest hospital; but not masked to up; prospective capable of PCI vs 30 day: intervention; randomized trial; interhospital transfer for death/reinfarction/stroke/revascularization 24% high proportion (≈99%) Czech Republic primary PCI; outcome: in fibrinolytic group vs 14% in PCI group, follow-up death, reinfarction, difference 10%; NNT 10 (P<.001); stroke, and 5 y: death any cause/re- revascularization at 30 MI/stroke/revascularization 53% in fibrinolytic days and 5 y group vs 40% in PCI group, difference 13%; NNT 8 (P<.001) Wöhrle et al21 III Secondary Comparison of patients 988 (24.7%) patients were transferred for Secondary analysis of a (2010) analysis of the who required transfer for primary PCI and 2,614 were directly admitted randomized trial; groups HORIZONS-AMI primary PCI vs direct for PCI; at 30 days and 1 y, there were no different from the allocation trial, which admission for PCI; significant differences between study groups scheme, thus not balanced or included 1:1 outcome: MACE (death, (5.8% vs 5.4%); use of multivariable modeling comparable at baseline; randomization of reinfarction, to adjust for differences between groups outcome blinded to study patients to revascularization, or resulted in similar nonsignificant differences in group bivalirudin vs stroke) or major bleeding outcomes unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor 0 o : 5 no. 70, November 2017 Volume 0 o : 5 no. 70,

Evidentiary Table (continued). Study & Year Class of Setting & Study Methods & Outcome Results Limitations & Comments Published Evidence Design Measures November Meine et al28 III Retrospective Compared patients who N=57,039; 17,003 (30%) patients received Doses and timing of (2005) cohort from 443 received IV morphine morphine; rates of adverse clinical not collected; outcomes not hospitals in the US with those who did not outcomes were higher in patients who adjudicated; adverse clinical

2017 with respect to outcomes received IV morphine compared with outcomes even though these (eg, postadmission those who did not; MI increased from patients were more likely to be infarction, cardiogenic 3.0% to 3.8% (OR 1.3; 95% CI 1.2 to 1.5), treated with evidence-based shock, congestive heart death increased from 4.7% to 5.5% (OR medications and to undergo failure, death, and the 1.5; 95% CI 1.3 to 1.6), and the composite invasive cardiac procedures composite outcome of end point of death or MI increased from postadmission infarction 7.1% to 8.5% (OR 1.4; 95% CI 1.3 to or death); propensity 1.6); these findings persisted even when score matching used to controlled for the concomitant use of IV account for potential nitroglycerin imbalance between those who received morphine and those who did not, in an effort to isolate the effect of morphine on outcomes; also compared patients who received IV morphine vs IV nitroglycerin only, and both IV morphine and IV nitroglycerin, where the comparator was patients who received IV nitroglycerin

Annals ACTION, Acute Coronary Treatment and Intervention Outcomes Network; AMI, acute myocardial infarction; CI, confidence interval; ECG, electrocardiogram; FINESSE, Facilitated Intervention With Enhanced Reperfusion Speed to Stop Events; h, hour; HORIZONS-AMI, Harmonizing Outcomes With Revascularization IV MACE MI min mo NNT

of and Stents-Acute Myocardial Infarction; , intravenous; , major adverse cardiac event; , myocardial infarction; , minute; , month; , number NS OR PCI PRAGUE-2 mrec Medicine Emergency needed to treat; , not significant; , odds ratio; , percutaneous coronary intervention; , Primary Angioplasty in Patients Transferred From General Community Hospitals to Specialized Percutaneous Coronary Intervention Units With or Without Emergency Thrombolysis-2; RR, relative risk; STEMI, ST-segment elevation myocardial infarction; TRANSFER-AMI, Trial of Routine Angioplasty and Stenting After Fibrinolysis to Enhance Reperfusion-Acute Myocardial Infarction; US, United States; vs, versus; y, year. lnclPolicy Clinical 739