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National Heart Foundation of Australia & Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the Management of Acute Coronary Syndromes 2016
Internal Medicine and Clinical Epidemiology, Princess Alexandra Hospital, Brisbane, Qld, Australia; School of Medicine, University of Queensland, Brisbane, Qld, Australia; Medicine, Monash University, Melbourne, Vic, Australia
Integrated Cardiovascular Clinical Network (iCCnet), Country Health SA Local Health Network and Southern Adelaide Local Health Network, Adelaide, SA, Australia
Network Director, Division of Medicine, Cardiac and Critical Care, Southern Adelaide Local health Network, Flinders Medical Centre and University, SAHMRI, Adelaide, SA, Australia
These clinical guidelines have been developed to assist in the management of patients presenting with chest pain suspected to be due to an acute coronary syndrome (ACS) and those with confirmed ACS. These guidelines should be read in conjunction with the ACS Clinical Care Standards developed by the Australian Commission for Safety and Quality in Health Care (ACSQHC) [
]. Additional guidance around the timing and use of therapies is detailed in the accompanying practice advice.
Key Evidence-Based Recommendations
Tabled
1
Recommendation
GRADE strength of recommendation
NHMRC Level of Evidence (LOE)
Initial assessment of chest pain
It is recommended that a patient with acute chest pain or other symptoms suggestive of an ACS receives a 12-lead ECG and this ECG is assessed for signs of myocardial ischaemia by an ECG-experienced clinician within 10 minutes of first acute clinical contact.
Strong
IIIC
A patient presenting with acute chest pain or other symptoms suggestive of an ACS should receive care guided by an evidence-based Suspected ACS Assessment Protocol (Suspected ACS-AP) that includes formal risk stratification.
Strong
IA
Using serial sampling, cardiac-specific troponin levels should be measured at hospital presentation and at clearly defined periods after presentation using a validated Suspected ACS-AP in patients with symptoms of possible ACS.
Strong
IA
Non-invasive objective testing is recommended in intermediate-risk patients, as defined by a validated Suspected ACS-AP, with normal serial troponin and ECG testing and who remain symptom-free.
Weak
IA
Patients in whom no further objective testing for coronary artery disease (CAD) is recommended are those at low risk, as defined by a validated Suspected ACS-AP: age <40 years, symptoms atypical for angina, in the absence of known CAD, with normal troponin and ECG testing, and who remain symptom-free.
Weak
III-3C
Diagnostic considerations and risk stratification of
The routine use of validated risk stratification tools for ischaemic and bleeding events (e.g. GRACE score for ischaemic risk or CRUSADE score for bleeding risk) may assist in patient-centric clinical decision-making in regards to ACS care.
Weak
IIIB
Acute reperfusion and invasive management strategies in ACS
For patients with ST elevation myocardial infarction (STEMI) presenting within 12 hours of symptom onset, and in the absence of advanced age, frailty and comorbidities that influence the individual's overall survival, emergency reperfusion therapy with either primary percutaneous coronary intervention (PCI) or fibrinolytic therapy is recommended.
Strong
IA
Primary PCI is preferred for reperfusion therapy in patients with STEMI if it can be performed within 90 minutes of first medical contact; otherwise fibrinolytic therapy is preferred for those without contra-indications.
Strong
IA
Among patients treated with fibrinolytic therapy who are not in a PCI-capable hospital, early or immediate transfer to a PCI-capable hospital for angiography, and PCI if indicated, within 24 hours is recommended.
Weak
IIA
Among patients treated with fibrinolytic therapy, for those with ≤50% ST recovery at 60–90 minutes, and/or with haemodynamic instability, immediate transfer for angiography with a view to rescue angioplasty is recommended.
Strong
IB
Among high- and very high-risk patients with non-ST elevation acute coronary syndromes (NSTEACS) (except Type 2 MI), a strategy of angiography with coronary revascularisation (PCI or coronary artery bypass grafts) where appropriate is recommended.
Strong
IA
Patients with NSTEACS who have no recurrent symptoms and no risk criteria are considered at low risk of ischaemic events, and can be managed with a selective invasive strategy guided by provocative testing for inducible ischaemia.
Strong
IA
Timing of invasive management for NSTEACS
Very high-risk patients: Among patients with NSTEACS with very high-risk criteria (ongoing ischaemia, haemodynamic compromise, arrhythmias, mechanical complications of MI, acute heart failure, recurrent dynamic or widespread ST-segment and/or T-wave changes on ECG), an immediate invasive strategy is recommended (i.e. within 2 hours of admission).
Strong
IIC
High-risk patients: In the absence of very high-risk criteria, for patients with NSTEACS with high-risk criteria (GRACE score >140, dynamic ST-segment and/or T-wave changes on ECG, or rise and/or fall in troponin compatible with MI) an early invasive strategy is recommended (i.e. within 24 hours of admission).
Weak
IC
Intermediate risk patients: In the absence of high-risk criteria, for patients with NSTEACS with intermediate-risk criteria (such as recurrent symptoms or substantial inducible ischaemia on provocative testing), an invasive strategy is recommended (i.e. within 72 hours of admission).
Weak
IIC
Pharmacology for ACS
Aspirin 300 mg orally initially (dissolved or chewed) followed by 100–150 mg/day is recommended for all patients with ACS in the absence of hypersensitivity.
Strong
IA
Among patients with confirmed ACS at intermediate to very high- risk of recurrent ischaemic events, use of a P2Y12 inhibitor (ticagrelor 180 mg orally, then 90 mg twice a day or; prasugrel 60 mg orally, then 10 mg daily; or clopidogrel 300–600 mg orally, then 75mg per day) is recommended in addition to aspirin. (Ticagrelor or prasugrel preferred: see practice advice)
Strong
IA
Intravenous glycoprotein IIb/IIIa inhibition in combination with heparin is recommended at the time of PCI among patients with high-risk clinical and angiographic characteristics, or for treating thrombotic complications among patients with ACS.
Strong
IB
Either unfractionated heparin or enoxaparin is recommended in patients with ACS at intermediate to high risk of ischaemic events.
Strong
IA
Bivalirudin (0.75 mg/kg IV with 1.75 mg/kg/hr infusion) may be considered as an alternative to glycoprotein IIb/IIIa inhibition and heparin among patients with ACS undergoing PCI with clinical features associated with an increased risk of bleeding events.
Weak
IIB
Discharge management and secondary prevention
Aspirin (100–150 mg/day) should be continued indefinitely unless it is not tolerated or an indication for anticoagulation becomes apparent.
Strong
IA
Clopidogrel should be prescribed if aspirin is contraindicated or not tolerated.
Strong
IA
Dual-antiplatelet therapy with aspirin and a P2Y12 inhibitor (clopidogrel or ticagrelor) should be prescribed for up to 12 months in patients with ACS, regardless of whether coronary revascularisation was performed. The use of prasugrel for up to 12 months should be confined to patients receiving PCI.
Strong
IA
Consider continuation of dual-antiplatelet therapy beyond 12 months if ischaemic risks outweigh the bleeding risk of P2Y12 inhibitor therapy; conversely consider discontinuation if bleeding risk outweighs ischaemic risks.
Weak
IIC
Initiate and continue indefinitely, the highest tolerated dose of HMG-CoA reductase inhibitors (statins) for a patient following hospitalisation with ACS unless contraindicated or there is a history of intolerance.
Strong
IA
Initiate treatment with vasodilatory beta blockers in patients with reduced left ventricular (LV) systolic function (LV ejection fraction [EF] ≤40%) unless contraindicated.
Strong
IIA
Initiate and continue angiotensin converting enzyme (ACE) inhibitors (or angiotensin receptor blockers [ARBs]) in patients with evidence of heart failure, LV systolic dysfunction, diabetes, anterior myocardial infarction or co-existent hypertension.
Strong
IA
Attendance at cardiac rehabilitation or undertaking a structured secondary prevention service is recommended for all patients hospitalised with ACS.
Strong
IA
Note: Refer to Appendix 4 for details on the National Health and Medical Research Council (NHMRC) guideline development methodology, including grades of evidence, and Appendix 5 for details on the GRADE methodology.
Acute coronary syndromes (ACS) – myocardial infarction (MI) and unstable angina (UA) – are the result of unstable atheromatous plaques or endothelial disruption with associated transient or permanent thrombotic occlusion of the coronary vascular tree leading to myocardial ischaemia and infarction. As a result of the improved sensitivity of troponin assays, incidence of unstable angina is decreasing with a proportionate increase in the incidence of MI. In 2012, the Australian Institute of Health and Welfare estimated there were 68,200 ACS events [
Australian Institute of Health and Welfare. Cardiovascular disease, diabetes and chronic kidney disease—Australian facts: Prevalence and incidence. Cardiovascular, diabetes and chronic kidney disease series no. 2.(Cat. no. CDK 2.)
]. It is estimated that over 500,000 patients present in Australia each year with chest pain, but more than 80% of all patients investigated for ACS will not have this diagnosis confirmed [
]. In unselected patients presenting with acute chest pain to the ED in the Australian setting, the prevalence of different diagnostic groups are: 2-5% ST elevation MI (STEMI), 5-10% Non-STEMI (NSTEMI), 5-10% UA, 15-20% other cardiac conditions and 50-70% non-cardiac diseases [
]. The costs and burden of the diagnostic process to patients, clinicians and the healthcare system are significant.
1.2 Contemporary Outcomes of ACS and Chest Pain in Australia
Patient level estimates of overall 30-day outcomes and 12-month mortality rates within Australian contemporary practice, as ascertained by recent clinical audits, are provided as a reference for estimating the absolute benefits for various guideline recommended therapies and strategies (Table 1) in the ‘average’ patient. In deriving estimates of the absolute reduction or increase in events as a result of specific treatments, the relative effects for each treatment seen in trials is applied to the estimated baseline absolute event rates seen in audits. This absolute change in events is then used to calculate the number needed to treat to benefit (NNTB) (e.g. reducing recurrent MI) and the number needed to treat to harm (NNTH) (e.g. treatment-related bleeding or adverse events). These figures should be considered an approximation as clinical audits comprise patients who have received varying intensities of different interventions, as opposed to clinical trials where, apart from the specific intervention under study, all other forms of care are provided equally. When considering the use of evidence-based recommendations in individual patients, patient-specific disease and treatment risks, and therefore potential benefits and harms from therapies, should be weighed. The relative increase in both risks associated with key clinical and demographic characteristics within the Australian and New Zealand clinical experience is provided in Table 2.
Table 1Kaplan-Meier event rates for ACS diagnosis adjusted for age from SNAPSHOT ACS
1.3 The Process of Developing the 2016 ACS Guidelines
This clinical guideline for the management of ACS seeks to provide guidance regarding the clinical care of patients presenting with suspected or confirmed ACS. It is intended to replace the National Heart Foundation of Australia (NHFA)/Cardiac Society of Australia and New Zealand (CSANZ) ACS guideline published in 2006, 2008 and 2011[
2007 addendum to the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand Guidelines for the management of acute coronary syndromes 2006.
2011 Addendum to the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand Guidelines for the management of acute coronary syndromes (ACS) 2006.
In mid-2014, officers of the NHFA and a small group of senior cardiologists representing the CSANZ, together with a methodologist, formed an ad hoc group to initiate the process of developing the 2016 guideline.
•
This group approached the Cardiac Clinical Networks around Australia seeking feedback regarding the content and development process for the guideline.
•
In December 2014, the ad hoc group, under a formal partnership between NHFA and CSANZ, and acting on advice from the previous expert panel responsible for prior editions of the guideline, sought representation from key stakeholder organisations for experts in ACS management to contribute to the process of guideline development.
•
Among those canvassed as recognised clinical experts in chest pain and ACS management, proposed contributors where offered roles in either a reference group, which had the role of critical review of the entire guideline content, or work groups focussing on guideline writing related to specific topics.
Reference group
•
This group comprised nominated representatives of identified key stakeholder organisations with national relevance in the provision of ACS care in Australia.
•
The roles of the group were to review and provide input into the scope of the guidelines, the questions being submitted for literature review, draft guideline content and recommendations, and issues of implementation.
Guideline work groups
•
Work groups were established for each of four topics: chest pain assessment, STEMI, non-ST segment elevation ACS (NSTEACS) and secondary prevention. For each work group, among all those who agreed to join the group, a primary author and senior advisor were appointed by group consensus on the basis of expertise and previous experience in guideline development.
•
Each work group was then supplemented with members with recognised expertise from stakeholder groups and the clinical community.
•
Members of each work group met on several occasions to discuss the content of each of the four sections of the guideline.
Executive group
•
The primary author and senior advisor from each of the four workgroups and representatives from the NHFA formed an executive group with overall responsibility for the progression, content and consistency of the guideline, and for resolving disputes within or between work groups relating to guideline content and recommendations or conflicts of interest.
•
The executive group had several meetings throughout 2015 and 2016, to discuss and refine the full content of the draft guidelines, with particular focus on the wording and grading of final recommendations.
•
The executive group had the authority for final approval of guideline content and recommendations.
Literature reviews
•
Informed by stakeholder consultation, each of the work groups proposed sentinel questions, presented in PICO format (population, intervention, comparator and outcome), for external literature review. These questions were reviewed and refined by the reference group. The questions proposed for literature review are provided in the appendix.
•
The literature reviewer was appointed through an open tender process. The literature review sought published studies from 2010 to 2015. The process of literature review was commenced in the second quarter of 2015 and completed in the fourth quarter of 2015. Evidence summaries were reviewed and signed off by the work groups and, where deemed appropriate, were supplemented with additional studies published after the literature search dates.
Finalisation phase
•
In December 2015, the full first draft of the guideline was given to members of the reference group for detailed comments. These comments were received and responses drafted in February 2016.
•
A public consultation period of 30 days was conducted in April 2016.
•
Final approval and submission for publication was undertaken in June 2016.
1.4 Conflicts of Interest Process
Conflicts of interest were considered within a framework of both the relationship (direct or indirect) of the participating individual to any third party with interest in the topic under consideration within the guideline development process, and the nature (financial and non-financial) of the potential conflict. All members of the work groups and reference group were asked to declare all potential conflicts of interest and these declarations were updated every six months and at each meeting. Individuals with pecuniary or academic conflicts of interest deemed to be high were excluded from the drafting of specific recommendations. All other conflicts of interest were managed by the work group chair or senior advisor, under guidance from the executive group. The executive group was responsible for managing conflicts of interest. A summary of the conflicts of interest and executive group responses is provided in the online appendix and a full description of the governance process for the development of this guideline will be available on the NHFA website.
1.5 Development of Recommendations
In developing this document, we sought to provide practical guidance for contemporary ACS care in Australia derived from the extensive evidence base regarding the clinical effectiveness of different interventions and treatment strategies. In addition to reviews of published trials and systematic reviews, guideline content was informed by other international clinical guidelines, the Acute Coronary Syndrome Clinical Care Standard and local clinical expertise. In formulating recommendations, we focussed on clinical actions likely to be associated with the largest impact on patient-important outcomes. The guidelines are presented in the format described below.
The key ‘Recommendations’ are presented up-front for easy identification. In making these recommendations, we chose to provide a strength of recommendation (strong or weak) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system (12) (Refer to Appendix 5) alongside the National Health and Medical Research Council (NHMRC) level of evidence scheme [
] (Refer to Appendix 4). The executive group considered that providing a clear dichotomous statement regarding the strength of the recommendation – strong versus weak - would benefit clinicians seeking to prioritise use of interventions in clinical practice, develop systems designed to provide more consistent care, or formulate quality indicators for reviewing clinical performance. Each of the final recommendations was independently reviewed and refined by the work groups and the reference group, with final review and endorsement by the executive group. The definition of consensus was >80% agreement of all members of the executive group.
The ‘Rationale’ section provides a very brief summary of the key evidence. In this section, treatment effects are presented in relative terms, i.e. odds ratios [OR], risk ratios [RR] or hazard ratios [HR] (with 95% confidence intervals). Hence an OR of 0.90 represents a 10% relative reduction in the event. We have confined the reporting of treatment effects to those that were significant to a p-value of <0.05, with the exception of mortality outcomes where relevant to the weighing of the evidence.
To assist in the translation of these treatment effects into clinical decision-making, we have attempted to provide, wherever possible, estimates of the absolute changes in intervention-specific outcomes such as ischaemic episodes or care-related adverse events for the ‘average’ patient, in the section ‘Benefits and harms’. This approach has been used to assist clinicians in their discussions with patients by quantifying the likely absolute benefits or risks associated with each guideline recommendation.
In formulating recommendations, we were mindful of their implications for use of resources although, unfortunately, there is a lack of robust cost-effectiveness analyses for almost all ACS interventions within the Australian context. Commentary regarding the key economic implications or other relevant system factors are included in the ‘Resources and other considerations’ section where appropriate.
Aspects of care associated with a very limited evidence base and reliant on consensus opinion, or where the impact of interventions on clinical outcomes was considered to be modest, are highlighted in the ‘Practice advice’ sections of the guideline. While medication dosing is generally provided, clinicians are advised to refer to additional resources such as the Australian Medicines Handbook for relevant contraindications, precautions, drug interactions and adverse effects.
The writing groups were aware that much of the evidence has focussed on ‘hard’ clinical events such as mortality, recurrent MI and stroke. As a consequence, the recommendations and practice advice are strongly influenced by this literature, which has been used to generate estimates of treatment effect within the benefits and harms commentaries. However, within clinical practice, it is recognised that these endpoints are not universally valued as the highest priority by patients when compared with other outcomes such as quality of life. It is also recognised that the evidence base for ACS care is very limited in regards to older patients with substantial multi-morbidity, which precludes specific recommendations being made for this patient group for most ACS interventions. In such circumstances, users of these guidelines must rely on their own clinical judgment and a shared decision-making process involving individual patients that recognises their values and preferences. Furthermore, clinical decisions should take into account the cultural and linguistic diversity of Australia's community, in particular the Aboriginal and Torres Strait Islander community. Practice advice sections include relevant comments wherever published research has specifically focussed on such patients.
2. Assessment of Possible Cardiac Chest Pain
The single most important consideration in the assessment of patients presenting with chest pain to an emergency medical setting is to identify all patients with ACS or another life-threatening condition. The inappropriate discharge of patients with acute MI (AMI) and unstable angina (UA) from the emergency department (ED) is associated with a substantial increase in mortality compared with admitted patients [
]. Thus, the sensitivity and negative predictive value (NPV) of Suspected ACS Assessment Protocols (Suspected ACS-AP) for the exclusion of ACS is paramount. It is equally important to use rapid and efficient assessment protocols that maximise specificity and positive predictive value (PPV) for ACS in reducing unnecessary investigations and minimising delays in the decision to discharge or admit from the ED.
Patients with ACS may present with a variety of typical (e.g. chest pain) and atypical (e.g. fatigue) symptoms (Refer to warning signs of a heart attack http://heartfoundation.org.au/your-heart/heart-attack-warning-signs). The most frequent symptoms of ischaemia other than chest discomfort include shoulder, arm, jaw and upper abdominal pain; shortness of breath; nausea; vomiting and sweating (diaphoresis).
While there are many causes for chest pain and other symptoms of possible AMI, the recommendations in this section of the guidelines relate to patients with symptoms suggestive of a coronary origin and in whom a diagnosis of an ACS (AMI or UA) has to be considered. It is beyond the scope of these recommendations to provide detailed assessment, investigation and management strategies for all conditions causing chest pain.
2.1 Initial Evaluation
Chest pain assessment is a time critical, hierarchical diagnostic process based upon the history of the presenting complaint, serial electrocardiographs (ECGs), serial biomarkers for myocardial necrosis and an assessment of the patient's risk of having an ACS. The chest pain diagnostic process can be represented by a stepped series of clinical questions:
1.
Does this patient have a ST elevation MI (STEMI)? (Rule-in STEMI)
2.
What alternative life-threatening or other high-risk conditions (e.g. aortic dissection, pulmonary embolus) need to be considered in the differential diagnosis, especially in the presence of cardiac biomarker elevation?
3.
Does this patient have evidence of non-ST-elevation ACS (NSTEACS)? (Rule-in NSTEMI/UA)
4.
Does the patient have symptomatic obstructive coronary artery disease (CAD)? (Rule-in angina)
5.
Can patients at low likelihood of major adverse cardiac events (MACE) be identified with a high degree of certainty (>99%)? (Rule-out high-risk patients)
6.
Does the patient understand what to do in the event of future episodes of chest pain or other symptoms after discharge?
2.1.1 Outpatient Presentation
Initial clinical assessment including history, examination, ECG and single troponin testing are unable to exclude a diagnosis of ACS by themselves. For this reason, patients who present to primary care physicians or to clinicians in other outpatient settings with chest pain (within 24 hours) and suspected ACS should be referred as soon as possible to the ED or a facility capable of definitive risk stratification and diagnosis of ACS. Patients presenting with high-risk features such as ongoing chest pain, dyspnoea, syncope/presyncope or palpitations should be referred immediately to the ED. For these patients, the goals of initial management include establishing the diagnosis with an ECG if available, and ensuring immediate access to cardiac defibrillation where possible. For this reason, patients should not drive themselves to the ED and transport by emergency medical services is recommended. Referral to ED should not depend on troponin testing. Care should be initiated where possible and includes administering aspirin and sublingual GTN in the absence of contraindications (i.e. avoid IM injections) (See 2.3.1.1-2.3.1.2).
2.1.2 Emergency Department Presentation
Patients with suspected ACS must be evaluated rapidly to identify patients with life-threatening non-ACS causes for their acute presentation, quantify risk for ACS and promptly institute appropriate management. Evidence-based clinical pathways that guide assessment and management of patients presenting with acute chest pain or other symptoms suggestive of an ACS should be used. The Australasian Triage Scale recommendation for patients presenting to the ED with chest pain is to commence assessment within 10 minutes of presentation (i.e. Category 2 priority). Historical features may alter estimates of pre-test probability for ACS, but no feature or combination of features alone rules out ACS in the absence of further investigations. Consideration should be given to patient cohorts in whom atypical presentations of ACS are more frequently encountered (e.g. people with diabetes, women, older patients, those with mental-illness, those from culturally and linguistically diverse (CALD) populations, and Aboriginal and Torres Strait Islander peoples).
2.1.3 Initial ECG and Assessment
Recommendation: It is recommended that a patient with acute chest pain or other symptoms suggestive of an ACS receives a 12-lead ECG and this ECG is assessed for signs of myocardial ischaemia by an ECG-experienced clinician within 10 minutes of first acute clinical contact. (NHMRC Level of Evidence (LOE): IIIC; GRADE strength of recommendation: Strong).
Rationale: This initial assessment is to rapidly identify patients with an acute STEMI, for whom emergency reperfusion is clinically appropriate, and who require immediate activation of a defined STEMI pathway. (Refer to Section 3.1.1). Initial assessment may also disclose patients with a high probability of NSTEMI or UA who require admission, further confirmatory investigation and appropriate management [
Frequency and consequences of recording an electrocardiogram >10 minutes after arrival in an emergency room in non-ST-segment elevation acute coronary syndromes (from the CRUSADE Initiative).
] (Refer to Section 3.1.2 and 3.2). There is limited evidence exploring optimum timing of ECG acquisition and interpretation.
Benefits and harms: Approximately 2–5% of all patients with possible cardiac chest pain have a STEMI, for whom delays in identification and initiation of optimum treatment incur significant morbidity and mortality (Refer to Section 3.1.1).
Resources and other considerations: Training in ECG acquisition is required for all health services. Interpretation should be performed by an experienced clinician. Computer-assisted interpretation of the ECG may increase diagnostic accuracy, particularly for STEMI, among clinicians less experienced in reading ECGs. In some settings (e.g. rural and remote areas), ECG interpretation may be supported by linking local clinicians with experienced clinicians via one or other telemedicine modalities (fax/telephone, digital ECG network, video consultation) within a clinical network [
Effectiveness of prehospital wireless transmission of electrocardiograms to a cardiologist via hand-held device for patients with acute myocardial infarction (from the Timely Intervention in Myocardial Emergency, NorthEast Experience [TIME-NE]).
2.1.3.1. Serial ECGs should be taken every 10-15 minutes until the patient is pain-free and compared in sequence and, where possible, with pre-existing ECGs.
2.1.3.2. Blood samples for biomarkers (cardiac troponin being preferred) should be drawn on presentation (Refer to Section 2.5).
2.1.3.3. A chest X-ray is recommended in the assessment for cardiac enlargement and identification of other non-coronary causes of chest pain where the diagnosis is yet to be established, though the utility of this investigation may be limited. If a recent chest X-ray is available for review, repeat radiological investigation may not be required.
2.2 Differential Diagnosis
The differential diagnosis of patients with chest pain is broad and includes non-ACS conditions that may be associated with ECG changes and normal or elevated troponin values (Table 3 and Refer to Section 3.1.3: Type 2 AMIs). In the absence of ECG evidence consistent with STEMI, potentially treatable, life-threatening conditions that should always be considered in the differential diagnosis of chest pain include aortic dissection, pulmonary embolism and tension pneumothorax. Non-life-threatening causes for chest pain that should be considered include gastro-oesophageal pathology, pleuritis and other pulmonary disease, muscular and skeletal causes including costochondritis, and herpes zoster. In addition, patients with myocardial oxygen supply–demand mismatch due to non-atherosclerotic and non-coronary conditions (e.g. Type 2 MI, Refer to Section 3.1.3) may also present with chest pain but who require a different management pathway to patients with type 1 MI (i.e. plaque rupture).
Table 3Differential diagnosis of causes of chest pain
Ischaemic cardiovascular causes
• ACS (e.g. acute myocardial infarction, unstable angina) • Stable angina • Severe aortic stenosis • Tachyarrhythmia (atrial or ventricular)
Non-ischaemic cardiovascular causes of chest pain
• Aortic dissection (tear between the layers of the wall of the aorta) and expanding aortic aneurysm
There are no randomised comparisons of the routine use of oxygen therapy versus room air that demonstrate improvements in clinical outcomes in patients with suspected or confirmed ACS. A randomised comparison has suggested an increase in infarct size with routine supplemental oxygen among patients who are not hypoxic [
Part 5: Acute Coronary Syndromes 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations.
]. The routine use of oxygen therapy among patients with a blood oxygen saturation (SaO2) >93% is not recommended, but its use when the SaO2 is below this level is advocated despite the absence of clinical data [
The Effects of Oxygen Therapy on Myocardial Salvage in ST Elevation Myocardial Infarction Treated with Acute Percutaneous Coronary Intervention: The Supplemental Oxygen in Catheterized Coronary Emergency Reperfusion (SOCCER) Study.
]. However care should be exercised in patients with chronic obstructive airways disease where the target SaO2 is to be 88-92%.
2.3.1.2 Initial pharmacotherapy
In the presence of ongoing chest pain, nitro-glycerine (GTN) sublingual tablet (0.3-0.6 mg) or spray (0.4-0.8 mg) should be administered every 5 minutes for up to three doses if no contraindications exist (such as hypotension). If the symptoms are unrelieved, assessment for the need for intravenous (IV) GTN and/or alternative therapy should be made. In the absence of contraindications, it is reasonable to administer titrated morphine or fentanyl intravenously (not pethidine) for ongoing chest discomfort at any time during the initial management (note: morphine administration has been shown to slow absorption of oral medications including ticagrelor). Non-steroidal anti-inflammatory medications should not be given due to the increased risk of MACE [
Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction.
Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials.
In all patients with possible ACS and without contraindications, aspirin (300 mg orally, dissolved or chewed) should be given as soon as possible after presentation.
2.3.1.4 Other Anti-Thrombotic Therapies
Additional antiplatelet and anticoagulation therapy or other therapies such as beta blockers should not be given to patients without a confirmed or probable diagnosis of ACS.
2.4 Risk Scores and Clinical Assessment Protocols
The process of risk stratification is to assist in estimating the probability of ACS and ACS-related morbidity and mortality. In patients presenting acutely with chest pain this process aids evaluation, treatment (drug therapies or an early invasive therapeutic approach) and disposition (cardiac care unit, monitored environment, short stay units or discharge). The process of risk stratification reduces unnecessary investigations and therapies and decreases avoidable inpatient admissions among low-risk patients [
Introduction of an accelerated diagnostic protocol in the assessment of emergency department patients with possible acute coronary syndrome: the Nambour Short Low-Intermediate Chest pain project.
Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE).
]. No risk score in isolation identifies patients at low risk for ACS who can be safely discharged without further investigation (Refer to Table 5). Suspected ACS Assessment Protocols (Suspected ACS-AP), sometimes called accelerated diagnostic protocols (ADPs), integrate risk scores and define a process of assessment that includes recommendations for biomarker testing intervals for patients with possible cardiac symptoms.
Table 5Performance of various risk scores and Clinical Assessment Protocols in the management of suspected ACS#
Prospective validation of a modified thrombolysis in myocardial infarction risk score in emergency department patients with chest pain and possible acute coronary syndrome.
2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial.
Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess 30-day outcomes in emergency department patients with possible acute coronary syndrome.
Development of a clinical prediction rule for 30-day cardiac events in emergency department patients with chest pain and possible acute coronary syndrome.
Note: All values are rounded to nearest whole number
#Table was modified from Fanaroff AC, et al. “Does This Patient With Chest Pain Have Acute Coronary Syndrome?: The Rational Clinical Examination Systematic Review.” JAMA. 2015;314(18):1955-65.
Recommendation: A patient presenting with acute chest pain or other symptoms suggestive of an ACS should receive care guided by an evidence-based Suspected ACS Assessment Protocol that includes formal risk stratification. (NHMRC Level of Evidence (LOE): IA; GRADE strength of recommendation: Strong).
Rationale: A single meta-analysis, two randomised controlled trials (RCTs) and a large number of prospective observational trials have been published describing risk scores and Suspected ACS-APs. Risk scores include those originally derived from cohorts with ACS (TIMI [
Application of the TIMI risk score for unstable angina and non-ST elevation acute coronary syndrome to an unselected emergency department chest pain population.
Evaluation of Global Registry of Acute Cardiac Events and Thrombolysis in Myocardial Infarction scores in patients with suspected acute coronary syndrome.
Treatment and Outcomes of Patients With Suspected Acute Coronary Syndromes in Relation to Initial Diagnostic Impressions (Insights from the Canadian Global Registry of Acute Coronary Events [GRACE] and Canadian Registry of Acute Coronary Events [CANRACE]).
] rules). Formal risk stratification allows quantification of risk of MACE in patients with chest pain up to 30 days after presentation. However, if used alone, these scores lack the ability to define a low-risk population suitable for limited assessment and early discharge from ED. For example, the NPV for MACE for low-risk patients using the HEART score is 96-98% (i.e. up to 4% missed MACE rate) [
2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial.
]). Several Suspected ACS-APs facilitate the early disposition of patients identified as low risk for 30-day MACE. The pathways with consistently high NPV (>99%) for MACE in validation studies, and which allow identification of patients safe for early discharge, include the ADAPT (using sensitive troponin assays), modified-ADAPT (using highly sensitive troponin assays) rules [
2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial.
Development of a clinical prediction rule for 30-day cardiac events in emergency department patients with chest pain and possible acute coronary syndrome.
] currently have limited validation to support widespread use. Risk scores such as the TIMI score, GRACE score and HEART score cannot rule-out ACS in primary care or hospital-based settings. Suspected ACS-APs have not been assessed in a primary care setting [
]. The estimates of benefits and harms listed below are based on these Suspected ACS-APs (Table 5).
Benefits and harms: Formal risk assessment of patients with symptoms of possible ACS supports quantification of MACE risk within 30 days of assessment, may reduce misdiagnosis and inappropriate discharge from ED of patients with ACS from 2-8% to less than 1%, and increase absolute rates of early discharge of low-risk patients from ED by up to 20-40% [
2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial.
Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess 30-day outcomes in emergency department patients with possible acute coronary syndrome.
]. Use of Suspected ACS-APs can assist in identifying low-risk patients (up to 40% of all patients presenting to ED with chest pain) for whom early discharge from ED may be appropriate.
Resources and other considerations: Use of formal risk scores and Suspected ACS-APs in assessing patients with chest pain should be documented and may be aided by the use of electronic decision aids. Suggested pathways/protocols and methods for monitoring their effectiveness are provided in Figure 1, Figure 2, Figure 3. Such documentation may inform local audit and quality improvement processes aimed at optimising appropriateness of care. Accelerated management and disposition of patients as a result of formal risk scoring integrated with Suspected ACS-APs could be highly cost-effective.
Figure 1Example of Assessment Protocol for suspected ACS using point-of-care assays.
In choosing among different Suspected ACS-APs, for hospitals using sensitive or highly sensitive troponin assays, the ADAPT or modified-ADAPT protocol, respectively identifies low-risk patients (<1% MACE at 30 days) on the basis of negative troponin measurement at both 0 and 2 hours, TIMI score of 0 (ADAPT) or TIMI score of 0 and 1 (Modified-ADAPT), and no ischaemic changes on ECG at both 0 and 2 hours. Suggested implementation of an ADP is presented in the Figure 1, Figure 2, Figure 3.
2.4.1.2 Local Validation of Suspected ACS-AP
Some centres may choose to assess and implement an alternate strategy to the recommended Suspected ACS-AP for the assessment of ED patients with possible ACS. The performance of any pathway for suspected ACS depends on the incidence of ACS within the local ED population and the sub-population among whom the pathway is applied. Validation of an alternate locally implemented Suspected ACS-AP, including the assessment of 30-day mortality and representation with confirmed ACS in all patients presenting with chest pain, is recommended (Refer to Section 7).
2.4.1.3 Identification of Patients at High Risk for a Cardiac Cause of Chest Pain
The clinical characteristics of patients at high risk for a cardiac cause of chest pain (including ACS and other cardiac diagnoses) are described in Table 6. More than 25% of patients with these high-risk features will have a confirmed diagnosis of ACS and should be referred for inpatient investigation [
]. Several recognised high-risk groups of patients are underrepresented in current trials, including patients over the age of 85 years, patients with renal disease, HIV, familial hypertriglyceridaemia, rheumatoid arthritis or mental health disorders, and certain ethnic groups. It is also recognised that women and the elderly may present more commonly than men with atypical symptoms. A higher index of suspicion of ACS should be exercised when assessing risk in such situations.
Table 6Risk classification for possible cardiac causes of chest pain
High risk
• Ongoing or recurrent chest discomfort despite initial treatment • Elevated cardiac troponin level • New ischaemic ECG changes (such as persistent or dynamic electrocardiographic changes of ST segment depression ≥ 0.5 mm, transient ST-segment elevation (≥0.5 mm) or new T-wave inversion ≥2 mm in more than two contiguous leads; or ECG criteria consistent with Wellens syndrome • Diaphoresis • Haemodynamic compromise — systolic blood pressure <90 mmHg, cool peripheries, Killip Class >I, and/or new-onset mitral regurgitation • Sustained ventricular tachycardia • Syncope • Known left ventricular systolic dysfunction (left ventricular ejection fraction <40%) • Prior AMI, percutaneous coronary intervention, or prior CABG
Low risk
• age <40 years • symptoms atypical for angina • remain symptom-free • absence of known CAD • normal troponin level • normal ECG
2.4.1.4 Identification of Patients at Low Risk for a Cardiac Cause of Chest Pain
A central consideration in determining which Suspected ACS-APs are most appropriate for clinical use is the miss rate (false negative rate) for MACE that is acceptable to both patients and clinicians. One study has defined the miss rate for MACE for ED physicians as <1% at 30 days following ED presentation [
What is an acceptable risk of major adverse cardiac event in chest pain patients soon after discharge from the Emergency Department?: a clinical survey.
]. Little is known about patient expectations. Shared decision-making tools have reduced rates of exercise testing and hospital admission in patients with undifferentiated chest pain [
Cardiac troponins are the most sensitive and specific biomarker for myocardial injury and necrosis. Both troponin I and T subtypes are cardio-specific. Troponin levels become elevated in the blood stream within 1-3 hours after AMI and may remain elevated for up to 14 days. The rise and/or fall of troponin with at least one value greater than the 99th percentile is a key criterion for diagnosis of MI according to the 2012 Third Universal Definition of MI [
]. For the vast majority of patients being investigated for possible AMI, a rising pattern is suggestive of AMI. In patients who present late following AMI, troponin elevations may have peaked, and in this context a fall in troponin is significant.
Five clinical presentations of MI have been defined on the basis of pathological, clinical, and prognostic factors (Refer to Section 3.1.2 and Table 7). In the clinical setting of patients with chest pain and identification of possible AMI, Type 1 MI (spontaneous MI related to atherosclerotic plaque rupture, with ulceration fissuring, erosion or dissection) is the focus of treatment strategies. Increasingly sensitive assays (highly sensitive troponin assays) have reduced the time interval before an elevated troponin value can be detected in the setting of AMI, and may increase the diagnostic rate of NSTEMIs [
Diagnosis of type 1 and type 2 myocardial infarction using a high-sensitivity cardiac troponin I assay with sex-specific 99th percentiles based on the third universal definition of myocardial infarction classification system.
]. In addition, highly sensitive troponin assays have reduced the time interval over which a clinically significant change in serial troponin levels can be reliably detected.
Table 7Universal classification of myocardial infarction
Spontaneous MI related to atherosclerotic plaque rupture, ulceration, erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary arteries leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis.
Type 2: MI secondary to an ischaemic imbalance
Myocardial injury with necrosis where a condition other than CAD contributes to an imbalance between myocardial oxygen supply and/or demand, e.g. coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachy-/bradyarrhythmias, anaemia, respiratory failure, hypotension, and hypertension with or without LVH.
Type 3: MI resulting in death when biomarker values are unavailable
Cardiac death with symptoms suggestive of myocardial ischaemia and presumed new ischaemic ECG changes or new LBBB, but death occurring before blood samples could be obtained, before cardiac biomarker could rise, or when cardiac biomarkers were not collected.
Type 4a: MI related to percutaneous coronary intervention (PCI)
MI associated with PCI (refer to reference for specific criteria)
Type 4b: MI related to stent thrombosis
MI associated with stent thrombosis (refer to reference for specific criteria)
Type 5: MI related to coronary artery bypass grafting (CABG)
MI associated with CABG (refer to reference for specific criteria)
Recommendation: Using serial sampling, cardiac-specific troponin levels should be measured at hospital presentation and at clearly defined periods after presentation using a validated Suspected ACS-AP in patients with symptoms of possible ACS [
Diagnostic performance of cardiac Troponin I for early rule-in and rule-out of acute myocardial infarction: Results of a prospective multicenter trial.
]. (NHMRC Level of Evidence (LOE): 1A; GRADE strength of recommendation: Strong).
Rationale: Newer, more sensitive troponin assays can detect increasingly lower concentrations of troponin in the setting of myocardial necrosis, thus allowing earlier detection of patients with AMI. In addition, Suspected ACS-APs have been derived using both sensitive and highly sensitive troponin assays that support the early rule-in and rule-out of AMI when applied as per protocol. Serial measurement of cardiac-specific troponin levels is necessary to accommodate differences in time of presentation and to identify instances of acutely or chronically elevated troponin attributable to factors other than ACS. While the quality of evidence is moderately high, consideration must be given to the varying analytical characteristics and performance of different troponin assays.
Benefits and harms: The effects of routinely implementing troponin testing within a validated Suspected ACS-AP on the rate of missed MI and early mortality are difficult to quantify due to study heterogeneity and varying levels of expertise within current practice [
Introduction of an accelerated diagnostic protocol in the assessment of emergency department patients with possible acute coronary syndrome: the Nambour Short Low-Intermediate Chest pain project.
Resources and other considerations: Biomarker-based strategies for the rule-in and rule-out of AMI have variable accuracy. Biomarker elevation portending a clinical diagnosis of AMI may not occur in a small proportion of patients until 8–12 hours after pain onset [
Comparison of high sensitivity troponin T and I assays in the diagnosis of non-ST elevation acute myocardial infarction in emergency patients with chest pain.
]. Clinically usable strategies must maintain safety, with missed MI rates ≤1% (NPV ≥ 99%). Clinicians must understand the analytical and performance characteristics of the local assay in use and the specific Suspected ACS-APs used in their setting which incorporate that assay. Of importance, quantitative comparisons cannot be made between troponin I and troponin T, or between point-of-care (POC) devices and laboratory based immunoassays.
Practice Advice
2.5.1.1 Definition of Elevation and Biomarker Evidence of AMI
An elevated troponin value indicating myocardial necrosis is one greater than the 99th percentile (upper reference level) for a specific assay [
]. For the diagnosis of AMI, serial samples are required to determine a rise and/or fall in values. The optimum change value for identification of AMI is usually assay specific and depends on the degree of initial elevation (if present), the time interval between consecutive samples, the time of pain onset and the possible presence of non-ACS causes of elevated troponin (Refer to Section 3.1.2). Absolute changes in nanograms per litre using highly sensitive troponin assays have better diagnostic accuracy for AMI than relative change values [
]. In patients with a high clinical suspicion of ACS, troponin values below or close to the 99th percentile, changes of ≥ 2–3 standard deviations of variation around the initial value, depending on the assay, should prompt additional testing, as this is unlikely to reflect normal biological variability [
]. Laboratory reports should indicate whether clinically significant changes in troponin values of a specific assay have occurred. It should be noted that non-ACS causes of chest discomfort may also result in a rise and fall in serial troponin levels (e.g. pulmonary embolus, myocarditis and extreme exercise: See Table 8). False positive results due to analytical issues may be detected by using an alternate assay.
Life–threatening, non-coronary conditions highlighted in bold
Cardiac contusion, or other trauma including surgery, ablation, pacing, frequent defibrillator shocks Congestive heart failure — acute and chronic Coronary vasculitis, e.g. SLE, Kawasaki syndrome Aortic dissection Aortic valve disease Hypertrophic cardiomyopathy Tachy- or bradyarrhythmias, or heart block Stress cardiomyopathy (Takotsubo cardiomyopathy) Rhabdomyolysis with cardiac injury Pulmonary embolism, severe pulmonary hypertension Renal failure Acute neurological disease, including stroke or subarachnoid haemorrhage Infiltrative diseases, e.g. amyloidosis, haemochromatosis, sarcoidosis, and scleroderma Inflammatory diseases, e.g. myocarditis or myocardial extension of endo-/pericarditis Drug toxicity or toxins e.g. anthracyclines, CO poisoning Critically ill patients, especially with respiratory failure or sepsis
Hypoxia
Burns, especially if affecting > 30% of body surface area Extreme exertion False positives: Cross reacting heterophile antibodies
* Life–threatening, non-coronary conditions highlighted in bold
Nomenclature used for describing assay types may cause misunderstandings of assay capabilities and performance that could lead to incorrect use of early assessment strategies. The majority of cardiac troponin assays are performed on automated platforms within centralised laboratories using sensitive or highly sensitive assays. Without access to central laboratories or automated assay platforms, POC assays are also in use and those with highest sensitivity for detecting troponin are recommended [
Highly sensitive assays are those with total imprecision (coefficient of variation) at the 99th percentile value ≤10% and the ability to measure troponin concentrations below the 99th percentile that are above the assay's limit of detection in at least 50% (and ideally >95%) of healthy individuals [
]. All other troponin assays are labelled sensitive or contemporary assays.
POC assays currently have lower analytical sensitivity for detecting troponin, with no currently commercially available assay meeting high sensitivity criteria [
Diagnostic accuracy of a point-of-care troponin I assay for acute myocardial infarction within 3 hours after presentation in early presenters to the emergency department with chest pain.
Point-of-care troponinT is inferior to high-sensitivity troponinT for ruling out acute myocardial infarction in the emergency department.
European Journal of Emergency Medicine.2014; (Available at: http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L601102416. http://dx.doi.org/10.1097/MEJ.0000000000000225)
]. The shorter turnaround times for POC assays may aid further management for patients with elevated values detected on early (within 2 hours of presentation) or late (>12 hours) sampling. In addition, serial sampling over 6–12 hours after presentation may be used for the rule-out of AMI, while early repeat testing (1-3 hours) in patients with initial troponin elevation may be useful for documenting a rise/fall in troponin for ruling in MI. Strategies to use POC assay results in isolation of an evidence-based Suspected ACS-AP in early rule-out for AMI are insufficiently sensitive and cannot be supported at this time. Decisions based on POC testing are not recommended if laboratory troponin test results are available within one hour of request.
Patients with suspected or proven ACS, in whom transfer to another site is necessary, should have blood samples, stored at 4° C, accompany them for repeat analysis using the troponin assay used at that site.
2.5.1.3 Timing of Testing
The majority of patients with an underlying diagnosis of AMI have elevated troponin values within 3-6 hours of symptom onset, although some assays may not show elevated values for up to 12 hours [
] (Table 9). Despite improvements in troponin assay sensitivity and use of Suspected ACS-APs, an initial troponin value from a blood sample taken on ED presentation that is below the 99th percentile of a sensitive or highly sensitive assay cannot be used by itself for the rule-out of AMI [
]. Whether an initial value below the limit of detection for a highly sensitive assay rules out AMI is yet to be established in prospective studies that i) clearly delineate the time interval between pain onset and collection of initial troponin [
Rapid exclusion of acute myocardial infarction in patients with undetectable troponin using a high-sensitivity assay. [Erratum appears in J Am Coll Cardiol 2012 Sep 18 60 (12)1122].
High-sensitivity cardiac troponin T for early prediction of evolving non-ST-segment elevation myocardial infarction in patients with suspected acute coronary syndrome and negative troponin results on admission.
Diagnostic accuracy of single baseline measurement of Elecsys Troponin T high-sensitive assay for diagnosis of acute myocardial infarction in emergency department: systematic review and meta-analysis.
2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial.
Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess 30-day outcomes in emergency department patients with possible acute coronary syndrome.
2011 Addendum to the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand Guidelines for the management of acute coronary syndromes (ACS) 2006.
The time of symptom onset, even if reliable, does not define the time point of coronary occlusion. Early rule-out biomarker strategies must incorporate serial samples that detect a rising/falling pattern, timed from the initial sample taken at ED presentation. Possible exceptions to this are patients who are symptom-free for 12 hours prior to assessment, or present >3 hours after symptom-onset with values less than the limit of detection (LoD) using a highly sensitive troponin assay. Additional troponin testing should be performed in patients with ongoing or recurrent symptoms of ischaemia.
Validated rapid rule-in and rule-out algorithms for AMI incorporated into Suspected ACS-APs and/or using highly sensitive troponin assays may reduce the serial testing time to one to two hours after presentation [
]. Incorporation of sensitive or highly sensitive troponin assay results into the ADAPT- and modified ADAPT-ADP respectively allows early (two hours after ED presentation) risk stratification [
2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial.
Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess 30-day outcomes in emergency department patients with possible acute coronary syndrome.
2.5.1.4 Cut Points for the Determination of an Abnormal Troponin Value
While the universal definition of myocardial infarction defines an elevated troponin value of greater than the 99th percentile as abnormal, novel strategies often report values in alternate troponin concentrations [
]. Some strategies have been assessed in multiple large cohorts and the results are reassuring in regards to safety for the exclusion of AMI when the specific parameters are met. Further research reporting the outcomes in clinical practice of utilisation of such strategies are needed. The evidence for the use of sex-specific reference ranges for high sensitivity assays is evolving [
Diagnosis of type 1 and type 2 myocardial infarction using a high-sensitivity cardiac troponin I assay with sex-specific 99th percentiles based on the third universal definition of myocardial infarction classification system.
]. Further research is needed to clarify the optimum strategy for both males and females.
2.5.1.5 Other Biomarkers Beyond Troponin
Creatine kinase myocardial enzyme (CK and CK-MB) and myoglobin are not useful for the initial diagnosis of ACS where there is access to troponin testing
2.5.1.6 Observation and Continuous ECG Monitoring
Patients in whom symptoms have resolved, initial ECG shows no ischaemic changes (including the absence of left bundle branch block (LBBB)) and initial troponin value is within normal reference range can be observed in an ED observation unit or chest pain unit, and do not require continuous ECG monitoring. Reinstitution of ECG monitoring should be considered for patients with subsequent elevation of troponin on serial testing.
2.6 Further Diagnostic Testing
The aims of further diagnostic testing in patients with resolved symptoms, non-ischaemic ECGs and normal serial troponin values are to diagnose significant underlying CAD and provide prognostic information. Increasingly, the utility of such testing is questioned in patients at low risk for an evolving ACS as defined by Suspected ACS-APs, which includes those with atypical symptoms, no or very few vascular risk factors, no arrhythmias or clinical features suggestive of arrhythmia and no prior heart disease. Evidence suggests that such patients are at negligible risk of MACE and further testing is not warranted [
Limited utility of exercise stress testing in the evaluation of suspected acute coronary syndrome in patients aged less than 40 years with intermediate risk features.
In patients defined as having intermediate risk, such as those with more typical pain and/or multiple risk factors, further testing may be safely performed during admission or shortly after discharge. Patients at high risk, in whom one in three will prove to have ACS, and who include those with classical crescendo angina symptoms and/or prior history of CAD, should be investigated early, as an inpatient, and managed empirically as having ACS.
Various studies have shown that a normal exercise ECG (based on achieving more than 85% predicted maximum heart rate), dobutamine or dipyridamole stress echocardiogram or coronary computerised tomography angiography (CTCA) has high NPV for ischaemia and is associated with excellent patient outcomes [
Incremental diagnostic and prognostic value of contemporary stress echocardiography in a chest pain unit: mortality and morbidity outcomes from a real-world setting.
Stress Echocardiography Expert Consensus Statement--Executive Summary: European Association of Echocardiography (EAE) (a registered branch of the ESC).
Safety and utility of exercise testing in emergency room chest pain centers: An advisory from the Committee on Exercise, Rehabilitation, and Prevention Council on Clinical Cardiology, American Heart Association.
64-Multislice detector computed tomography coronary angiography as potential alternative to conventional coronary angiography: A systematic review and meta-analysis.
Meta-analysis: diagnostic performance of low-radiation-dose coronary computed tomography angiography.[Erratum appears in Ann Intern Med 2011 Jun 21;154(12):848].
European Society of Cardiology (ESC) Task Force 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology.
], exercise ECG is a widely available, low-cost method which, in patients with an interpretable ECG and who can exercise, can identify patients at low risk for MACE [
Safety and utility of exercise testing in emergency room chest pain centers: An advisory from the Committee on Exercise, Rehabilitation, and Prevention Council on Clinical Cardiology, American Heart Association.
]. However, the quality of evidence for all objective testing strategies is inconsistent and limited to the period prior to the advent of highly sensitive troponin assays. If clinical suspicion is high despite meeting clinical criteria for very low risk, patients should continue to be evaluated according to local protocols for intermediate- or high-risk patients.
2.6.1 Selection of Patients for Further Diagnostic Testing
(a)
Recommendation: Non-invasive objective testing is recommended in intermediate-risk patients, as defined by a validated Suspected ACS-AP, with normal serial troponin and ECG testing and who remain symptom free (NHMRC Level of Evidence (LOE): IA; GRADE strength of recommendation: Weak).
(b)
Recommendation: Patients in whom no further objective testing for CAD is recommended are those at low risk, as defined by a validated Suspected ACS-AP: age <40 years, symptoms atypical for angina, in the absence of known CAD, with normal troponin and ECG testing and who remain symptom free (NHMRC Level of Evidence (LOE): III-3C; GRADE strength of recommendation: Weak).
Rationale: A small but significant proportion (<4%) of patients presenting with possible cardiac chest pain in whom biomarker and ECGs are normal have UA and underlying CAD [
]. Important diagnostic and prognostic information is derived from objective testing which may guide further diagnostic procedures and support therapeutic interventions to alter short- and long-term coronary risk.
Benefits and harms: The benefit of diagnosing UA is to allow the timely instigation of therapy to improve prognosis. The harms include needless downstream interventions (including invasive strategies and each with their own risks) and provocation of patient anxiety in response to an incorrect or highly unlikely diagnosis of coronary-related pain. Appropriate identification of pre-test risk is required to optimally balance the benefits and harms.
Resources and other considerations: Considerable healthcare resources may be consumed by the inappropriate use of testing procedures in patients with low pre-test probability of ACS. The aim of improving short- and long-term outcomes in patients with UA must be balanced against the cost effectiveness of downstream interventions [
]. Conversely, constraints on the availability and expertise of local investigative facilities in regional and smaller community hospital settings can hamper appropriate evaluation of patients at higher risk in the absence of service networks which link these locales with expert advice.
Practice Advice
2.6.1.1 Test Selection – Functional Versus Anatomical
The choice of objective test is based on patient criteria (ECG interpretability, ability to exercise), diagnostic accuracy, local expertise and available technologies, and risks and costs associated with specific investigations, including equipment, radiation and contrast risks. Treadmill exercise testing is useful in patients without contraindications and able to exercise, due to widespread access, simplicity, low risk, low cost and understanding of its utility in prognostication by clinicians; however its overall benefit is not clearly defined. Studies available prior to the availability of troponin assays showed NPV of 97-99% for AMI and death [
Safety and utility of exercise testing in emergency room chest pain centers: An advisory from the Committee on Exercise, Rehabilitation, and Prevention Council on Clinical Cardiology, American Heart Association.
]. Anatomical investigations including CTCA and functional imaging tests such as stress echocardiography are sensitive for the diagnosis of CAD. While there is evidence that stress echocardiography and CTCA are superior to exercise stress testing [
A systematic review of the clinical effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of suspected coronary artery disease.
], access to these modalities is limited in many ED settings and the overall incremental benefit is not proven. Whether CTCA can be used, as part of a Suspected ACS-AP, to identify a subset of low-risk patients with normal coronary arteries who do not need delayed troponin testing is under active investigation [
A systematic review of the clinical effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of suspected coronary artery disease.
], although cost, access, resource implications and risk of radiation exposure to large numbers of low risk patients may counterbalance any benefits.
Note: Clinical scenarios where ECG-only exercise testing may be inappropriate or provide sub-optimal diagnostic accuracy: bundle branch block; left ventricular hypertrophy (LVH) on voltage criteria or previous LV imaging; digoxin therapy; mitral valve prolapse; severe valvular disease; pre-excitation syndromes; severe cardiomyopathy; pacemaker in situ; women <50 years; anaemia (Hb <90 g/dL); uncorrected electrolyte abnormalities; inability to exercise to achieve maximum predicted heart rate; concomitant beta blocker therapy.
2.6.1.2 Timing of Testing
High-risk patients require further objective testing during the index admission. Intermediate risk patients may be safely accelerated for early inpatient testing or discharged for outpatient testing ideally within 7 days, although acceptable up to 14 days after presentation. Investigation prior to discharge from the ED is desirable among patients with characteristics associated with significant failure to re-attend for medical review given the higher rates of MACE in such patients [
Safety and utility of exercise testing in emergency room chest pain centers: An advisory from the Committee on Exercise, Rehabilitation, and Prevention Council on Clinical Cardiology, American Heart Association.
2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial.
Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess 30-day outcomes in emergency department patients with possible acute coronary syndrome.
In patients without high-risk features and with negative biomarker and ECG testing, and who remain symptom-free, the risk of an ACS event within 30 days is <4%. A high clinical suspicion is needed in identifying patients who are at high risk for serious adverse events but who have initial normal troponin and ECG testing (e.g. classical crescendo angina symptoms, such as increasing episodes of ischaemic symptoms with less exercise or lasting longer). For a proportion of non-high-risk patients, well-defined accelerated strategies may allow early inpatient testing or delayed outpatient testing up to 30 days after presentation [
2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial.
Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess 30-day outcomes in emergency department patients with possible acute coronary syndrome.
2.6.1.3 Criteria for Patients Requiring no Further Testing
The criteria used to define low-risk patients in whom further investigation may not be warranted has varied in studies, and criteria we have defined may be contested [
Limited utility of exercise stress testing in the evaluation of suspected acute coronary syndrome in patients aged less than 40 years with intermediate risk features.
]. If clinical suspicion is high (e.g. patients of Aboriginal and Torres Strait Islander decent) despite meeting clinical low-risk criteria, patients should continue to be evaluated according to local protocols for intermediate or high-risk patients.
2.7 Representation With Symptoms
Patients who represent to ED with possible symptoms of NSTEACS within 30 days and who have not already undergone objective testing may warrant consideration of exercise testing, stress echocardiography, nuclear perfusion scanning or CTCA, as well as a detailed re-appraisal for alternate diagnoses. If representation has occurred after prior negative exercise testing, use of investigations with greater sensitivity and specificity should be considered.
2.8 Discharge Advice
On discharge from ED, patients who have been assessed for possible cardiac chest pain should receive a management plan which includes information about their likelihood of ACS, advice about representation with recurrent symptoms, hospital follow-up arrangements regarding subsequent testing and timing of the test (if required), and review by their local general practitioner (GP) for risk factor modification. Consideration should be given to discharge with aspirin and GTN as required.
3. Diagnostic Considerations and Risk Stratification of Acute Coronary Syndromes
The following sections pertain to those patients where ACS is the working or confirmed diagnosis.
ST-segment elevation on the 12-lead ECG suggests an acute epicardial coronary occlusion as a cause for the clinical presentation. The diagnostic criteria are a clinical history of typical chest discomfort or pain of ≥20 minutes duration (which may have resolved by the time of presentation) and ECG criteria with persistent (>20 minutes) ST segment elevation in ≥2 contiguous leads of:
•
≥2.5 mm ST elevation in leads V2-3 in men under 40 years, or
•
≥2.0 mm ST elevation in leads V2-3 in men over 40 years, or
•
≥1.5 mm ST elevation in V2-3 in women, or
•
≥1.0 mm in other leads
•
or development of new onset left bundle-branch block (LBBB) [
In patients with LBBB, the modified Sgarbossa Criteria is useful in identifying MI: ST elevation ≥1 mm concordant with QRS (5 points); ST depression ≥ 1 mm in lead V1-V3 (3 points); ST elevation ≥ 5 mm discordant with QRS (2 points) (i.e. >3 points associated with 98% MI, but score of 0 does not rule out STEMI). It should be noted that occlusion of the left circumflex artery may not be associated with any ST segment changes on the standard 12-lead ECG, and pursuing the diagnosis with posterior lead placement may be useful, while ST segment depression in V1-3 and abnormal R waves in V1 may also indicate posterior infarction.
The differential diagnosis for ST segment elevation includes pericarditis (which is distinguished by more global ST segment elevation [often concave] across most ECG leads, often accompanied by PR depression in lead II), stress cardiomyopathy (i.e. Takotsubo cardiomyopathy) which is often difficult to differentiate without coronary angiography, and Brugada Syndrome.
In situations where expertise in ECG interpretation may not be available, an electronic algorithm for ECG interpretation (coupled with remote review by an expert) can assist in diagnosing STEMI. Local/state care pathways should incorporate means for allowing expert ECG reading within 10 minutes of first contact, integrated with clinical decision-making around timely reperfusion. The diagnosis of STEMI and therefore the decision to initiate reperfusion therapy, does not depend on results of serial ECGs or troponin testing, or chest X-ray, although these may assist in prognostication and determining the extent of myocardial injury.
The diagnosis of NSTEACS is often more challenging than STEMI, as is the differentiation of NSTEMI from UA. In such cases, implementation of the criteria for MI contained within the Third Universal Definition of MI should be considered rather than relying on investigational evidence of cardiac injury alone (i.e. troponin elevation) [
] (Refer to Table 7). Also to be considered are alternative, and sometimes life-threatening, non-ACS diagnoses in patients with atypical features but who demonstrate elevated cardiac biomarkers. Similarly, among patients with biomarker elevation without a culprit coronary lesion identified on coronary angiography, a broad differential diagnosis including Takotsubo cardiomyopathy, myocarditis, coronary embolism, pulmonary embolus and coronary spasm should be considered. (See Table 8)
3.1.3 Type 1 Versus Type 2 Myocardial Infarction
Among those patients with confirmed MI, applying the diagnostic classification in Table 7 may help inform the choice of potential treatment pathways for ACS. Importantly, though often clinically challenging, Type 1 MI (i.e. plaque rupture) must be differentiated from Type 2 MI (oxygen supply-demand imbalance) in the context of another concurrent acute illness (e.g. pneumonia or tachyarrhythmia), and which often presents as NSTEMI. Evidence-based recommendations regarding the use of ACS interventions for patients with Type 2 MI cannot currently be made. In such circumstances, clinical assessment should be guided by pre-event likelihood of prognostically significant CAD and increased risk of recurrent cardiac events and mortality proportional to the degree of injury, while also weighing the potential impact of non-cardiac competing risks [
High sensitivity-troponin elevation secondary to non-coronary diagnoses and death and recurrent myocardial infarction: An examination against criteria of causality.
European Heart Journal Acute Cardiovascular Care.2015; 4: 419-428
3.2 Risk Stratification for Patients with Confirmed ACS
When clinician intuition of ongoing ischaemic risk is compared directly with risk estimation using risk scores such as the Global Registry of Acute Cardiac Events (GRACE) and the Thrombolysis In Myocardial Infarction (TIMI) scores, the latter show better discrimination and calibration than the former [
Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE).
TIMI risk score for ST-elevation myocardial infarction: A convenient, bedside, clinical score for risk assessment at presentation: An intravenous nPA for treatment of infarcting myocardium early II trial substudy.
] and may thus be preferred for clinical decision-making and communication with patients and families. Similarly, risk scores for bleeding risk exist, such as those derived from the CRUSADE and ACUITY cohort studies, with CRUSADE being most discriminatory [
Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score.
]. Stratification of ischaemic and bleeding risks may be useful for guiding initiation of antithrombotic therapies, use and timing of early invasive management, and transfer to larger institutions when access to expertise or invasive facilities are not locally available. For both ischaemic and bleeding risk scores, prospective evidence that their routine use improves care or outcomes is not currently available. Clinical features associated with the risk of mortality and recurrent ischaemic events are described in Table 10.
Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE).
Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score.
% risk at 14 days of all-cause mortality, new or recurrent MI, or severe recurrent ischaemia requiring urgent revascularisation
% risk by 6 months for all-cause mortality
% risk of in-hospital major bleeding
• 0–1=4.7% risk
• 60–100 = ∼3% risk
• <20 = ∼3% risk
• 2=8.3% risk
• 100–140 = ∼8.0% risk
• 20–30 = ∼6% risk
• 3=13.2% risk
• 140–180 = ∼20% risk
• 30–40 = ∼10% risk
• 4=19.9% risk
• >180 = >40% risk
• >40 = >15% risk
• 5=26.2% risk
Derived from international registry of ACS patients
Derived from US-based registry of ACS patients
• 6–7=at least 40.9% risk
Derived from clinical trial patients
Reference
Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, Papuchis G, et al. The TIMI Risk Score for Unstable Angina/Non-ST Elevation MI, JAMA, 2000; 284:335–42
Fox KAA, Dabbous OH, Goldberg RJ, et al. Prediction of risk of death and myocardial, infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE), BMJ, 2006:333:1091.
Subherwal S, Bach RG, Chen AY, et al. Baseline Risk of Major Bleeding in Non-ST-Segment-Elevation Myocardial Infarction: The CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) Bleeding Score. Circulation. 2009; 119:1873–82
Table 10Markers of increased risk of mortality and recurrent events among patients with confirmed ACS
Risk classification
Clinical characteristic
Very High
• Haemodynamic instability, heart failure, cardiogenic shock or mechanical complications of MI • Life-threatening arrhythmias or cardiac arrest • Recurrent or ongoing ischaemia (i.e. chest pain refractory to medical treatment), or recurrent dynamic ST-segment and/or T-wave changes, particularly with intermittent ST-segment elevation, de Winter T-wave changes, or Wellens’ syndrome, or widespread ST-segment elevation in two coronary territories
High
• Rise and/or fall in troponin level consistent with MI • Dynamic ST-segment and/or T-wave changes with or without symptoms • GRACE Score>140
3.2.1 Integrating Stratification of Ischaemic and Bleeding Risk into Clinical Decision-Making
Recommendation: The routine use of validated risk stratification tools for ischaemic and bleeding events (e.g. GRACE score for ischaemic risk or CRUSADE score for bleeding risk) may assist in patient-centric clinical decision-making in regards to ACS care. (NHMRC Level of Evidence (LOE): IIIB; GRADE strength of recommendation: Weak).
Rationale: Several studies of ACS practice have demonstrated a mismatch between physician assessment of ischaemic and bleeding risks and those derived from validated risk models [
]. Over and under estimation of these risks may contribute to the misapplication of evidence-based guideline recommendations that are poorly aligned with individual patient choice or clinical need [
An examination of clinical intuition in risk assessment among acute coronary syndromes patients: observations from a prospective multi-center international observational registry.
Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score.
]. Nevertheless, it should be noted that many of these tools have not been validated within Aboriginal and Torres Strait Islander populations and the higher risk profile of these patients should be recognised. As yet, there are no prospective randomised trials comparing clinical judgement and use of risk scores against clinical judgment alone in deciding the use of diagnostic and therapeutic interventions and assessing downstream effects on clinical outcomes.
Benefits and harms: For the endpoint of mortality or recurrent ischaemic events, no estimates of effect can be currently provided. The likelihood of an increase in adverse outcomes or the over/under use of therapies is thought to be low, but remains unproven.
Resources and other considerations: The routine use of risk tools may provide modest improvements in individualising care decisions, and may be more relevant to rural settings where clinical experience may be limited and where decisions regarding transfer to other institutions and its timing are more frequently encountered. Incorporation of routine risk scoring into local protocols with the aid of electronic risk calculators (web/mobile apps) may assist development of patient-specific clinical care plans and evaluation of the appropriateness of care within local audit and quality assurance efforts.
Practice Advice
3.2.1.1 Choice of Risk Score
For ischaemic risk, the GRACE risk score is superior to the TIMI risk score in terms of discriminating between high- and intermediate- or low-risk patients. However, estimating risk of recurrent MI or death for an individual patient depends on local validation [
]. In regards to bleeding risk scores, the CRUSADE risk score is preferred, although it has limited validation in the Australian setting.
4. Acute Reperfusion and Invasive Management Strategies in Acute Coronary Syndromes
In patients with confirmed STEMI, the immediate priority is initiation of an emergency reperfusion strategy to improve short- and long-term survival and cardiac function.
4.1 Reperfusion for STEMI
4.1.1 Eligibility for Reperfusion
Recommendation: For patients with STEMI presenting within 12 hours of symptom onset, and in the absence of advanced age, frailty and co-morbidities that influence the individual's overall survival, emergency reperfusion therapy with either primary percutaneous coronary intervention (PCI) or fibrinolytic therapy is recommended. (NHMRC level of evidence (LOE) 1A; GRADE strength of recommendation: Strong).
Rationale: The aim of reperfusion therapy is the timely restoration of coronary flow and myocardial perfusion which limits the extent of MI and reduces mortality by minimising the total ischaemic time (i.e. symptom onset to reperfusion) (Refer to Section 4.1.2). Within current practice, the options for reperfusion are primary PCI or fibrinolytic therapy. Fibrinolytic therapy, compared with control groups, reduces overall mortality at 35 days with a relative risk of 0.82 (95% CI 0.77-0.87) based on data from nine trials involving 58,600 patients [
Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients: Fibrinolytic Therapy Trialists’ (FTT) Collaborative, Group.
]. This benefit was greater among those patients with anterior MI, and those presenting earlier after symptom onset. The impact on mortality through myocardial salvage is greatest in the first hour after symptom onset and diminishes with time, virtually dissipated by 12 hours [
Primary Coronary Angioplasty vs. Thrombolysis Group. Does time matter?. A pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients.
]. An analysis of 22 randomised trials (n=50246) demonstrated an attenuation of the mortality benefit with fibrinolysis of 1.6 lives per 1,000 patients per hour delay. Within analyses of primary PCI, this loss of benefit with delay persists, although the attenuation is less prominent. In the absence of large-scale studies comparing primary PCI with conservative management, evidence of efficacy is drawn from studies comparing this strategy with in-hospital fibrinolysis.
Benefits and harm: Refer to Section 4.1.2.
Practice Advice
4.1.1.1 Confirming the Diagnosis of STEMI/LBBB: The Diagnostic Criteria are Described in Section 3.1.1
In situations where expertise in ECG interpretation may not be available, an electronic algorithm for ECG interpretation (coupled with remote review by an expert) can assist in diagnosing STEMI. Local care pathways should incorporate means for allowing expert ECG reading within 10 minutes of first contact, integrated with clinical decision-making to enable timely reperfusion.
4.1.1.2 Patients With Advanced Age and Multiple Co-Morbidities
While age is not a contraindication to reperfusion therapy, decisions regarding reperfusion should include the patient's and their family's or carer's values and preferences, and the relative benefits and harms of each reperfusion strategy (Refer to Section 4.1.2).
4.1.1.3 Patients With Resolved Chest Pain or ECG Changes
The benefit of reperfusion is not dependent on the presence of ongoing chest pain and it should be provided to patients with persistent (>20 minutes) ST elevation/LBBB within 12 hours, despite resolution of chest pain.
4.1.1.4 Patients With Ongoing Chest Pain and ECG Criteria Presenting After 12 Hours
Persistent ischaemic chest pain or haemodynamic compromise beyond 12 hours after symptom onset suggests ongoing ischaemia and potential for myocardial salvage and reperfusion for these patients should be considered. Given the lower efficacy and persistent bleeding risks associated with fibrinolysis among patients presenting late, reperfusion with primary PCI in this setting is preferred (Refer to Section 4.1.2.1).
4.1.1.5 Patients with Out-of-Hospital Cardiac Arrest
In patients with a shockable rhythm and spontaneous return of circulation associated with persistent ST elevation on the ECG, reperfusion therapy either with primary PCI or fibrinolytic therapy, is recommended. In patients with ST segment depression, emergency angiography and revascularisation, if indicated, should be considered.
4.1.2 Choice of Reperfusion Strategy
Recommendation: Primary PCI is preferred for reperfusion therapy in patients with STEMI if it can be performed within 90 minutes of first medical contact; otherwise fibrinolytic therapy is preferred for those without contra-indications. (NHMRC level of evidence (LOE) 1A; GRADE strength of recommendation: Strong).
Rationale: The choice of reperfusion strategy requires consideration of time from symptom onset to first medical contact, extent of ischaemic myocardium, presence of haemodynamic compromise, bleeding risk from fibrinolytic therapy and expected delays in providing PCI, including transfer times to PCI-capable hospitals. Meta-analyses of comparative trials show primary PCI to be superior to fibrinolytic therapy in reducing mortality, recurrent MI and stroke. Compared to fibrinolysis, primary PCI provides an additional benefit of 1.5–2 lives saved per 100 patients treated [
] based on a 2003 analysis of 23 trials involving 7,739 patients. Further reductions in rates of recurrent MI and stroke were also seen. Importantly, these trials predate coronary artery stenting and contemporary peri-procedural antithrombotic therapy. For patients presenting to non-PCI-capable centres, withholding fibrinolysis and transferring in a timely manner to a PCI-capable hospital for primary PCI, compared to on-site fibrinolysis, was associated with a reduction in mortality (5.6% vs 6.8%, p<0.02), re-infarction (2.1% vs 4.7%; p<0.001) and stroke (0.7% vs 1.7%, p=0.0005) by 30 days in a meta-analysis of 11 trials (n=5741) [
]. Hence, compared with in-hospital fibrinolysis, primary PCI may provide further reductions in 30-day mortality (0.73 [95% CI 0.62-0.86]) with additional benefits in reducing recurrent MI (OR 0.35 [95% CI 0.27-0.45] and stroke risk (OR 0.46 [95% CI 0.30-0.72]) [
However, the benefits of PCI over fibrinolysis depend on context. An observational analysis from the National Registry of MI in the United States demonstrated the relative benefit of primary PCI over fibrinolysis was lost after a delay to PCI of 121 minutes [
Benefit of transferring ST-segment-elevation myocardial infarction patients for percutaneous coronary intervention compared with administration of onsite fibrinolytic declines as delays increase.
]. In addition, many trials of primary PCI (with and without transfer) did not include early angiography in the fibrinolytic arms. Data from three relatively small trials [
The influence of time from symptom onset and reperfusion strategy on 1-year survival in ST-elevation myocardial infarction: a pooled analysis of an early fibrinolytic strategy versus primary percutaneous coronary intervention from CAPTIM and WEST.
] comparing primary PCI with fibrinolytic therapy as part of a ‘pharmaco-invasive’ strategy using more contemporary antiplatelet therapy and higher rates [∼30%] of rescue PCI and early routine angiography (6-24 hours) among ∼3,000 patients showed no difference in mortality. Furthermore, very early administration of fibrinolysis in the pre-hospital setting (i.e. pre-hospital fibrinolysis) may confer superior outcomes to PCI, especially among patients presenting within two hours of symptom onset [
Benefits and harms: Estimates of the absolute reduction in mortality by 30 days with fibrinolysis is 4% (NNTB 25) with a further 1.5-2% reduction associated with primary PCI (NNTB 50-63). This relative benefit is diminished with pre-hospital fibrinolysis and when delay to PCI is >2 hours. Fibrinolysis is associated with a 2% risk of stroke (NNTH 50) [
]. Compared with fibrinolysis, primary PCI is associated with a 1% lower risk of stroke (NNTB 100).
Practice Advice
4.1.2.1 Clinical Circumstances where the Administration of Fibrinolytic Therapy (Assuming ‘Door-to-Needle’ Time ≤30 Minutes) Should be Considered the Default Reperfusion Strategy
•
Patients presenting to ED or suitably trained pre-hospital paramedic teams within 60 minutes of symptom onset.
•
Patients presenting within 60-120 minutes after symptom onset in whom the expected delay to first device time is >90 minutes.
•
Unacceptable delays in cardiac catheter laboratory activation for primary PCI.
•
Patient factors likely to impede successful performance of primary PCI: e.g. severe contrast allergy or poor vascular access.
4.1.2.2 Contra-Indications to Administration of Fibrinolytic Therapy (Consider Expert Consultation)
•
BP>180/110 mmHg
•
Recent trauma/surgery
•
Gastrointestinal or genitourinary bleeding within previous 2–4 weeks
•
Stroke/TIA within 12 months
•
Prior Intracranial haemorrhage at any time
•
Current anticoagulation or bleeding diathesis (relative contraindication with warfarin)
4.1.2.3 Clinical Circumstances where Primary PCI may be the Preferred Reperfusion Strategy due to Reduced Efficacy or Increased Bleeding Risk with Fibrinolytic Therapy
•
Longer patient delay from symptom onset (2-4 hours), primary PCI is preferred if delay between first medical contact and first device time is expected to be <120 minutes.
•
Late presentation after symptom onset (>4 hours), primary PCI is preferred due to lower efficacy with fibrinolytic therapy.
•
Patients with haemodynamic compromise or cardiogenic shock, with the option of urgent coronary artery bypass grafting (CABG).
•
Increased bleeding risk: among the elderly, patients with significant co-morbidity.
4.1.2.4 Strategies for Reducing the Time to Reperfusion Therapy
Coordinated protocols with planned decision-making that incorporates ambulance services and paramedics, first responder primary care physicians, emergency and cardiology departments are critical for achieving acceptable reperfusion times. While strategies need to be tailored to the local community and their distribution of emergency services, strategies that effectively shorten the time to reperfusion include: developing hospital networks with pre-determined management pathways for reperfusion; pre-hospital ECG and single-call catheter laboratory activation; pre-hospital fibrinolysis by suitably trained clinicians (e.g. paramedics), the bypassing, where appropriate, of non-PCI capable hospitals; and bypassing the ED on arrival in PCI centres. Furthermore, an established capability for timely expert consultation for complex clinical scenarios is highly desirable. In the context of a system-based approach to reperfusion, the capacity for continuous audit and feedback is also recommended.
4.1.3 Practical Considerations Regarding Administration of Fibrinolytic Therapy
4.1.3.1 Choice of Fibrinolytic
Currently available fibrinolytics include: tenecteplase (weight adjusted [30-50 mg] IV bolus); reteplase 10 units IV followed by 10 units IV, 30 minutes later; alteplase (weight adjusted accelerated bolus and infusion regimen); and streptokinase 1.5 million units IV infusion over 30–60 minutes. (Note that streptokinase is associated with a higher rate of hypotension and intracerebral haemorrhage and, due to a high prevalence of streptococcal antibodies, should not be used for Aboriginal and Torres Strait Islander patients). A fibrinolytic agent that can be given as a bolus dose such as tenecteplase is advisable for ease of administration, especially in the pre-hospital setting. In patients aged ≥75 years, administration of half the standard dose of tenecteplase should be considered in reducing risk of intracranial bleeding [
Enoxaparin vs. unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction in elderly and younger patients: results from ExTRACT-TIMI 25.
Antiplatelet therapy: For fibrinolytic-treated patients, clopidogrel (300 mg loading dose and 75 mg per day) is recommended at the time of fibrinolytic therapy. Currently, the safety and efficacy of ticagrelor or prasugrel has not been studied in conjunction with fibrinolysis (i.e. within 24 hours of fibrinolytic therapy).
4.1.4 Technical Aspects of Primary PCI
4.1.4.1 Mode of Arterial Access
Radial access is preferred over femoral access, largely due to reduced local bleeding, unless there are compelling reasons to use femoral access (such as imminent deployment of an intra-aortic balloon pump (IABP) [
Stroke in the TOTAL trial: a randomized trial of routine thrombectomy vs. percutaneous coronary intervention alone in ST elevation myocardial infarction.
Unfractionated heparin (UFH) or enoxaparin is indicated in patients undergoing primary PCI. Similarly, substantial data supports the use of glycoprotein IIb/IIIa inhibitors, or alternatively, bivalirudin in primary PCI (refer to Section 5).
4.1.4.3 Aspiration Thrombectomy of Infarct-Related Artery (IRA)
Meta-analysis of several studies of this procedure has shown no reduction in mortality and a small increased risk of stroke with the routine use of thrombo-aspiration of the IRA [
Impact of routine manual aspiration thrombectomy on outcomes of patients undergoing primary percutaneous coronary intervention for acute myocardial infarction: A meta-analysis.
]. Thrombus aspiration can be considered when large thrombus burden impairs achievement of a satisfactory PCI result.
4.1.4.4 IABP for Ongoing Cardiogenic Shock
Routine IABP use in cardiogenic shock complicating STEMI treated by primary PCI has not been shown to reduce 30-day or 6-month mortality and should be avoided.
4.1.4.5 Complete Revascularisation at the Time of Primary PCI
In several small studies, complete revascularisation of all stenosed coronary arteries in patients with multi-vessel disease at the time of primary PCI, rather than IRA stenosis alone, may lessen onset of recurrent ischaemia, although the number of objective late cardiovascular events in these trials was small [
Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial.
4.2 Ongoing Management of Fibrinolytic-Treated Patients
4.2.1 Transfer and Subsequent Angiography Post Fibrinolysis
(a)
Recommendation: Among patients treated with fibrinolytic therapy who are not in a PCI-capable hospital, early or immediate transfer to a PCI-capable hospital for angiography, and PCI if indicated, within 24 hours is recommended. (NHMRC level of evidence (LOE) IIA; GRADE strength of recommendation: Weak).
(b)
Recommendation: Among patients treated with fibrinolytic therapy, for those with ≤50% ST recovery at 60–90 minutes, and/or with haemodynamic instability, immediate transfer for angiography with a view to rescue angioplasty is recommended. (NHMRC level of evidence (LOE) 1B; GRADE strength of recommendation: Strong).
Rationale: Among patients receiving fibrinolysis but who were not in a PCI-capable hospital, immediate or early transfer for angiography, and PCI if indicated, within 24 hours after fibrinolytic therapy is associated with reduced ischaemic events [
Immediate angioplasty versus standard therapy with rescue angioplasty after thrombolysis in the Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI): an open, prospective, randomised, multicentre trial.
]. In a meta-analysis of seven trials of 2,961 patients, no difference in mortality was observed. There was a relative risk reduction in recurrent MI and recurrent ischaemia, (OR 0.55, 95% CI 0.36-0.82) and (OR 0.25, 95%, CI 0.13-0.49). The benefit in recurrent MI persisted to 6-12 months, with no increase in bleeding or stroke risk. However, the benefits may be confounded by ascertainment bias among those having early angiography/PCI [
Early routine percutaneous coronary intervention after fibrinolysis vs. standard therapy in ST-segment elevation myocardial infarction: a meta-analysis.
Among fibrinolytic-treated patients who do not achieve 50% reduction in ST segment elevation at 60–90 minutes after commencement of fibrinolytic therapy, and/or have persistent haemodynamic instability, immediate transfer for angiography with a view to rescue angioplasty is associated with a non-significant reduction in mortality (RR 0.69 [95% CI 0.46-1.05), but a significant reduction in re-infarction (RR 0.58 [95% CI 0.35-0.97) [
Rescue angioplasty or repeat fibrinolysis after failed fibrinolytic therapy for ST-segment myocardial infarction: a meta-analysis of randomized trials.
]. However, stroke was increased five-fold (RR 4.98, 95% CI 1.10-22.5), albeit in an era with predominant femoral access and a significant proportion of patients receiving streptokinase.
Benefits and harms: For the endpoint of recurrent MI, routine early transfer and angiography for patients receiving effective fibrinolysis is estimated to provide a 2.8% absolute reduction in recurrent MI by 6-12 months (NNTB 35) without any increase in bleeding events.
Current data for rescue PCI demonstrates a reduction in recurrent MI but no significant reduction in mortality. Local estimates of re-infarction rates among patients with failed reperfusion are uncertain. While no estimates of absolute benefit are provided, event rates in untreated patients are high.
Resources and other considerations: Systems of care should be developed to achieve these transfer timelines (refer to Figure 4) [
]. Urgent consultation and transfer to centres with higher clinical expertise and interventional facilities should be considered. Systems of care should be developed to provide advice and enable, when appropriate, immediate or early transfer for angiography among fibrinolytic-treated patients who are not in a PCI-capable hospital.
Figure 4Decision-making and timing considerations in reperfusion for STEMI. (Adapted from
European Society of Cardiology (ESC) The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC) ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation.
Among fibrinolytic-treated patients, failed reperfusion is defined as ≤50% ST recovery on an ECG performed at 60-90 minutes. Also ongoing haemodynamic instability, and ongoing ischaemic chest pain are indications for immediate angiography
4.3 Early Invasive Management for NSTEACS
The routine provision of early coronary angiography with subsequent revascularisation (i.e. PCI or CABG as indicated) has been studied in several randomised clinical trials, observational studies and systematic reviews spanning two decades in the context of evolving patient selection criteria, adjunctive pharmacotherapies, and interventional practices. Overall, a net benefit in terms of reduction in late composite endpoints of death, recurrent MI and re-hospitalisation for ischaemia have been observed. However, no reduction in mortality alone has been observed. Patient preferences and goals of therapy, ischaemic and bleeding risk, impacts of other major co-morbidities, and the patient burden of travel from rural and remote settings to tertiary centres all need to be considered in decision-making. The following recommendations allow for latitude according to individual patient circumstances.
4.3.1 Routine Versus Selective Invasive Management for NSTEACS
(a) Recommendation: Among high- and very high-risk patients with NSTEACS (except Type 2 MI), a strategy of angiography with coronary revascularisation (PCI or CABG) where appropriate is recommended. (NHMRC Level of Evidence (LOE): IA; GRADE strength of recommendation: Strong).
(b) Recommendation: Patients with NSTEACS who have no recurrent symptoms and no risk criteria are considered at low risk of ischaemic events, and can be managed with a selective invasive strategy guided by provocative testing for inducible ischaemia (NHMRC Level of Evidence (LOE): IA, GRADE strength of recommendation: Strong).
Rationale: Several meta-analyses and systematic reviews have examined invasive management of NSTEACS [
Long-Term Cardiovascular Mortality After Procedure-Related or Spontaneous Myocardial Infarction in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome: A Collaborative Analysis of Individual Patient Data From the FRISC II, ICTUS, and RITA-3 Trials (FIR).
Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome a meta-analysis of individual patient data.
]. In a Cochrane review of five randomised trials (7,818 participants) performed in the modern stent era, all-cause mortality during initial hospitalisation was associated with a non-significant early hazard with an invasive strategy (RR 1.59, 95% CI 0.96-2.64) with no difference seen on longer-term follow-up (RR 0.90, 95% CI 0.78-1.08). Rates of recurrent MI assessed at 6-12 months (five trials) and 3-5 years (three trials) were significantly decreased by an invasive strategy (RR 0.73, 95% CI 0.62-0.86; and RR 0.78, 95% CI 0.67-0.92 respectively). The incidence of early (< 4 months) and intermediate (6-12 months) refractory angina were also significantly decreased by an invasive strategy (RR 0.47, 95% CI 0.32-0.68; and RR 0.67, 95% CI 0.55-0.83 respectively), as were rates of early and intermediate re-hospitalisation for recurrent ACS (RR 0.60, 95% CI 0.41-0.88; and RR 0.67, 95% CI 0.61-0.74 respectively). The invasive strategy was associated with a two-fold increase in risk of peri-procedural MI (as variably defined) and an increase in risk of bleeding (RR 1.71, 95% CI 1.27-2.31) with no increased risk of stroke [
In another meta-analysis, a routine invasive strategy reduced the composite end-point of death and MI although this benefit was confined to biomarker-positive patients (OR 0.68, 95% CI 0.56-0.82) [
Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction: a meta-analysis.
]. An individual patient data meta-analysis of three randomised trials with long-term follow-up out to five years reported a lower risk of cardiovascular death or MI in favour of a routine invasive strategy (14.7% vs 17.9%; HR 0.81, 95% CI 0.71-0.93), with benefit increasing according to patient risk (absolute risk reduction of 2.0%, 3.8% and 11.1% among low-, intermediate- and high-risk patients respectively) [
Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome a meta-analysis of individual patient data.
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