clinical policy: emergency department management of ......the evaluation and management of patients...

CARDIOLOGY/CLINICAL POLICY

724 Annals of

Clinical Policy: Emergency DepartmentManagement of Patients Needing ReperfusionTherapy for Acute ST-Segment Elevation

Myocardial Infarction

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)

Richard Byyny, MD, MSc (Methodologist)

Deborah B. Diercks, MD, MSc

Seth R. Gemme, MD

Charles J. Gerardo, MD, MHS

Steven A. Godwin, MD

Sigrid A. Hahn, MD, MPH

Benjamin W. Hatten, MD, MPH

Jason S. Haukoos, MD, MSc (Methodologist)

Graham S. Ingalsbe, MD (EMRA Representative 2015-2017)

Amy Kaji, MD, MPH, PhD (Methodologist)

Heemun Kwok, MD, MS (Methodologist)

Bruce M. Lo, MD, MBA, RDMS

Sharon E. Mace, MD

Devorah J. Nazarian, MD

Jean A. Proehl, RN, MN, CEN, CPEN (ENA Representative

2015-2017)

Susan B. Promes, MD, MBA

Kaushal H. Shah, MD

Richard D. Shih, MD

Scott M. Silvers, MD

Emergency Medicine

Michael D. Smith, MD, MBA

Molly E. W. Thiessen, MD

Christian A. Tomaszewski, MD, MS, MBA

Jonathan H. Valente, MD

Stephen P. Wall, MD, MSc, MAEd (Methodologist)

Stephen J. Wolf, MD

Stephen V. Cantrill, MD (Liaison with Quality and Patient

Safety Committee)

Jon Mark Hirshon, MD, MPH, PhD (Board Liaison 2016-

2017)

Rhonda R. Whitson, RHIA, Staff Liaison, Clinical Policies

Committee and Subcommittee Revising the Reperfusion

Therapy for Acute Myocardial Infarction Clinical Policy

Travis Schulz, MLS, AHIP, Staff Liaison, Clinical Policies

Committee

Approved by the ACEP Board of Directors June 28, 2017

Endorsed by the Emergency Nurses Association

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 matterCopyright © 2017 by the American College of Emergency Physicians.https://doi.org/10.1016/j.annemergmed.2017.09.035

Volume 70, no. 5 : November 2017

https://doi.org/10.1016/j.annemergmed.2017.09.035

http://crossmark.crossref.org/dialog/?doi=10.1016/j.annemergmed.2017.09.035&domain=pdf

Clinical Policy

[Ann Emerg Med. 2017;70:724-739.]

ABSTRACTIschemic heart disease is the leading cause of death in the

world. More than half a million patients present toemergency departments across the United States each yearwith ST-segment elevation myocardial infarctions.1 Timelyreperfusion is critical to saving myocardium at risk.Multiple studies have been conducted that demonstratethat improved care processes are linked to improvedsurvival in patients having an acute myocardial infarction.This clinical policy from the American College ofEmergency Physicians addresses key issues in reperfusionfor patients with acute ST-segment elevation myocardialinfarction. A writing subcommittee conducted a systematicreview of the literature to derive evidence-basedrecommendations to answer the following clinicalquestions: (1) In adult patients having an ST-segmentelevation myocardial infarction, are there patients forwhom treatment with fibrinolytic therapy decreases theincidence of major adverse cardiac events whenpercutaneous coronary intervention is delayed? (2) In adultpatients having an ST-segment elevation myocardialinfarction, does transfer to a percutaneous coronaryintervention center decrease the incidence of major adversecardiac events? (3) In adult patients undergoing reperfusiontherapy, should opioids be avoided to prevent adverseoutcomes? Evidence was graded and recommendationswere made based on the strength of the available data.

INTRODUCTIONAlthough timely percutaneous coronary intervention

(PCI) has become the standard treatment for ST-segmentelevation myocardial infarction (STEMI), the fact remainsthat only a minority of hospitals in the United States arecapable of performing this intervention on site, and evenfewer can provide 24-hour access to the intervention.When a patient presents with STEMI, national guidelinesrecommend a first medical-contact-to-device time of lessthan 90 minutes for individuals presenting to a PCI-capable site and less than 120 minutes from first medical-contact-to-device time for those who need to be transferredto a PCI-capable hospital.2 Although very few patients aretreated solely with fibrinolytic therapy without anangiographic assessment of their coronary arteries, the time-dependent nature of getting the patient to a PCI centerrequires knowledge of how delays affect clinical outcomes.

Systems have been developed for rapid out-of-hospitaltriage to PCI-capable centers and for rapid interhospitaltransfer from a noncapable PCI facility to one that can


perform the intervention. What are the sources of thesedelays? What are the indications for fibrinolytic therapy inthe age of PCI? These questions are critical for emergencyphysicians who practice in rural and remote locationswithout immediate access to PCI centers. Aside from theimmediate outcomes for reperfusion and death, data onlong-term functional outcomes are critical to determine theimpact these interventions ultimately have on patient lives.Finally, the role of pain relief—in particular, opioid use—isdiscussed in light of newer research that raises someconcern over long-term outcomes in chest pain patientstreated with opioids.

This clinical policy addresses 3 issues that are relevant topracticing emergency physicians. The first 2 questionsaddress whether there is a benefit to giving fibrinolytictherapy to STEMI patients when PCI will be delayed andwhether transfer to a PCI-capable facility for the STEMIpatient decreases the incidence of major adverse cardiacevents (MACE). The clinical heterogeneity among theresearch studies investigating these topics makeinterpretation of the results challenging. For example, thereis no standard definition of MACE. MACE may includesuch endpoints as death, revascularization, stroke, andcongestive heart failure, but not all studies use the sameendpoints. Definitions for MACE will be identified in thepolicy as appropriate for clarity. In addition, there is nouniformity on timing metrics. The final critical questionexamines the safety of opioid use in this population.

This is a revision of the 2006 American College ofEmergency Physicians (ACEP) clinical policy onreperfusion therapy in emergency department (ED)patients with suspected acute myocardial infarction (MI).3

METHODOLOGYThis clinical policy is based on a systematic review with

critical analysis of the medical literature meeting theinclusion criteria. Searches of MEDLINE, MEDLINEInProcess, Cochrane, EMBASE, and Scopus databases wereperformed. All searches were limited to human studiespublished in English. Specific key words/phrases, years usedin the searches, dates of searches, and study selection areidentified under each critical question. In addition, relevantarticles from the bibliographies of included studies andmore recent articles identified by committee members andreviewers were included.

This policy is a product of the ACEP clinical policydevelopment process, including internal and externalreview, and is based on the existing literature; whenliterature was not available, consensus of Clinical PoliciesCommittee members was used and noted as such in the

Annals of Emergency Medicine 725

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recommendation (ie, consensus recommendation). Reviewcomments were received from emergency physicians,cardiologists, individual members of the American Collegeof Cardiology Foundation/American Heart Association, apatient representative, and members of ACEP’s Medical-Legal Committee. Comments were received during a 60-day open-comment period, with notices of the commentperiod sent in an e-mail to ACEP members, published inEM Today, and posted on the ACEP Web site. Theresponses were used to further refine and enhance thisclinical policy; however, responses do not implyendorsement. Clinical policies are scheduled for revisionevery 3 years; however, interim reviews are conducted whentechnology, methodology, or the practice environmentchanges significantly. ACEP was the funding source for thisclinical policy.

Assessment of Classes of EvidenceTwo methodologists independently graded and assigned

a preliminary Class of Evidence for all articles used in theformulation of this clinical policy. Class of Evidence isdelineated whereby an article with design 1 represents thestrongest study design and subsequent design classes (ie,design 2 and design 3) represent respectively weaker studydesigns for therapeutic, diagnostic, or prognostic studies, ormeta-analyses (Appendix A). Articles are then graded ondimensions related to the study’s methodological features,such as randomization processes, blinding, allocationconcealment, methods of data collection, outcomemeasures and their assessment, selection andmisclassification biases, sample size, generalizability, datamanagement, analyses, congruence of results andconclusions, and conflicts of interest. Using apredetermined process combining the study’s design,methodological quality, and applicability to the criticalquestion, articles received a Class of Evidence grade. Anadjudication process involving discussion with the originalmethodologist graders and at least one additionalmethodologist was then used to address any discordance inoriginal grading, resulting in a final Class of Evidenceassignment (ie, Class I, Class II, Class III, or Class X)(Appendix B). Articles identified with fatal flaws orultimately determined to not be applicable to the criticalquestion received a Class of Evidence grade “X” and werenot used in formulating recommendations for this policy.However, content in these articles may have been used toformulate the background and to inform expert consensusin the absence of robust evidence. Grading was done withrespect to the specific critical questions; thus, the Class ofEvidence for any one study may vary according to the

726 Annals of Emergency Medicine

question for which it is being considered. As such, it waspossible for a single article to receive a different Class ofEvidence rating when addressing a different criticalquestion. Question-specific Classes of Evidence gradingmay be found in the Evidentiary Table included at the endof this policy.

Translation of Classes of Evidence toRecommendation Levels

Based on the strength of evidence grading for eachcritical question (ie, Evidentiary Table), the subcommitteedrafted the recommendations and the supporting textsynthesizing the evidence using the following guidelines:

Level A recommendations. Generally acceptedprinciples for patient care that reflect a high degree ofclinical certainty (eg, based on evidence from one or moreClass of Evidence I or multiple Class of Evidence IIstudies).

Level B recommendations. Recommendations forpatient care that may identify a particular strategy or rangeof strategies that reflect moderate clinical certainty (eg,based on evidence from one or more Class of Evidence IIstudies or strong consensus of Class of Evidence IIIstudies).

Level C recommendations. Recommendations forpatient care that are based on evidence from Class ofEvidence III studies or, in the absence of any adequatepublished literature, based on expert consensus. Ininstances in which consensus recommendations are made,“consensus” is placed in parentheses at the end of therecommendation.

The recommendations and evidence synthesis were thenreviewed and revised by the Clinical Policies Committee,which was informed by additional evidence or contextgained from reviewers.

There are certain circumstances in which therecommendations stemming from a body of evidenceshould not be rated as highly as the individual studies onwhich they are based. Factors such as heterogeneity ofresults, uncertainty about effect magnitude, andpublication bias, among others, might lead to adowngrading of recommendations.

When possible, clinically oriented statistics (eg,likelihood ratios, number needed to treat) are presented tohelp the reader better understand how the results may beapplied to the individual patient (Appendix C).

This policy is not intended to be a complete manual onthe evaluation and management of patients with STEMIbut rather a focused examination of critical issues that haveparticular relevance to the current practice of emergency


Clinical Policy

medicine. Potential benefits and harms of implementingrecommendations are briefly summarized within eachcritical question.

It is the goal of the Clinical Policies Committee toprovide an evidence-based recommendation when themedical literature provides enough quality information toanswer a critical question. When the medical literature doesnot contain adequate empirical data to answer a criticalquestion, the members of the Clinical Policies Committeebelieve that it is equally important to alert emergencyphysicians to this fact.

This clinical policy is not intended to represent a legalstandard of care for emergency physicians.Recommendations offered in this policy are not intended torepresent the only diagnostic or management optionsavailable to the emergency physician. ACEP recognizes theimportance of the individual physician’s judgment andpatient preferences. This guideline provides clinicalstrategies for which medical literature exists to answer thecritical questions addressed in this policy.

Scope of Application. This guideline is intended forhealth care providers working in EDs.

Inclusion Criteria. This guideline is intended for adultpatients presenting to the ED with suspected acuteSTEMI.

Exclusion Criteria. This guideline is not intended forpediatric patients, pregnant patients, or patients withcontraindications to fibrinolytic treatment.

CRITICAL QUESTIONS1. In adult patients having a STEMI, are there patients

for whom treatment with fibrinolytic therapydecreases the incidence of MACE when PCI isdelayed?

Patient Management RecommendationsLevel A recommendations. None specified.Level B recommendations. Fibrinolytics may be

administered to patients when door-to-balloon (D2B) timeis anticipated to exceed 120 minutes.

Level C recommendations. A dose reduction should beconsidered when administering fibrinolytics to patientsaged 75 years or older.

Potential Benefit of Implementing theRecommendations: The use of fibrinolytics when D2Btime is delayed may result in better long-term outcomeswith a decrease in MACE.

Potential Harm of Implementing theRecommendations: Time estimates are challenging toobtain in the context of an emergency, therefore patientsmay not receive the recommended therapy within the


appropriate time frame necessary to achieve optimaloutcomes.

Key words/phrases for literature searches: STEMI,myocardial infarction, angioplasty, balloon, coronary,percutaneous coronary intervention, adverse effects,mortality, fibrinolytic agents, thrombolytic therapy,recombinant proteins, antithrombins, platelet aggregationinhibitors, risk assessment, risk factors, time factors,survival rate, survival analysis, treatment outcome, adversecardiac, delay, transportation of patients, patient transfer,health services accessibility, emergency medical services,myocardial reperfusion, time-to-treatment, pharmaco-invasive therapy, facilitated PCI, and variations andcombinations of the key words/phrases. Searches includedJanuary 1, 2006 to search dates of January 12, 2016,January 29, 2016, February 9, 2016, February 24, 2016,and January 10, 2017.

Study Selection: Two hundred thirty-four articles wereidentified in the search. Forty-three articles were selectedfrom the search results for further review, with 6 Class IIIstudies included for this critical question.

Many hospitals in the United States with inpatient bedsdo not have a cardiac catheterization laboratory with directaccess to PCI. Although PCI as a revascularizationprocedure is desirable within 90 minutes of first medicalcontact, this time frame is impossible to achieve in suchfacilities. Quality initiatives have demonstrated time benefitto coordination of out-of-hospital performance andtransmission of ECG data with emergency care and withresponse of catheterization laboratory personnel andinterventional cardiology. There are barriers to efficienttransfer, including the availability of on-call specialists andimpediments to transportation, such as inclement weather;therefore, time to PCI will vary between health systems andindividual situations.

With the rise of freestanding emergency centers fromwhich any patient sustaining an MI must be transferredfor care, and with the closure of rural hospitals, it isexpected that the number of patients with chest painand STEMI presenting to non-PCI-capable facilities willincrease. Given the availability of fibrinolytic therapy toany practitioner of emergency care, it is important todefine a time frame during which these patients willderive benefit from fibrinolysis as initial therapy forSTEMI.

Rather than using fibrinolytics, multiple studies favorPCI with a D2B time of less than 120 minutes, includingtransfer time.4-11 It is not always feasible to achieve PCI inless than 120 minutes even at PCI-capable hospitals;therefore, fibrinolytics followed by PCI may be consideredin select circumstances. There is variation in the dosing of


Clinical Policy

fibrinolytics before transfer for PCI, namely full-dose versusreduced dose.

A Class III study by Vora et al12 consisting of a registryof 22,481 patients (Acute Coronary Treatment andIntervention Outcomes Network Registry) indicated thatwhen estimated interhospital drive time exceeded 30minutes, only 42.6% of transferred patients achieved thefirst D2B time of less than 120 minutes. Among 15,437patients eligible for full-dose fibrinolysis or PCI withestimated transfer drive times of 30 to 120 minutes, 34.3%received fibrinolysis (median door-to-needle time of 34minutes). Median transfer time was 49 minutes. Patientstreated with fibrinolysis versus PCI had no significantmortality difference (3.7% versus 3.9%; odds ratio 1.1;95% confidence interval [CI] 0.9 to 1.4), but had higherbleeding risk, which included a decrease in hemoglobinlevel (�4 g/dL), or intracranial hemorrhage, or RBCtransfusion (10.7% versus 9.5%; odds ratio 1.2; 95% CI1.0 to 1.3). The mortality rates took into considerationmultiple confounders such as transfer times, presence ofheart failure, shock, and within-hospital clustering. A ClassIII study13 from Canada measured the primary endpoint,which was the composite of death, cardiogenic shockwithin 30 days, new or worsening heart failure,reinfarction, recurrent ischemia, or new or worseningcongestive heart failure within 30 days in all patients whoreceived full-dose fibrinolysis. Five hundred thirty-sevenpatients were randomly assigned to be immediatelytransferred for PCI within 6 hours after fibrinolytics. Fivehundred twenty-two patients were randomized to standardfibrinolytic therapy without PCI, but 182 patients (39.9%)received urgent catheterization (rescue PCI), with stentsimplanted in 98.3%. The immediate transfer for PCIgroup had better primary endpoints (11% versus 17.2%).However, no patients received PCI within 90 minutes.13

A 2008 Class III report14 of 2,869 STEMI patientstreated at 5 high-volume centers demonstrated significantlylower mortality with reduced dose fibrinolysis followed byurgent PCI compared with primary PCI. Mean time toPCI was 253 minutes, whereas mean time to fibrinolysiswas 54 minutes. A Class III randomized study15 of a totalof 2,452 patients suggested a mortality benefit to reduced-dose reteplase plus abciximab as opposed to abciximabalone, or placebo, followed by expedited primary PCI whenPCI delays of greater than 1 hour were anticipated. Data ina Class III study16 from Minnesota attempted to addressreperfusion options in STEMI patients with expecteddelays to a PCI-capable hospital. More than 2,600consecutive STEMI patients from 31 referral hospitals wereentered into a registry, as well as 600 who presented to thePCI center. Patients who presented to the PCI hospital or


who were transferred from a zone 1 hospital (<60 milesaway) underwent primary PCI as the reperfusion method.Patients transferred from zone 2 hospitals (�60 miles away)received aspirin, clopidogrel, unfractionated heparin, a b-blocker, and reduced-dose fibrinolytic, most frequentlytenecteplase with comparable outcomes in stroke, majorbleeding, 30-day mortality, and reinfarction. The authors’conclusions were that an argument should be made forfibrinolytic therapy if there is inclement weather or for a60-mile transport cutoff if there is no inclement weather.16

Finally, in a Class III study,17 STEMI patients whopresented within 3 hours of symptom onset and could notreceive PCI within 1 hour were randomized in the out-of-hospital setting to either transport for primary PCI ortreatment with full-dose tenecteplase plus clopidogrel andenoxaparin before transfer to a PCI-capable hospital. Theprimary endpoints were a composite of death, shock,congestive heart failure, or reinfarction within 30 days.Emergency angiography was required in 36% of thetenecteplase group and the remainder underwentangiography at a median 17 hours after randomization. Inthis study, the composite endpoint was similar regardless ofwhether the patient received fibrinolytic therapy or primaryPCI (12.4% versus 14.3%, respectively). There was ahigher incidence of intracranial hemorrhage in patients whoreceived fibrinolytic therapy. This increase was mitigated bythe use of half-dose tenecteplase in patients older than 75years.17

In summary, use of fibrinolytics is recommended when,by physician judgment, the D2B time will exceed 120minutes for any reason. When fibrinolytics are used inpatients older than 75 years, consideration should be givento using half-dose to mitigate the potential for bleedingcomplications.

Future ResearchThere may be a subset of patients who benefit from

fibrinolysis before PCI depending on, for example, age oranatomic location of the infarction, as well as time to PCI.It is unknown whether a given time limit for, say, a 45-year-old man with an inferior MI applies to a 77-year-oldwoman with an anterior MI. It may be that the benefit ofPCI over fibrinolysis is most pronounced in high-riskpatients: those with anterior MI or with hemodynamiccompromise.

Transport time to a PCI-capable institution is frequentlynot known with any precision and may be underestimatedby receiving PCI centers. If timing is really important, waysto accurately estimate transfer times must be identified.How accurate is any assessment of time given weather and


Clinical Policy

transport conditions? This question should be answeredbefore any hard and fast guidelines are developed on PCIversus fibrinolysis. Emergency physicians should know theframework within which they are working. Anyrecommendations must be predicated on a realistic estimateof time to transport and time to intervention.

Many studies, especially those from overseas, havedisparate endpoints, such as stroke, recurrent ischemia,reinfarction, death, cardiogenic shock, congestive heartfailure, and readmissions. Although this policy looked atMACE, future research should explore functional status(functional capacity or ejection fraction) and survival.

2. In adult patients having a STEMI, does transfer to aPCI center decrease the incidence of MACE?

Patient Management RecommendationsLevel A recommendations. None specified.Level B recommendations. To decrease the incidence of

MACE, patients with STEMI should be transferred to aPCI-capable hospital as soon as possible.

Level C recommendations. None specified.

Potential Benefit of Implementing theRecommendations: Patients who receive timely PCI mayexperience better outcomes with a decrease in MACE.

Potential Harm of Implementing theRecommendations: Patients may decompensate en route tothe PCI facility resulting in poor outcomes.

Key words/phrases for literature searches: ST-elevationmyocardial infarction, myocardial infarction, percutaneouscoronary intervention, thrombolytic therapy, PCIcenter, time factors, time-to-treatment, treatmentoutcomes, patient transfer, survival rate, survival rates,risk, timing, complications, adverse effects, delayedintervention, emergency medical services, hospital, andvariations and combinations of the key words/phrases;Searches included January 1, 2006, to search dates ofJanuary 12, 2016, January 29, 2016, and February24, 2016.

Study Selection: Two hundred two articles wereidentified in the search. Forty-five articles were selectedfrom the search results for further review, with 1 Class IIand 1 Class III study included for this critical question.

There are many articles and guidelines published on thistopic. Given the rigorous methodological process to answerthis specific critical question, 2 studies were used to informthe final recommendation. Many articles were eliminatedbecause they were indirectly or not applicable. There hasbeen a significant paradigm shift in the treatment of acutecoronary syndrome (ACS) worldwide during the past fewdecades. Previously, treatment choices included PCI andfibrinolytic therapy. The literature has shifted away from


choosing between these 2 therapies and is now centered onthe expedited treatment of patients with PCI and theconstruction of systems and networks to facilitate this,including interhospital transfer. The introduction ofSTEMI care programs has reduced mortality.18 This raisesthe question of which patients benefit the most fromrushing to the PCI-capable institution and what thosebenefits are. The American Heart Association guidelinesrecommend transfer of patients with STEMI to a PCIcenter even if they have received fibrinolytic therapy.19

There is literature in regard to the out-of-hospitalactivation of catheterization laboratories and the timingeffects of emergency medical services’ selection of thereceiving facility. However, the question was framed fromthe perspective of a community emergency physician whoneeds to make critical decisions about transferring aSTEMI patient who presents to a non-PCI-capablehospital.

According to a Class II study by Widimsky et al,20 thetreatment of STEMI with PCI has a mortality and MACEadvantage over fibrinolytic administration alone and thattreatment is time dependent. This study was a randomizedcontrolled trial in the Czech Republic that comparedfibrinolysis at a community hospital not capable of PCI(421 patients) versus interhospital transfer (429 patients)for PCI. Pain onset to randomization was similar in bothgroups. Transfer time was 48 minutes (SD 20), and D2Bonce arrived at a PCI capable center was 26 minutes (SD11). Inclusion criteria for this study were that patienttransport to a PCI facility was feasible within 30 minutes ofenrollment and the distance to the PCI center was less than120 km (approximately 75 miles). Clinical outcomesmeasured were 30-day and 5-year death, MI, stroke, andrevascularization. The incidence of MACE was lower in thetransfer for PCI group for both 30-day (24% in thefibrinolytic group versus 14% in the PCI group; difference10% [95% CI 4% to 15%]; number needed to treat 10)and 5-year MACE (53% in the fibrinolytic group versus40% in the PCI group; difference 13% [95% CI 6% to20%]; number needed to treat 8), respectively.20

A Class III study by Wöhrle et al21 compared theoutcomes of STEMI patients who presented to a PCIcenter versus patients who presented to a non-PCI centerand were transferred to a PCI-capable hospital and foundno significant difference in MACE at 30 days and 1 year.There was a total delay (symptom-to-balloon inflation) of67 minutes because of transfer to a PCI facility in thisstudy. The actual time from symptom onset to a PCI-capable facility for transferred patients was 195 versus 116minutes for patients who presented directly to a PCIhospital.


Clinical Policy

Transfer to PCI-capable hospitals can result in delaysto D2B time. How long can a patient wait before PCIloses its advantage over fibrinolytics? Patients showfavorable outcomes when they receive PCI for STEMI. Thegoal is to begin transfer from a non-PCI-capable hospitalonce a STEMI is identified with a goal of total time fromfirst medical contact to intervention of less than 120minutes.19

In summary, best outcomes will likely be met bydeveloping systems in which STEMI is identified earlyin the out-of-hospital process and the patient istransported directly to a PCI-capable facility. For patientswho develop STEMI after ED presentation in thenon-PCI-capable hospital, systems can be constructedto expedite transfer to a PCI-capable facility. Therefore,the recommendation is to transfer patients with STEMIto a PCI-capable facility to decrease the incidence ofMACE.

Future ResearchNo studies exist to determine the exact interval after

symptom onset when the benefits of emergent transferdissipate. Current literature cited as support for transfers asbest practice are based on observational studies with littleuniformity with respect to measured outcomes or thepatient populations. The development of standardizedmetrics, definitions, and outcomes would allow comparisonof studies and robust meta-analyses. For example, whatdoes first medical contact mean? Does it mean the timewhen a patient is cared for by out-of-hospital providers orby the first hospital contact point? Standardized prospectivetrials using well-designed integrated network protocols inthe United States or abroad may be the best setting forfuture prospective trials needed to provide a high degree ofclinical certainty while avoiding ethical concerns inrandomizing patients to different treatment arms. Betterdelineation of the expected delay that would lead tofibrinolytic administration, as well as the optimal dose offibrinolytics, would be useful to the referring emergencyphysician.

3. In adult patients undergoing reperfusion therapy,should opioids be avoided to prevent adverseoutcomes?

Patient Management RecommendationsLevel A recommendations. None specified.Level B recommendations. None specified.Level C recommendations. Because safety has not been

established, clinical judgment should be used in decidingwhether to provide or withhold morphine in patientsundergoing reperfusion therapy.


Potential Benefit of Implementing theRecommendations: Opioids offer relief to chest painpatients by reducing discomfort and helping them relaxduring a highly stressful medical event.

Potential Harm of Implementing theRecommendations: Opioids can potentially result in lesssalvageable myocardium if administered to patients havingan MI.

Key words/phrases for literature searches: opioids,opiates, analgesics, fentanyl, morphine, hydromorphone,drug interactions, age factors, adenosine, piperazines,platelet aggregation, thiophenes, acute coronary syndrome,suspected acute coronary syndrome, myocardial infarction,reperfusion therapy, percutaneous coronary intervention,angioplasty, thrombolytics, fibrinolytics, harm, risk,adverse, treatment outcome, patient risk, and variationsand combinations of the key words/phrases; Searchesincluded January 1, 2006, to search dates of January 12,2016, January 29, 2016, and February 24, 2016.

Study Selection: Twenty-five articles were identified inthe search. Nine articles were selected from the searchresults for further review, with 1 Class III study includedfor this critical question.

In the absence of a history of hypersensitivity, judicioususe of opioids has generally been considered safe inhemodynamically stable patients with suspected ACS.Largely based on expert opinion, current guidelines fromthe American College of Cardiology/American HeartAssociation2 and European Society of Cardiology22

recommend intravenous morphine as the drug of choice torelieve pain and anxiety and warn against the use ofnonsteroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase (COX)-2 inhibitors due to increased risk forMACE associated with their use in patients with STEMIand non–ST-segment elevation ACS. The AmericanCollege of Cardiology/American Heart Association recentlyreduced the level of recommendation for morphineadministration in non-STEMI chest pain and unstableangina patients to a Class IIb recommendation.23

As background, a retrospective cardiac magneticresonance study of STEMI patients reperfused by PCIshowed that patients who received intravenous morphinedisplayed larger infarct size, larger extent of microvascularobstruction and less salvageable myocardium comparedwith those who did not.24 Evidence arguing against theroutine use of opioids for patients with ACS who areundergoing reperfusion therapy comes from studies aimedat evaluating the pharmacokinetic and pharmacodynamicsof P2Y12 receptor inhibitors (such as prasugrel andticagrelor).25 A recent retrospective study26 and a 2016prospectively designed study27 demonstrate delayed


Clinical Policy

absorption and activity of P2Y12 receptor inhibitors andtheir metabolites in patients receiving morphine comparedwith those who did not. Impaired gastrointestinalabsorption is the suspected cause of the underlyingmechanism of morphine’s effect. Although provocative, thelast 4 studies24-27 cited received Class of Evidence grade“X” because they lacked the methodological design todefinitively address the clinical question.

The traditional support for use of opioids in patients withACS undergoing reperfusion therapy has been challenged inrecent years, with studies suggesting that morphine mayactually be harmful in this population; given that cliniciansoften cannot predict which chest pain patients will beundergoing reperfusion therapy, the routine use ofmorphineto treat chest pain has been called into question. Initialconcerns for potential harmful effects of morphine wereraised as a result of registry data revealing higher rates ofadverse clinical outcomes in non-STEMI ACS patientstreated with clopidogrel who received intravenous morphinecompared with those who did not. Using a propensity-score-matching method, the use of morphine was associated withincreased inhospital mortality (odds ratio 1.5; 95%CI 1.3 to1.6), and the increased risk of death in patients persistedacross all risk groups in a study by Meine et al28 (Class III).

Taken together, these data show that a therapeuticdilemma exists between the traditional beliefs inmorphine’s beneficial effects for non-STEMI ACS patientsversus the recently identified potential harmful effects whenmorphine is used in the context of reperfusion therapy.Therefore, physicians should be aware of this theoreticaltreatment dilemma and understand the lack of evidence torecommend for or against the use of opiates in STEMIpatients. Physicians are left with making case-by-casedecisions until further data helps delineate a strongerrecommendation.

Future ResearchAdequately powered prospective trials are needed to

support or refute and quantify a potential negative clinicaleffect of opioids on patient outcomes for patientsundergoing revascularization. If the causal effect is real, thedetailed underlying mechanism of the interaction requiresfurther study because it may apply only to morphine andnot to other opioids, such as those that are ultrashort-lasting. If the effect is mostly related to gastrointestinalabsorption, then intravenous preparations of P2Y12inhibitors may provide alternatives to oral routes forpatients who benefit most from opioids such as those withsevere pain or those with ongoing pain and anticipated longtravel times from non-PCI to PCI centers.


Relevant industry relationships: There were norelevant industry relationships disclosed by thesubcommittee members for this topic.

Relevant industry relationships are those relationshipswith companies associated with products or services thatsignificantly impact the specific aspect of diseaseaddressed in the critical question.

REFERENCES1. Ward MJ, Kripalani S, Zhu Y, et al. Incidence of emergency department

visits for ST-elevation myocardial infarction in a recent six-year periodin the United States. Am J Cardiol. 2015;115:167-170.

2. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guidelinefor the management of ST-elevation myocardial infarction: a report ofthe American College of Cardiology Foundation/American HeartAssociation Task Force on Practice Guidelines. J Am Coll Cardiol.2013;61:e78-e140.

3. Fesmire FM, Brady WJ, Hahn S, et al. American College of EmergencyPhysicians. Clinical policy: indications for reperfusion therapy inemergency department patients with suspected acute myocardialinfarction. Ann Emerg Med. 2006;48:358-383.

4. Aplin R, Tiede D, Lovitz C, et al. A regional system for delivery ofprimary percutaneous coronary intervention in ST-elevation myocardialinfarction: STEMI–St. Cloud. J Invasive Cardiol. 2009;21:639-644.

5. Pinto DS, Kirtane AJ, Nallamothu BK, et al. Hospital delays inreperfusion for ST-elevation myocardial infarction. Implicationswhen selecting a reperfusion strategy. Circulation.2006;114:2019-2025.

6. Pinto DS, Frederick PD, Chakrabarti AK, et al. Benefit of transferringST-segment–elevation myocardial infarction patients for percutaneouscoronary intervention compared with administration of onsitefibrinolytic declines as delays increase. Circulation.2011;124:2512-2521.

7. Beri A, Printz M, Hassan A, et al. Fibrinolysis versus primarypercutaneous intervention in ST-elevation myocardial infarction withlong interhospital transfer distances. Clin Cardiol.2010;33:162-167.

8. Bohmer E, Hoffmann P, Abdelnoor M, et al. Efficacy and safety ofimmediate angioplasty versus ischemia-guided management afterthrombolysis in acute myocardial infarction in areas with very longtransfer distances. Results of the NORDISTEMI (NORwegian study onDIstrict treatment of ST-Elevation Myocardial Infarction). J Am CollCardiol. 2010;55:102-110.

9. Manari A, Ortolani P, Guastaroba P, et al. Clinical impact of an inter-hospital transfer strategy in patients with ST-elevation myocardialinfarction undergoing primary angioplasty: the Emilia-Romagna ST-segment elevation acute myocardial infarction network. Eur Heart J.2008;29:1834-1842.

10. Nielsen PH, Maeng M, Busk M, et al. Primary angioplasty versusfibrinolysis in acute myocardial infarction. Circulation.2010;121:1484-1491.

11. Stenestrand U, Lindback J, Wallentin L; for the RIKS-HIA Registry.Long-term outcome of primary percutaneous coronary intervention vsprehospital and in-hospital thrombolysis for patients with ST-elevationmyocardial infarction. JAMA. 2006;296:1749-1756.

12. Vora AN, Holmes DN, Rokos I, et al. Fibrinolysis use among patientsrequiring interhospital transfer for ST-segment elevation myocardialinfarction care. A report from the US National Cardiovascular DataRegistry. JAMA Intern Med. 2015;175:207-215.

13. Cantor WJ, Fitchett D, Borgundvaag B, et al. Routine early angioplastyafter fibrinolysis for acute myocardial infarction. N Engl J Med.2009;360:2705-2718.


http://refhub.elsevier.com/S0196-0644(17)31743-2/sref1























































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14. Denktas AE, Athar H, Henry TD, et al. Reduced-dose fibrinolyticacceleration of ST-segment elevation myocardial infarction treatmentcoupled with urgent percutaneous coronary intervention compared toprimary percutaneous coronary intervention alone. Results of theAMICO (Alliance for Myocardial Infarction Care Optimization) Registry.JACC Cardiovasc Interv. 2008;1:504-510.

15. Ellis SG, Tendera M, de Belder MA, et al. 1-Year survival in arandomized trial of facilitated reperfusion. Results from the FINESSE(Facilitated Intervention With Enhanced Reperfusion Speed to StopEvents) Trial. J Am Coll Cardiol Intv. 2009;2:909-916.

16. Larson DM, Duval S, Sharkey SW, et al. Safety and efficacy of apharmaco-invasive reperfusion strategy in rural ST-elevationmyocardial infarction patients with expected delays due to long-distance transfers. Eur Heart J. 2012;33:1232-1240.

17. Armstrong PW, Gershlick AH, Goldstein P, et al. Fibrinolysis or primaryPCI in ST-segment elevation myocardial infarction. N Engl J Med.2013;368:1379-1387.

18. Blankenship JC, Scott TD, Skelding KA, et al. Door-to-balloon timesunder 90 min can be routinely achieved for patients transferred for ST-segment elevation myocardial infarction percutaneous coronaryintervention in a rural setting. J Am Coll Cardiol. 2011;57:272-279.

19. O’Connor RE, Al Ali AS, Brady WJ, et al. Part 9: acute coronarysyndromes: 2015 American Heart Association guidelines update forcardiopulmonary resuscitation and emergency cardiovascular care.Circulation. 2015;132:S483-S500.

20. Widimsky P, Bilkova D, Penicka M, et al. Long-term outcomes of patientswith acute myocardial infarction presenting to hospitals withoutcatheterization laboratory and randomized to immediate thrombolysis orinterhospital transport for primarypercutaneouscoronary intervention. Fiveyears’ follow-up of the PRAGUE-2 trial. Eur Heart J. 2007;28:679-684.

21. Wöhrle J, Desaga M, Metzger C, et al. Impact of transfer for primarypercutaneous coronary intervention on survival and clinical outcomes(from the HORIZONS-AMI Trial). Am J Cardiol. 2010;106:1218-1224.

Annals’ Impa

Impact Factor score, one of many metricsof the frequency with which the average

over a given per

Annals’ Impact Factor rose to an a


22. Steg PG, James SK, Atar D, et al; for the Task Force on theManagement of ST-Segment Elevation Acute Myocardial Infarctionof the European Society of Cardiology. ESC guidelines for themanagement of acute myocardial infarction in patientspresenting with ST-segment elevation. Eur Heart J. 2012;33:2569-2619.

23. Amsterdam EA, Wenger NK, Brindis RG, et al; ACC/AHA Task ForceMembers; Society for Cardiovascular Angiography and Interventionsand the Society of Thoracic Surgeons. 2014 ACC/AHA guideline for themanagement of patients with non–ST-elevation acute coronarysyndromes: executive summary: a report of the American College ofCardiology/American Heart Association Task Force on PracticeGuidelines. Circulation. 2014;130:2354-2394.

24. de Waha S, Eitel I, Desch S, et al. Intravenous morphine administrationand reperfusion success in ST-elevation myocardial infarction: insightsfrom cardiac magnetic resonance imaging. Clin Res Cardiol.2015;104:727-734.

25. Parodi G, Valenti R, Bellandi B, et al. Comparison of prasugrel andticagrelor loading doses in ST-segment elevation myocardial infarctionpatients. J Am Coll Cardiol. 2013;61:1601-1606.

26. Parodi G, Bellandi B, Xanthopoulou I, et al. Morphine is associated witha delayed activity of oral antiplatelet agents in patients with ST-elevation acute myocardial infarction undergoing primarypercutaneous coronary intervention. Circ Cardiovasc Interv.2015;8:e001593.

27. Kubica J, Adamski P, Ostrowska M, et al. Morphine delays andattenuates ticagrelor exposure and action in patients with myocardialinfarction: the randomized, double-blind, placebo-controlledIMPRESSION trial. Eur Heart J. 2016;37:245-252.

28. Meine TJ, Roe MT, Chen AY, et al; for the CRUSADE Investigators.Association of intravenous morphine use and outcomes in acutecoronary syndromes: results from the CRUSADE quality improvementinitiative. Am Heart J. 2005;149:1043-1049.

ct Factor

of a journal’s influence, is a measurearticle in a journal has been citediod of time.

ll-time high this year, to 5.352.





































































Appendix A. Literature classification schema.*

Design/Class Therapy† Diagnosis‡ Prognosis§

1 Randomized, controlled trial ormeta-analysis of randomized trials

Prospective cohort using a criterion standard ormeta-analysis of prospective studies

Population prospective cohort ormeta-analysis of prospective studies

2 Nonrandomized trial Retrospective observational Retrospective cohortCase 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.

Downgrading

Design/Class

1 2 3

None I II III1 level II III X2 levels III X XFatally flawed X X X

Appendix C. Likelihood ratios and number needed to treat.*

LR (D) LR (–)

1.0 1.0 Does not change pretest probability1–5 0.5–1 Minimally changes pretest probability10 0.1 May be diagnostic if the result is

concordant with pretest probability20 0.05 Usually diagnostic100 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 toachieve 1 additional good outcome; NNT¼1/absolute risk reduction�100, whereabsolute risk reduction is the risk difference between 2 event rates (ie, experimentaland control groups).

Clinical Policy


Evidentiary Table.Study & Year

PublishedClass of

Evidence Setting & Study

DesignMethods & Outcome

MeasuresResults Limitations & Comments

Vora et al12

(2015)III Secondary analysis

of ACTION registry, the largest ongoing quality improvement registry of AMI in the U.S.;objective to assess the association of estimated interhospital drive times with reperfusion strategy selection (fibrinolysis vs primary PCI)

1,771 STEMI referring centers to 366 STEMI receiving centers;outcomes: inhospital mortality and major bleeding

22,481 patients with STEMI eligible for fibrinolysis or PCI;no significant mortality benefit between fibrinolysis vs PCI (3.7% vs 3.9%; OR=1.1; 95% CI 0.9 to 1.4), but had a higher bleeding risk (10.7% vs 9.5%; OR=1.2; 95% CI 1.0 to 1.3)

Generalizable; MACE not specifically evaluated

Cantor et al13

(2009)III Randomized

clinical trial (TRANSFER-AMI Trial); 52 sites in Canada

Random allocation of fibrinolytic therapy+rescue or delayed PCI vs fibrinolytic therapy+immediate transfer to another hospital for PCI within 6 h of fibrinolysis; all patients received aspirin, heparin or enoxaparin, and fibrinolysis (tenecteplase);outcome: MACE at 30 days (death, reinfarction, cardiogenic shock, or new or worsening heart failure)

N=1,059; 522 to fibrinolytic group, 537 to fibrinolytic+transfer group; 89% of fibrinolytic+rescue or delayed PCI underwent PCI, median 33 h after randomization; 99% of fibrinolytic+immediate transfer for PCI underwent PCI, median 3 h after randomization;17.2% of those with fibrinolysis+rescue or delayed PCI met outcome vs 11% of those with fibrinolysis+immediate transfer and PCI met outcome (RR=0.6; 95% CI 0.5 to 0.9, P=.004)

Unblinded; concern that patients in intervention group were ultimately cared for more aggressively; early PCI was notearly: no attempts made within 90 min

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PublishedClass of




Denktas et al14

(2008)III Secondary analysis

of registry datafrom multiple centers in the US;objective to evaluate reduced-dose out-of-hospital fibrinolysis for STEMI patients followed by PCI vs PCI alone

Local protocols dictated use of aspirin, heparin, clopidogrel, and low-molecular-weight heparin; multivariable analyses used to adjust for differences between groups; primary outcome: mortality at 30 days;secondary outcomes: death, reinfarction, stroke, PCI, and shock

N=2,869; 1,200 fibrinolysis+PCI, 1,669 PCI; significant differences in baseline characteristics between study groups;mean time to PCI was 253 min; mean time to fibrinolysis was 54 min;mortality significantly lower with fibrinolysis+PCI vs PCI alone; however, fibrinolysis+PCI was not a significant predictor of any outcome after adjusting for age, creatinine level, hyperlipidemia, and diabetes mellitus

Use of stepwise logistic regression; no blinding;protocols were locally dependent

Ellis et al15

(2009)III Randomized

clinical trial (FINESSE Trial);objective to evaluate 12-mo outcomes of facilitated PCI

Random allocation to reduced-dose reteplase+abciximab, abciximab alone, or placebo, followed by expedited PCI; outcome: 1-y mortality (prespecified secondary endpoint of principal study)

N=2,452; no significant differences in mortality among the 3 groups (6.3%, 7.4%, and 7.0%; P=NS)

Outstanding follow-up rates (≈98%) in all groups;excluded patients <60 y with inferior MI because they were considered low risk;blinded, placebo controlled;MACE not considered;primary endpoint underpowered because principal study stopped early

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Larson et al16

(2012)III Prospective data

collection for STEMI registry;31 centers in Minnesota;objective to evaluate safety and efficacy of half-dose fibrinolysis+transfer for immediate PCI vs primary PCI

Standardized protocol across all hospitals; all patients received aspirin, clopidogrel, unfractionated heparin, and β-blocker;multivariable statistical methods, including use of propensity score matching to compare groups

N=2,634; 600 received primary PCI;excellent balance between propensity-score-matched groups; no significant difference between groups in regard tostroke, major bleeding, 30-day mortality or reinfarction

Although methodologically limited by use of a data registry, this may also incur strength in terms of pragmatic evaluation;no new data about optimal anticipated transfer time, but presents argument for fibrinolysis first if inclement weather, transfer using 60-mile cutoff if no inclement weather (distance and weather considerations)

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Armstrong et al17 (2013)

III Open-label, prospective, multicenter, randomized trial from 99 sites in 15 countries

Patients were randomized if they presented within 3 h of symptom onset and an ST-segment elevation on ECG but could not receive PCI within 1 h after first medical contact; the treatment group received fibrinolytic therapy and the PCI within 24 h, and the control group received PCI alone; in the event that there was not ST-segment resolution ofat least 50% in the fibrinolytic group, they 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 fibrinolytic dose was reduced by half for patients >75 y secondary to increased intracranial hemorrhage rate

N=1,915 patients, 1,892 of whom underwent randomization; after loss to follow-up and withdrawal of consent there were 944 patients in the fibrinolysis group and 948 in the PCI group; 36% of the patients randomized to the fibrinolysis group required rescue PCI; the composite endpoint occurred in 12.4% of the fibrinolysis group and 14.3% of the primary PCI group; RR=0.86 (95% CI 0.68 to 1.09); the total number of strokes was small but statistically greater in the fibrinolysis group at 1.6% vs 0.5% mainly driven by the rate of hemorrhagic stroke at 1.0% compared with 0.3%; there was no difference in nonintracranial major bleeding

Open label; study sponsored by Boehringer Ingelheim; baseline imbalance in the number who had previous PCI with 6.4% in the fibrinolytic group and 8.8% in the primary PCI group; 36% of patients in the fibrinolysis group underwent rescue PCI

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Widimsky et al20 (2007)

II PRAGUE-2 trial with 5-y follow-up; prospective randomized trial; Czech Republic

Fibrinolysis at a community hospital notcapable of PCI vs interhospital transfer for primary PCI; outcome: death, reinfarction, stroke, and revascularization at 30 days and 5 y

421 in fibrinolytic group and 429 in PCI group transported to nearest hospital;30 day: death/reinfarction/stroke/revascularization 24% in fibrinolytic group vs 14% in PCI group, difference 10%; NNT 10 (P<.001);5 y: death any cause/re-MI/stroke/revascularization 53% in fibrinolytic group vs 40% in PCI group, difference 13%; NNT 8 (P<.001)

Open label; outcome defined but not masked to intervention;high proportion (≈99%) follow-up

Wöhrle et al21

(2010)III Secondary

analysis of the HORIZONS-AMI trial, which included 1:1 randomization of patients to bivalirudin vs unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor

Comparison of patients who required transfer for primary PCI vs direct admission for PCI;outcome: MACE (death, reinfarction, revascularization, or stroke) or major bleeding

988 (24.7%) patients were transferred for primary PCI and 2,614 were directly admitted for PCI; at 30 days and 1 y, there were no significant differences between study groups (5.8% vs 5.4%); use of multivariable modeling to adjust for differences between groups resulted in similar nonsignificant differences in outcomes

Secondary analysis of a randomized trial; groups different from the allocation scheme, thus not balanced or comparable at baseline;outcome blinded to study group

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Meine et al28

(2005)III Retrospective

cohort from 443 hospitals in the US

Compared patients who received IV morphine with those who did not with respect to outcomes (eg, postadmission infarction, cardiogenic shock, congestive heart failure, death, and the composite outcome of postadmission infarction or death); propensity score matching used to account for potential 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

N=57,039; 17,003 (30%) patients received morphine; rates of adverse clinical outcomes were higher in patients who received IV morphine compared with those who did not; MI increased from 3.0% to 3.8% (OR 1.3; 95% CI 1.2 to 1.5), death increased from 4.7% to 5.5% (OR 1.5; 95% CI 1.3 to 1.6), and the composite end point of death or MI increased from 7.1% to 8.5% (OR 1.4; 95% CI 1.3 to 1.6); these findings persisted even when controlled for the concomitant use of IV nitroglycerin

Doses and timing of medications not collected; outcomes not adjudicated; adverse clinical outcomes even though these patients were more likely to be treated with evidence-based medications and to undergo invasive cardiac procedures

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 and Stents-Acute Myocardial Infarction; IV, intravenous;MACE, major adverse cardiac event;MI, myocardial infarction; min, minute; mo, month; NNT, number needed to treat; NS, not significant; OR, odds ratio; PCI, percutaneous coronary intervention; PRAGUE-2, 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.

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clinical policy: emergency department management of ......the evaluation and management of patients...

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