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Acute Coronary Syndromes

Author: Jason Kendall / Editor: Jason Kendall / Codes: CAP7, HAP8 / Published: 01/01/2014 / Review Date: 01/01/2017

Introduction

(a) Context and Definition

Acute chest pain accounts for approximately 700,000 presentations to the emergency department (ED) per year in England and Wales and for 25% of emergency medical admissions [1]. Chest pain is caused by a spectrum of pathology ranging from the innocent to the extremely serious; amongst the latter are a number of conditions which are potentially catastrophic and can cause death within minutes or hours. The large volume of patients presenting with a potentially serious condition places chest pain at the very core of emergency medicine work.

Emergency physicians are responsible for robustly identifying and treating a significant minority of patients with serious pathologies whilst also avoiding unnecessary investigation and admission for the majority of patients who can be safely discharged. This is a difficult challenge: it has been reported that 6% of patients discharged from a UK emergency department have subsequently been proven to have prognostically significant myocardial damage [2].

Acute coronary syndromes (ACS) encompass a broad range of presentations including unstable angina (UA), non ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). Myocardial infarction is defined pathologically as myocardial cell death following prolonged ischaemia [3].

Myocardial necrosis releases proteins (troponins, myoglobin, creatine kinase, etc.) into the circulation, which can be measured biochemically, and also gives rise to a clinical syndrome with characteristic symptoms and electrocardiographic changes. The criteria for acute, evolving or recent myocardial infarction are as shown in the text below [3]:

Criteria for acute, evolving or recent myocardial infarction [3]

1. Typical rise and fall of biochemical markers of myocardial necrosis with at least one of the following:

  • ischaemic symptoms
  • development of pathological Q waves on the ECG
  • ECG changes indicative of ischaemia (ST segment elevation or depression)
  • coronary artery intervention (e.g. coronary angioplasty)

OR

2. Pathological findings of an acute myocardial infarction.

In the context of cardiac marker rise, ST segment changes on the ECG will define either STEMI or NSTEMI (See Figure 1). At the time of presentation, however, cardiac marker status is unknown and classification of patients presenting with ischaemic chest pain is based largely on the ECG. Most patients with ST elevation at presentation have acute total coronary artery occlusion and progress to STEMI. However, many patients without ST elevation may not have a subsequent cardiac marker rise and are collectively termed Non-ST elevation acute coronary syndromes (NSTE-ACS) until their markers define them as Non-STEMI (marker rise) or UA (no marker rise) [3].

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(b) National/International Guidelines

(c) Pathophysiology

ACS occur when myocardial oxygen demand exceeds circulatory supply. This initially results in ischaemia; prolonged ischaemia results in infarction (myocardial cell necrosis). A reduction in oxygen supply is precipitated by mechanical or inflammatory disruption (rupture or erosion) of an atherosclerotic coronary artery plaque associated with varying degrees of local vasoconstriction, thrombosis and microembolisation. Atherosclerotic plaque disruption initiates thrombosis with platelet activation and platelet aggregation.

Thrombus formation in the context of STEMI is fibrin-rich; it causes coronary artery occlusion leading to myocardial ischaemia and subsequent infarction. This will manifest electrocardiographically as ST segment elevation with a distribution of changes depending upon the coronary artery affected.

Thrombus occurring in the context of NSTE-ACS is platelet-rich; spontaneous thrombolysis and fragmentation into smaller particles release platelet emboli, which may cause small areas of more distal infarction (micro-infarction ) without complete occlusion of the coronary artery. It is the process thought to be occurring in infarction without ST elevation (i.e. NSTEMI).

The thrombotic response to plaque disruption is a dynamic process of thrombosis and thrombolysis, mediator induced vasoconstriction, and varying degrees of platelet aggregation and embolisation (see Figure 2). Which particular process predominates determines the clinical syndrome (i.e. STEMI, NSTEMI or UA), and, in turn, the most appropriate subsequent therapy.

Figure 2: The dynamic pathophysiology of acute coronary syndromes

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(d) Natural history and epidemiology

The incidence of NSTE-ACS is higher than STEMI and it appears that the number of NSTE-ACS relative to STEMI is increasing with time [4]. Hospital mortality from STEMI is greater than that from NSTE-ACS but long term mortality is higher in NSTE-ACS [5]. This is thought to be due to the greater age and higher incidence of comorbidities (e.g. diabetes and renal impairment) in patients with NSTE-ACS.

Outcome from treated STEMI has improved significantly over the last few decades: in-hospital mortality prior to the 1960s was around 30% [4], dropping by the end of the 1980s to just below 20% [5], and currently is generally well under 10%, particularly in the research environment, where 30 day mortality figures as low as 5.4% have been reported [6].

Unfortunately, the overall natural history of AMI is more difficult to assess; the community and pre-hospital mortality of AMI appears to have changed little during the same period [7]. It is estimated that overall mortality from AMI is between 30 and 50% with the majority of deaths occurring within two hours of symptom onset, often prior to seeking or receiving definitive treatment [8]. The above factors have underpinned health education programmes to encourage rapid decision-making on the part of the patient to call for help. However, there is little evidence that public education campaigns reduce patient delay [9].

 

Clinical assessment

(a) History

The classic presenting symptom of ACS is chest pain, which is traditionally described as having a characteristic nature:

  • Heavy, aching or tight
  • Central chest or left sided
  • Not related to respiration or movement
  • May radiate to one or both arms, neck, or jaw

Likelihood ratios have been calculated linking features of the history with AMI [10-12] (see Table 1). Conventionally, a likelihood ratio greater than 10 provides very strong evidence to rule in a diagnosis whilst a ratio less than 0.1 provides very strong evidence to rule it out; ratios greater than 5 and less than 0.2 provide good evidence, and ratios greater than 2 and less than 0.5 provide moderate evidence to rule a diagnosis in or out respectively [13].

Table 1: Value of specific components of the chest pain history for the diagnosis of acute myocardial infarction [10-12]

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Therefore, based on these analyses, the history is a helpful, but not diagnostic, first step in the assessment of patients with chest pain. Specifically, no single factor in the history carries with it a consistently powerful enough likelihood ratio to allow the emergency physician to robustly diagnose ACS or exclude it. The history does, however, form a start point in the diagnostic process, broadly establishing whether pain is likely to be cardiac ischaemic (or not) in origin; it provides information to add to baseline cardiac risk factors (see Table 2) which makes the diagnosis of ACS significantly more or less likely. Ultimately other factors and, in particular, the ECG and cardiac markers, identify those patients with ACS and, specifically, AMI.

Atypical presentations of ACS are common, occurring in up to 33% of patients, mostly in the elderly, diabetics and women [14]. Advanced age, co-morbid factors, delay in diagnosis, delayed or reduced use of reperfusion therapy, and reduced use of adjuvant therapies all contribute to the increased mortality in this population.

Table 2: Risk factors associated with ACS

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(b) Physical Examination

Physical findings associated with ACS are generally non-specific and include pallor, anxiety, sweating, tachycardia and tachypnoea. Generally, specific physical findings are associated with other (not ischaemic cardiac) causes for chest pain or are associated with the complications of acute myocardial infarction (see Table 3).

Table 3: Value of specific components of the physical examination for the diagnosis of acute myocardial infarction [11,12]

image003_5

 

Differential Diagnosis

One of the main purposes of early and rapid assessment of a patient with chest pain is to identify life-threatening conditions and, in particular, to rule-in or rule-out an acute coronary syndrome (ACS).

A thorough description of the pain is the first step in the diagnostic process and will help to make the initial differentiation between cardiac and non-cardiac pain and ischaemic and non-ischaemic pain (See Table 4 and Figure 3). Symptom evaluation will include a description of the character of the pain, the location, severity and radiation of the pain, onset and duration of the pain, relieving and aggravating factors, and associated symptoms. Other important features of the history will include risk factor determination, previous episodes and relevant past medical history.

Table 4: Descriptions of pain

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Figure 3: Differential diagnosis of patients presenting with chest pain

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Investigation Strategies

(a)Electrocardiography

Broadly speaking, the ECG will directly determine whether a patients further management follows:

  • An immediate fibrinoytic or mechanical reperfusion strategy (i.e. ST elevation)
  • An anti-thrombotic and anti-platelet strategy (ST depression or T wave inversion)
  • A rule out strategy (normal ECG)

The following ECG changes are indicative of myocardial ischaemia that may progress to AMI [3]:

  • Patients with ST segment elevation in two or more contiguous leads (greater than 0.2mV in leads V1, V2, or V3 and greater than 0.1mV in other leads)
  • Patients with ST segment depression
  • Patients with T wave abnormalities only

Table 5 presents the likelihood ratios for the association of various ECG changes and AMI [11,12].

Table 5: Value of specific components of the ECG for the diagnosis of acute myocardial infarction [11,12]

image005_4

(i) ST-segment elevation (see Figures 4 and 5):

The presence of ST segment elevation, new Q wave formation, or a new conduction deficit (eg. left bundle branch block) in the context of acute ischaemic chest pain is associated with such significantly positive likelihood ratios for AMI (see Table 5) that the diagnosis can usually be made with confidence and appropriate therapy commenced.

However, the ECG by itself cannot define AMI, which also requires the demonstration of a cardiac marker rise. There are situations where this injury pattern (i.e. ST segment elevation) does not necessarily indicate that myocardial necrosis has or will occur:

  • Aborted myocardial infarction where early reperfusion has occurred [15]
  • Coronary artery vasospasm with spontaneous resolution.

ST segment elevation will typically be found in a territorial distribution on the ECG that reflects, and is determined by, coronary artery anatomy (see Figures 4 and 5).

Figure 4: Acute inferior myocardial infarction

image011_2

Note: ST segment elevation in the inferior leads (II, III, and aVF) with reciprocal ST segment depression in the anterior leads (V1, V2, V3), possibly representing posterior extension of the infarct.

Figure 5: Acute anterior myocardial infarction

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Note: ST segment elevation across the anterior leads (V1 to V4) with reciprocal ST segment depression in the inferior leads (II, III, and aVF).

(ii) ST-segment depression / T wave changes (see Figure 6):

The presence of ST segment depression and/or T wave changes (see Figure 6) in the context of acute ischaemic chest pain normally indicates myocardial ischaemia (i.e. unstable angina) but is also associated with a positive likelihood ratio for AMI (i.e. NSTEMI see Table 5). Approximately 50% of patients with ST depression and 33% of patients with T wave inversion will subsequently be shown to have myocardial infarction [2,16]. This group of patients are presenting with an ACS (i.e. UA or NSTEMI).

Figure 6: Acute coronary syndrome with ST depression and T wave inversion

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Note: ST segment depression most evident in lateral leads (V4-V6, I, aVL) and T wave inversion in inferior leads (II, III and aVF).

(iii) Additional chest leads

Additional chest leads are required if posterior (V7, V8, V9) or right sided (V4R) infarction is suspected following a standard (12 lead) ECG specifically in:

  • Patients with inferior ST segment elevation because the majority of right sided and posterior infarcts occur as extensions of inferior infarcts. This may affect management patients with right sided myocardial infarction and hypotension may respond to fluid resuscitation.
  • Patients with anteroseptal ST segment depression (indicating ischaemia) because this may be masking true posterior infarction; this will, if demonstrated, affect immediate treatment.

Figure 7: Acute inferior myocardial infarction (standard 12 lead ECG)

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Note: ST segment elevation in the inferior leads with reciprocal changes in the anteroseptal leads (V1-3)

Figure 8: Posterior ST elevation confirming posterior extension of infarct (additional leads)

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Note: ST segment elevation in the posterior leads (V7-9) in the same patient as Figure 7

(iv) What about left bundle branch block (see Figures 9 and 10)?
Patients with ischaemic cardiac chest pain and left bundle branch block (LBBB) should be assumed to be having an AMI and should be considered for immediate reperfusion therapy, since they have been shown to have amongst the highest mortality of patients with AMI, and also gain the greatest benefit from thrombolysis [17,18].

ECG criteria have been identified that have good specificity (but poor sensitivity) for AMI in patients with LBBB [19,20] (see below and Figures 9 and 10):

ECG criteria suggesting AMI in LBBB

  • ST elevation >1mm in leads where the QRS complex is predominantly positive (i.e. V5, V6)
  • ST depression >1mm in leads where the QRS complex is predominantly negative (i.e. V1, V2, V3)
  • ST elevation >5mm in leads where the QRS complex is predominantly negative (i.e. V1, V2, V3)

Figure 9: Left Bundle Branch Block pattern

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Note: T waves are discordant with the QRS complexes; this is a standard LBBB morphology

Figure 10: Left Bundle Branch Block pattern with features suggestive of acute infarction

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Note: ST segment elevation >1mm in leads where the QRS complex is predominantly positive (i.e. V5, V6)

(v) The Normal ECG:

A normal ECG reduces the probability of AMI [11,12]. It does not, however, reduce this probability enough to allow confident safe discharge based upon the history and ECG alone [2]. Therefore, patients who present with chest pain in whom cardiac ischaemia is suspected and who have a normal ECG should undergo further diagnostic testing (i.e. delayed cardiac markers, exercise testing etc.) before they can be confidently ascribed to a low risk group.

(b) Biochemical markers of myocardial necrosis

Troponins are currently the preferred and recommended markers of myocardial necrosis in the setting of ACS [2,21] because they are more sensitive and specific than CK-MB [22].

The timing of the troponin assay is of great importance: it needs to be delayed for 6 to 12 hours post onset of symptoms in order to safely assign a patient with a normal or non-diagnostic ECG to a low risk status [2,23]. In patients with an ECG suggestive of NSTEMI or UA, troponin assay can be performed at presentation since it will determine the diagnosis, forms part of initial risk stratification, and influences early treatment strategies [3]. Patients with ST elevation do not require urgent troponin assay since their initial treatment strategy is determined by their clinical presentation and ECG findings.

Troponin levels rise within 12 hours of AMI and remain elevated for up to 2 weeks: this prolonged period of elevation may mask episodes of early re-infarction. Serial assays of CK-MB, which rise and fall over a shorter time scale, may be useful in detecting re-infarction in these instances.

Troponins can also be elevated in non-ischaemic cardiac injury [24] or in conditions where secondary cardiac ischaemia occurs [25] and also in renal impairment (see below) [26].

Causes of troponin elevation other than ACS:

  • myocarditis
  • cardiac contusion
  • severe congestive cardiac failure
  • pulmonary embolism
  • thoracic aortic dissection
  • shock of any cause
  • renal impairment

(c) Risk stratification

In contrast to patients with STEMI, risk stratification in patients with NSTE-ACS not only determines prognosis but also directly influences early treatment options. Patients with STEMI are identified quickly, assigned a high short term risk and have a well-defined treatment strategy (ie. urgent reperfusion).

Patients with NSTE-ACS, however, are a heterogeneous population with varying degrees of atherosclerotic disease and thrombotic risk and, therefore, varying death and recurrent cardiac event rates. In order to select the most appropriate treatment, early and repeated risk stratification should be performed since the benefit from certain aggressive treatment strategies is related to risk the higher the risk, the greater the benefit.

The National Institute of Health and Clinical Excellence (NICE) recommends that risk assessment should be performed as soon as a clinical diagnosis of ACS is made [27]. It must be based upon readily available clinical and laboratory information, should be user-friendly, appropriately validated, and reproducible between observers. Several risk stratification scores are available and are based on clinical history, ECG findings and cardiac markers [28-30]. One of the most widely used is the Thrombolysis in Myocardial Infarction (TIMI) risk score (see below). It was designed, developed and validated in cohorts of patients with ACS [31-33]. The GRACE score [34] also uses accessible factors but is slightly more complicated to use than the TIMI risk score and requires computer software or a nomogram. The GRACE score is recmommended by NICE and is being increasingly adopted in the UK.

The TIMI risk score is composed of seven independent predictor variables, each carrying a similar prognostic weight (see below); the risk score is calculated as a simple arithmetic sum of the number of predictors that apply to an individual patient. The higher the score, the higher the adverse event rate [28].

Table 6: The components of the TIMI Risk score:

Age > 65 1
3 or more CAD risk factors: (FHx, HTN, Hyperchol, DM, active smoker) 1
Known CAD 1
Aspirin use in past 7 days 1
Recent (<24 hrs) severe angina 1
Increased cardiac marker 1
ST deviation >0.5mm 1
Risk Score = Total Points 7

The TIMI risk score can also identify patients that will benefit from certain interventions (e.g. glycoprotein IIb/IIIa (GpIIb/IIIa) Inhibitors and early percutaneous coronary intervention): the higher the risk, the greater the benefit from these interventions [33].

The GRACE Score

NICE recommends the GRACE Score for risk stratification because it is based on a very large (and growing) cohort of registry patients and gives robust mortality figures. The GRACE score uses a computer-based nomogram to predict various outcomes including 6 month mortality in patients with ACS (see Figure 11). The parameters are entered into the risk tool and the mortality figures are calculated by the nomogram. It is slightly less convenient to use in the ED than the TIMI score because it requires two blood assay results to complete the assessment (creatinine and troponin) and a computer to generate the risk.

GRACE_score

The predicted 6 month mortality expressed as a percentage is then stratified into a level of risk (see below):

1.5% or below Lowest

>1.5 3% Low

>3% 6% Intermediate

>6% 9% High

Over 9% Highest

Treatment strategies (pharmacological and mechanical) are then recommended by NICE based on the level of risk as determined by GRACE (see later in session).

 

Management

(a) General Measures

ACS are essentially due to an imbalance between coronary supply and myocardial demand of oxygen and nutrients; therapy (pharmacological and interventional) is aimed at redressing this imbalance. Pharmacological treatment can be divided into anti-thrombotic and anti-ischaemic: anti-thrombotic agents inhibit intracoronary thrombosis through effects on the clotting cascade or via anti-platelet mechanisms. Anti-ischaemic agents decrease myocardial oxygen demand through negative inotropic or chronotropic actions or through vasodilation.

Before treatments specifically tailored to patients with ACS are considered further, it is important to administer initial interventions to all patients presenting with ischaemic sounding cardiac pain. Specifically, these include the delivery of supplemental oxygen (if oxygen saturations are reduced below 94%), the relief of pain and anxiety, and the administration of aspirin and GTN. Pain and anxiety contribute to sympathetic over-activity which, in turn, causes vasoconstriction and increases workload of the heart. Therefore, the relief of pain and anxiety is physiologically beneficial in the setting of ACS. Intravenous opiates (diamorphine or morphine) are the drugs of choice.

Recurrent pain despite the use of opiates may respond to beta-blockers or further nitrates. These measures, and the administration of aspirin, should be instituted promptly to patients with ischaemic sounding chest pain whilst risk stratification and specific reperfusion strategies are considered.

(b) Specific therapies STEMI

The priority of early therapy is to establish reperfusion in the affected myocardium. Current alternatives to achieve this goal are mechanical (primary percutaneous coronary intervention (PPCI) [35] or pharmacological (thrombolysis [36,37].

Early Reperfusion Primary PCI

Primary Percutaneous Coronary Intervention (PPCI) is defined as angioplasty or stenting without prior or concomitant thrombolytic therapy. PPCI is effective in achieving and maintaining coronary artery patency without exposing the patient to the increased bleeding risks of thrombolysis. In the UK PPCI has become the favoured option and systems are evolving to develop an exclusively PPCI-based approach to reperfusion for STEMI.

There is robust evidence for the superiority of PPCI over in-hospital thrombolysis [38], with better short-term mortality, reduced re-infarction rates and a lower incidence of stroke. However, there is no robust evidence of superiority of PPCI over PHT [39,40]. The benefits of PPCI over thrombolysis are unequivocal in patients presenting later during the course of their event (symptom onset greater than 3 hours) [38] but are unproven early in the course of STEMI, and especially within the first two hours after symptom onset. In relation to the delay to PPCI when compared to thrombolysis (the balloon time minus the needle time ), any potential benefit from PPCI may become harm when a period of somewhere between one and two hours is exceeded [41], irrespective of the time of onset of symptoms. PPCI is the preferred option in patients presenting with cardiogenic shock irrespective of time of onset of symptoms [42] and in those patients with a contra-indication to thrombolysis. The nature of UK geography and the way that ambulance services are organised means that the vast majority of patients (approximately 95%) are suitable for PPCI based on these time criteria. There may still be some remote areas within the UK where thrombolysis (or, more specifically, pre-hospital thrombolysis) is the only reperfusion strategy which can be delivered in a timely manner.

Summary: Guidance from the National Institute of Health and Clinical Excellence (NICE) [43], the AHA/ACC and ESC [5,14]

Guidance from NICE [43]:

  • Offer coronary angiography, with follow-on primary PCI if indicated, as thepreferred coronary reperfusion strategy for people with acute STEMI if: presentation is within 12 hours of onset of symptoms and primary PCI can be delivered within 120 minutes of the time when fibrinolysis could have been given
  • Offer fibrinolysis to people with acute STEMI presenting within 12 hours of onset of symptoms if primary PCI cannot be delivered within 120 minutes of the time when fibrinolysis could have been given

Guidance from the AHA/ACC [44] and the ESC [45]:

PPCI is generally preferred:

  • If a skilled PCI laboratory is available: i.e. time from first medical contact to balloon inflation should be less than 2 hours in any case and less than 90 minutes in early presenters (<2 hours post onset of symptoms)
  • In patients with cardiogenic shock or a contraindication to thrombolysis

Thrombolysis is generally preferred:

  • Where there will be a delay to invasive strategy: i.e. when PCI is not available within 2 hours from first medical contact in any case or less than 90 minutes in early presenters (<2 hours post onset of symptoms)

Early reperfusion Thrombolysis

There is a non-linear relationship between time delay and outcome following thrombolysis, with much greater benefit in patients with short symptom onset to treatment times [46]: up to 60 deaths per thousand treated are prevented if thrombolysis is delivered within one hour of onset of symptoms. The clear relationship between delay to treatment and reduced benefit has been the rationale for the implementation of pre-hospital thrombolysis (PHT). The evidence comparing in-hospital thrombolysis with PHT demonstrates clear superiority of PHT in reducing mortality [47]; widespread implementation of PHT has led to significantly improved performance against National Service Framework standards (call-to-needle and door-to-needle times) [48]. Bolus agents (reteplase or tenecteplase) are most suitable for the pre-hospital environment.

The main hazard of thrombolysis is haemorrhage and, in particular, intracranial haemorrhage. There is an excess of 3.9 cerebral events per 1000 patients treated [49], the risk being maximal during the 24 hours immediately following thrombolysis. Specific risk factors for intracranial haemorrhage include female gender, advanced age, low body weight and elevated blood pressure at presentation.

Table 7 lists the conventional contra-indications to thrombolysis. Advanced age is not, in itself, a contra-indication to thrombolysis. Whilst there is an increased risk of intracranial haemorrhage associated with thrombolysis in the elderly, overall mortality is significantly reduced by thrombolytic therapy in patients over the age of 75 years who present within 12 hours of onset of symptoms [49].

Table 7: Contraindications to thrombolysis

Absolute contraindications Relative contraindications
  • Haemorrhagic stroke at any time
  • Ischaemic stroke within 6 months
  • Recent major surgery (within 3 weeks)
  • Recent major trauma / head injury (within 3 weeks)
  • Recent gastrointestinal bleeding (within 1 month)
  • Aortic dissection
  • Known bleeding disorder
  • Neurological deficit or central nervous system neoplasm
  • Warfarin therapy (check INR)
  • Pregnancy or immediate post-partum period
  • Transient ischaemic attack in preceding 6 months
  • Prolonged or traumatic resuscitation
  • Systolic blood pressure > 180 mmHg
  • Active peptic ulcer, advanced hepatic disease
  • Non-compressible puncture site
  • Infective endocarditis

The main limitation of thrombolysis is failure to reperfuse (defined by lack of resolution of ST segment elevation 90 minutes after thrombolytic administration). This is estimated to occur in up to 30% of patients. These patients should be referred for Rescue PCI (PCI performed on a coronary artery that has remained occluded despite thrombolysis) [50].

Thrombolysis, even if successful at achieving early reperfusion, should not be considered the definitive treatment pre-discharge angiography (within 6-24 hours of thrombolysis) results in improved outcome and is recommended by the European Society of Cardiology: Lyse now, stent later [51-53].

This should not be confused with Facilitated PCI which is when PCI is performed immediately after thrombolytic therapy; there is no robust evidence to support this strategy in routine clinical practice [38,54].

Dilemma: Should you thrombolyse a patient on warfarin?

This is a difficult question to which there is no evidence-based answer. By the very nature of the pathophysiology of ACS, it is unusual for patients who are on warfarin therapy to have an occlusive coronary event. Clearly, the concern is that, following thrombolysis, these patients will be at increased risk of bleeding and, in particular, of intracranial haemorrhage. One could argue, however, that, in presenting with a STEMI, they need anti-thrombotic / thrombolytic treatment even more because they have broken through their anticoagulation.

This situation will, as always, need to be dealt with on an individual patient basis balancing risks and benefits. However, in these cases, an urgent INR will help to inform the decision within a reasonable time frame (i.e. within 20 minutes). A sub-therapeutic INR (e.g. <2.0) would tend to favour administration of thrombolysis, particularly where the potential for benefit is great (e.g. anterior STEMI with an early presentation). Cases where the INR is above the therapeutic range (e.g. >3.0) would contraindicate thrombolysis irrespective of the potential benefit because the risk of intracranial haemorrhage is likely to be much higher. Where the INR is therapeutic (e.g. 2.0 3.0) the decision will have to be made based on likely benefit (territory of infarct, timing of presentation) balanced against risk of haemorrhage (advanced age, female gender, low body mass index).

Other approaches to treatment should also be considered: antiplatelet treatment should be given (i.e. aspirin) and, if it is available, PPCI will be a better alternative to thrombolysis in these patients.

Adjunctive Anti-thrombotic Therapy

(i) Aspirin

Aspirin irreversibly acetylates platelet cyclooxygenase and therefore inhibits platelet aggregation; it is also an indirect antithrombotic agent. Aspirin is the most cost-effective treatment available for patients with AMI (indeed, with any ACS) and should be administered early in all patients with ischaemic cardiac chest pain who do not have known allergy or active gastro-intestinal bleeding. Aspirin should be given in a dose between 150 and 325 mg, and continued indefinitely at a daily dose of between 75 and 150mg [55].

(ii) Clopidogrel

Clopidogrel is also an anti-platelet agent; it promotes formation of platelet c-AMP, lowering platelet calcium and reducing platelet aggregation. It also prevents the transformation of the glycoprotein IIB/IIIA receptor into its high affinity state, further reducing platelet aggregation. Two recent trials have reported the beneficial effects of clopidogrel in patients with STEMI: patients receiving clopidogrel, in addition to thrombolysis, aspirin and heparin, had a significantly reduced incidence of adverse events at 30 days [56,57].

(iii) Prasugrel

Prasugrel is, like clopidogrel, an oral anti-platelet agent and acts in a similar way to clopidogrel but with a faster onset of action. It has recently undergone a NICE Technology Appraisal which has recommended its use alongside aspirin as an alternative to clopidogrel in patients with STEMI undergoing PPCI [58].

Learning Bite

Prasugrel has become the preferred option over clopidogrel in patients receiving PPCI for STEMI.

(iv) Ticagrelor

Ticagrelor is another novel oral anti-platelet agent which is an antagonist to the P2Y12 ADP receptor and, co-administered with aspirin, is indicated in the management of patients with acute coronary syndromes. It has also recently undergone a NICE Technology Appraisal which has recommended its use in combination with aspirin as an alternative to clopidogrel in patients with STEMI undergoing PPCI [59]. Ticagrelor is being increasingly adopted instead of clopidogrel in STEMI patients undergoing PPCI who are unsuitable for prasugrel.

(v) Heparin

Unfractionated heparin (UH) inhibits clot formation by preventing the conversion of fibrinogen to fibrin. Low Molecular Weight Heparins (LMWH) inhibit the coagulation system in a similar way and also bind to Factor Xa which is resistant to inactivation by UH. LMWH also has a longer half-life, less individual variability of the anticoagulant response, more predictable kinetics and less platelet activation than UH. These agents do not enhance immediate clot lysis, but prevent re-occlusion following thrombolysis [60].

A recent direct comparison of UH and the LMWH enoxaparin in patients with STEMI receiving in-hospital thrombolysis reported improved outcome at 30 days in the enoxaparin group [61]. Indeed, one of the lowest 30 day mortality rates of recent trials (5.4%) was reported using the combination of thrombolysis and enoxaparin [62]. However, there have been concerns of increased intracranial haemorrhage in the elderly with this regime used in the pre-hospital setting [63].

With the increased use of PPCI and the emergence of the newer anti-thrombotic agents discussed above, heparins are used much less frequently as anti-thrombotic agents in the initial management of STEMI.

(vi) Fondaparinux

Fondaparinux is a selective Factor Xa Inhibitor that has recently been evaluated in the setting of STEMI: it was found to be associated with reduced mortality and reduced re-infarction when compared to UH or placebo [64]. It is indicated in patients who are managed initially with thrombolytics or who have no specific reperfusion therapy. It is not indicated in patients undergoing PPCI. It has a long half-life and is given once daily.

(vii) Glycoprotein IIB/IIIA Inhibitors

Clinical studies have not reported improved outcome with these agents as adjuvant therapy with thrombolysis in the setting of STEMI [62,65] and there is, therefore, no role for GpIIB/IIIA inhibitors in this context routine clinical practice.

(c) Specific therapies NSTEMI and UA

Anti-thrombotic agents

(i) Aspirin

Aspirin inhibits platelet aggregation by inhibiting cyclo-oxygenase and thus the formation of thromboxane A2. Consistent with the benefit seen in patients with STEMI, aspirin is unequivocally associated with short term and long term benefit in patients with all forms of ACS [66].

Accordingly, aspirin is recommended as part of the anti-thrombotic regime in all published guidelines for ACS management; it should be commenced (in the absence of contra-indications) at presentation of the patient to emergency services and continued long term (indefinitely) at a daily dose of 75-150 mgs.

(ii) Clopidogrel

Clopidogrel promotes formation of platelet c-AMP, lowering platelet calcium, and reducing platelet aggregation.

In addition to conventional therapy (aspirin, heparin and/or glycoprotein inhibitors), clopidogrel (300mgs immediately followed by 75mgs daily) results in a significant reduction in death and non-fatal MI [67] at the expense of an increase in major (but not life-threatening) bleeding but no increase in haemorrhagic stroke. This net benefit is consistent in low (TIMI risk score 0-2), intermediate (score 3-4) and high (score 5-7) risk patients supporting its use in all patients with non-ST elevation ACS [68]. NICE recommends that clopidogrel is administered to patients with a GRACE 6 month predicted mortality of >1.5% (ie. all but the lowest risk patients).

NICE Guidance (2010) recommends that clopidogrel is continued for 12 months [69].

(iii) Ticagrelor

Ticagrelor is another novel oral anti-platelet agent which is an antagonist to the P2Y12 ADP receptor and, co-administered with aspirin, is indicated in the management of patients with acute coronary syndromes. It has also recently undergone a NICE Technology Appraisal which has recommended its use in combination with aspirin as an alternative to clopidogrel in patients with confirmed non-STEMI and in selected patients with unstable angina in whom the diagnosis has been confirmed by a cardiologist [59].

(iv) Heparin

Unfractionated Heparin (UH) inhibits thrombin formation within the clotting cascade, thus preventing the conversion of fibrinogen to fibrin and subsequent clot formation. It needs to be administered at a weight-adjusted dose by intravenous infusion and has a fairly narrow therapeutic window requiring repeated monitoring of the aPTT.

Low Molecular Weight Heparin (LMWH) inhibits the coagulation system in a similar way but also binds to Factor Xa (which is resistant to inactivation by UH). LMWH also has a longer half-life, less individual variability of the anticoagulant response, more predictable kinetics and less platelet activation than UH.

UH has been included in ESC Guidelines for the management of UA and Non-STEMI, despite the lack of robust evidence for clinical benefit when co-administered with aspirin. In contrast to UH, a trial of the LMWH dalteparin vs placebo in aspirin treated-patients reported a significant reduction in the composite end point of death and recurrent MI in the LMWH group [70].

The benefit of heparin in UA and Non-STEMI appears intuitively consistent with heparins role in STEMI and the debate has moved on to determining which form of heparin should be used (i.e. UH or LMWH) rather than whether heparin (of any kind) should be used at all. Recent trials comparing the LMWH enoxaparin with UH have demonstrated significantly improved outcome in favour of enoxparin [71].

(v) Fondaparinux

Fondaparinux is a selective Factor Xa Inhibitor that has recently been studied in the context of UA and NSTEMI; compared to enoxaparin, there was no significant difference in death, MI or refractory ischaemia at 9 days but there were significantly less bleeding complications associated with fondaparinux [72]. There was an overall net clinical benefit associated with fondaparinux which extended to 6 months.

It is currently indicated for the treatment of UA and NSTEMI in patients for whom urgent (<120 minutes) PCI is not indicated. NICE and the ESC recommend fondaparinux over heparin for the treatment of ACS in the non-urgent setting (ie when a decision between an early invasive and a pharmacological strategy is still pending) because of its more favourable efficacy/safety profile [2,69].

(vi) Glycoprotein IIb/IIIa Receptor Inhibitors

Glycoprotein IIb/IIIa (GpIIb/IIIa) receptor cross-linking is the final common pathway of platelet activation and adhesion. Platelet activation results in the presentation of GpIIb/IIIa receptors on the surface of the platelet which allow binding of fibrin, cross-linking of platelets, and hence subsequent platelet aggregation. In theory, inhibition of these receptors should provide the most effective anti-platelet activity, even more so than aspirin or clopidogrel.

Several GpIIb/IIIa receptor inhibitors have been developed and tested in the context of ACS. There is little controversy about the concomitant use of GpIIb/IIIa receptor inhibitors in patients with NSTE-ACS undergoing percutaneous coronary intervention (PCI): they reduce peri-procedural thrombotic complications and composite adverse outcomes (death, target vessel re-vascularisation and re-infarction) [73-75].

Dilemma: What about the patient not routinely scheduled for PCI?

The picture is less clear in patients with NSTE-ACS who are not being routinely referred for PCI. Studies evaluating GpIIb/IIIa receptor inhibitors in this context have appeared inconsistent and open to differing interpretations [76-82], resulting in limited implementation of this therapy within the UK. Some trials [76,78,81] report clear benefit (reduced 30 day cardiac event rate) associated with GpIIb/IIIa receptor inhibitors whilst others do not [77,79,80,82].

There is significant heterogeneity between these trials in terms of:

  • Entry criteria with certain trials clearly recruiting a higher risk population
  • Referral rates for PCI
  • Specific GpIIb/IIIa receptor inhibitor evaluated

This heterogeneity may explain the inconsistent findings: specifically, the trials which recruited higher risk patients and which had higher referral rates for PCI reported significant benefit [76,78,81]. There also seems to be an agent specific effect, with no benefit reported in trials evaluating lamifiban [79,80] or abciximab [82].

It is known that GpIIB/IIIA receptor inhibitors are associated with benefit in patients referred for PCI (see above) and it seems that benefit is also associated with higher risk. Indeed, meta-analysis of trials where referral for PCI was not part of the routine therapeutic strategy reported that benefit occurs, but is restricted to higher risk patients (eg positive troponin, diabetic, high TIMI Score or GRACE 6 month mortality >3%) [83] and people with diabetes [84].

Learning Bite

NICE recommend the use of small molecule GpIIb/IIIa receptor inhibitors (tirofiban or eptifibatide) in patients presenting with NSTE-ACS who are at higher risk even where early PCI is not planned [69].

Anti-ischaemic agents

(i) Nitrates

Nitrates provide symptomatic benefit to patients with ischaemic chest pain as a consequence of their systemic and coronary vasodilatory effects.

Despite the unequivocal improvement in symptoms that is associated with nitrate use, there is no evidence of improvement in outcome (in terms of reduced cardiac events or mortality). Small trials have compared routes of administration of nitrates (intravenous, oral, and buccal) but have reported no significant benefit of one route over another [86,87].

The ESC Guidelines suggest that patients with NSTE-ACS who require admission may be commenced on intravenous nitrates in the absence of contraindications. It is common practice within the UK to commence intravenous nitrates on patients with ongoing ischaemic chest pain despite initial therapy (i.e. aspirin, opiates, buccal GTN, and oxygen) providing that the patient is not significantly hypotensive.

(ii) Beta-blockers

Beta-blockers reduce myocardial oxygen demand by reducing cardiac contractility and cardiac rate through their effects on beta-adrenergic receptors in the myocardium, the sino-atrial node and the atrio-ventricular node. Essentially, they inhibit the effects of circulating catecholamines.

Studies evaluating beta-blockers in this setting are now fairly dated, but pooled data demonstrate a reduction in progression to myocardial infarction of 13% [88]. No definitive reduction in mortality has been demonstrated with beta-blocker use in NSTE-ACS but, given their proven mortality benefit in STEMI, plus reduced progression to infarction in UA and Non-STEMI, it seems unlikely that it would ever be ethical to withhold beta blockers in any future scientific evaluation.

Beta-blockers should be used in patients with NSTE-ACS in the absence of contraindications (e.g. acute left ventricular failure, hypotension, bradycardia). There is no preference in terms of route of administration (i.e. intravenous or oral), although the intravenous route may be preferred if the patient is acutely hypertensive or is vomiting. The most commonly used beta-blockers in the UK are atenolol (12.5 50mgs oral, 1-5mgs intravenous), metoprolol (50-100mgs oral, 1-5mgs intravenous) or Bisoprolol (2.5 10mgs orally).

(iii) Calcium channel blockers

Calcium channel blockers have three physiological effects:

  • vasodilation
  • reduced myocardial contractility
  • reduced heart rate (via delayed atrio-ventricular conduction)

Like beta blockers, the trials evaluating calcium channel blockers are dated and report no significant mortality benefit [89]. Meta-analysis of pooled data demonstrates that calcium channel blockers are neither associated with a reduced progression to infarction nor a reduced mortality [90]. They may have a role in selected patients who have a contraindication to beta blockers.

 

Coronary angiography defines the anatomy of, and pathology within, the coronary artery vasculature. Findings at coronary angiography will determine the nature of any subsequent revascularisation strategy: either PCI or CABG.

Unstable patients with NSTE-ACS who have severe refractory angina, dynamic ECG changes, significant arrhythmias or haemodynamic instability should be treated with maximal medical therapy and referred for urgent angiography [91].

In patients with NSTE-ACS who are not unstable, evidence from trials comparing a routine early invasive approach with a conservative pharmacological or ischaemia-driven approach have yielded conflicting results. Most trials and contemporary meta-analyses demonstrate improved outcome with an early invasive approach [92-95]. However, a recent trial was unable to demonstrate that an early invasive strategy was superior to optimised medical therapy [95]. Furthermore, it appears that benefit from early angiography seems to be limited to patients with elevated troponins and/or who have a high TIMI risk score [92] or an intermediate or high GRACE Score [69]. NICE recommends that angiography for these patients should occur within 96 hours of first admission.

Patients undergoing PCI should receive intravenous Gp IIb/IIIa inhibitors in addition to aspirin heparin and clopidogrel.

A Guideline for the Initial Management of Patients with NSTE-ACS is shown below:

Figure 12: Initial risk assessment and management of ACS according to GRACE score as suggested by NICE Guidelines (2010) [69]:

NICE_guideline_2010_ACS_management

Mechanical Revascularisation

(d) Complications of ACS and their management

Pulmonary oedema:

Left ventricular failure associated with pulmonary oedema presents with increasing breathlessness, reduced arterial oxygen saturations, tachycardia, a third heart sound and pulmonary crepitations. Clinical examination should be directed to exclude other complications as causes of heart failure (arrythmias and valvular abnormalities). Chest X-Ray will confirm pulmonary congestion, and echocardiography may quantify mechanical left ventricular function (ventricular wall akinesis, reduced ejection fraction, etc.).

Treatment consists of measures to treat the underlying ACS (i.e. reperfusion if appropriate) and specific therapies for left ventricular failure and pulmonary odema: diuretics, intravenous nitrates, non-invasive ventilatory support, ACE inhibitors and, where appropriate, tracheal intubation.

Cardiogenic Shock:

(i) Left ventricular dysfunction:

Cardiogenic shock as a consequence of left ventricular dysfunction is an ominous complication of STEMI and indicates significant myocardial damage. It usually occurs as a consequence of anterior AMI, or in the presence of LBBB. It is characterised by systemic hypoperfusion (tachycardia, reduced systolic blood pressure, cool peripheries and reduced renal output), associated with adequate central venous filling pressures. Clinical assessment should aim to exclude other causes of hypotension (hypovolaemia, arrythmias, drug related side effects, right ventricular infarction and mechanical complications of STEMI).

The most effective treatment for cardiogenic shock is early and effective myocardial reperfusion: for these patients PPCI, if available, is superior to thrombolysis [96]. In addition to reperfusion, specific measures to treat hypotension may be required (eg. the use of inotropes and/or an intra-aortic balloon pump), particularly where there is evidence of poor cerebral or renal perfusion.

(ii) Right Ventricular Dysfunction:

Infarction of the right ventricle is normally associated with inferior infarction, but may occur in isolation. Patients present with hypotension and distended neck veins, but without signs of pulmonary odema. This clinical picture in the setting of inferior infarction should prompt the recording of a right sided chest lead (V4R) which may confirm ST elevation. Echocardiography demonstrates varying degrees of right ventricular myocardial wall dysfunction and/or functional tricuspid incompetence due to ventricular dilatation.

It is important to recognise hypotension due to right ventricular infarction because its management is significantly different to that for cardiogenic shock resulting from left ventricular dysfunction. In particular, it is vital to maintain right ventricular preload: the use of drugs that reduce preload (such as nitrates and opiates) can cause significant reductions in blood pressure. A fluid challenge is effective in maintaining venous return, and should be administered alongside careful haemodynamic monitoring. Rapid reperfusion is also necessary in order to improve the haemodynamic state.

Mechanical Complications:

(i) Mitral Regurgitation:

Mitral regurgitation is the commonest mechanical complication of STEMI. Patients develop signs of acute cardiac failure (associated with both pulmonary odema and hypotension). The underlying pathological causes of acute mitral regurgitation in this setting are chordal rupture, papillary muscle infarction and rupture, or functional regurgitation due to dilatation of the mitral valve ring associated with left ventricular dilatation. Clinical signs of sudden haemodynamic deterioration associated with a new murmur are suggestive of mitral regurgitation. Echocardiography confirms the diagnosis and distinguishes mitral regurgitation from ventricular septal rupture (see below). Definitive treatment of this complication requires urgent surgery and reperfusion of the infarct related coronary artery. In the meantime, treatment is aimed at controlling pulmonary odema and supporting the circulation.

(ii)Ventricular Septal Rupture:

This complication occurs most commonly with anterior or posterior AMI. The clinical presentation is similar to mitral regurgitation with haemodynamic compromise and a pan-systolic murmur. Echocardiography is required to distinguish between these two conditions. Definitive treatment requires urgent surgery to repair the defect, with interim measures to support the circulation, and reperfusion of the infarct related coronary artery.

(iii) Cardiac Rupture and Tamponade:

Acute cardiac wall rupture is a cause of sudden death following AMI, and is more common in the elderly [97]. In subacute cardiac rupture the pericardium contains the blood loss from myocardial rupture and a tamponade develops. There is sudden haemodynamic deterioration with signs of a cardiac tamponade: hypotension, distended neck veins and muffled heart sounds. Diagnosis is confirmed by echocardiography and, whilst pericardiocentesis may temporarily improve the haemodynamic state, definitive management requires urgent surgery.

Arrythmias and Conduction Disturbances:

Clinical assessment of an arrythmia should attempt to identify and correct reversible underlying causes (e.g. hypoxia, continuing ischaemia, acidosis, hypothermia, electrolyte disturbance, etc.), as well as quantify the haemodynamic consequences of the arrhythmia. The urgency of treatment depends upon the haemodynamic state of the patient.

(i) Ventricular arrythmias:

Ventricular fibrillation accounts for the majority of pre-hospital sudden deaths in patients suffering AMI. Treatment for ventricular fibrillation or pulseless ventricular tacycardia requires immediate defibrillation in accordance with current resuscitation guidelines [98]. Ventricular tachycardia without significant haemodynamic compromise may require treatment with amiodarone or lignocaine or, if haemodynamic compromise is significant, synchronised electrical cardioversion.

An accelerated idioventricular rhythm, which may resemble ventricular tachycardia, is an innocent finding that occurs during reperfusion: it does not cause haemodynamic compromise, is spontaneously self-limiting and requires no intervention. Ventricular extrasystoles are common following AMI, and usually require no specific treatment.

(ii) Supraventricular arrythmias:

Atrial fibrillation is the most common supraventricular tachycardia to complicate AMI. It is often recurrent and ultimately self-limiting. Treatment with beta-blockers, amiodarone or digoxin may be indicated or, if there is significant haemodynamic compromise, synchronised DC cardioversion. Patients with atrial fibrillation should also receive anti-thrombotic treatment, although this is already likely to have occurred in the setting of AMI.

(iii) Conduction defects:

Various conduction defects and degrees of heart block can occur following AMI. First-degree heart block is benign and requires no intervention.

Type 1 second-degree heart block (Wenckebach) in association with an inferior infarct is rarely associated with haemodynamic compromise, and is usually self-limiting. However, in the setting of anterior infarction Wenckebach has a worse prognosis and may require pacing. Atropine should be used as an initial measure.

Type 2 second-degree and third-degree (complete) heart block are indications for transvenous pacing, which is more likely to be permanent in the presence of anterior infarction. Axis deviation should be identified in patients with right bundle branch block, since this indicates bifascicular block that may progress to complete heart block.

 

Prognosis & Followup strategies

(a) Definition and clinical presentations of ACS:

  1. AMI is defined as the pathological finding of myocardial necrosis OR a troponin rise associated with at least one of: ischemic symptoms, characteristic ECG changes or coronary intervention.
  2. The clinical presentation of ACS is determined by a dynamic pathophysiology consisting of thrombosis, thrombolysis, vasoconstriction, and platelet aggregation and embolisation.
  3. The mortality from STEMI has dropped markedly over the last few decades, largely due to improvements in the delivery of treatment: most deaths occur prior to seeking medical help and this remains a major challenge.
  4. No single factor in the history is associated with a high enough likelihood ratio to confidently diagnose or exclude AMI (Grade of evidence 1b)
  5. The features of the chest pain history most likely to be associated with AMI are radiation to the right arm/shoulder or radiation to both arms/shoulders (Grade of evidence 1b)
  6. Examination findings which increase the likelihood of AMI in the context of chest pain are the presence of a third heart sound, hypotension and pulmonary crackles (Grade of evidence 1b)
  7. ECG findings diagnostic of AMI in the context of ischaemic chest pain are new ST segment elevation and new Q waves (Grade of evidence 1b)
  8. Right sided or posterior leads should be performed as routine in all patients with inferior ST elevation or anteroseptal ST depression
  9. A normal ECG in the context of ischaemic chest pain does not rule out prognostically significant myocardial damage and further diagnostic testing will be required (Grade of evidence 1b)
  10. Troponins are the current diagnostic standard for acute coronary syndromes and their elevation in this setting defines myocardial infarction.

(b) Management STEMI:

  1. Once STEMI is diagnosed, early reperfusion (pharmacological or mechanical) is critical (Grade A recommendation, level of evidence 1a).
  2. The choice of intervention (thrombolysis or PPCI) will depend on available resources and factors specific to the patient (e.g. contraindications to thrombolysis and the time since symptom onset) (Grade A recommendation, level of evidence 1).
  3. PPCI is the favoured reperfusion option for the significant majority of patients within the UK.
  4. Irrespective of the type of reperfusion therapy it is important to remember simple measures of cardiac first aid : aspirin, oxygen, opiates, GTN and beta-blockers (Grade A recommendation, levels of evidence 1a-1b).
  5. Rescue PCI should be considered in all patients who fail to reperfuse following thrombolysis (Grade A recommendation, level of evidence 1b).
  6. Currently there is no place in routine clinical practice for Facilitated PCI in the management of STEMI (Grade A recommendation, level of evidence 1a).
  7. In addition to aspirin, one of the anti-platelet agents Clopidogrel, Prasugrel or Ticagrelor should be administered to patients with STEMI. Prasugrel is preferred in patients undergoing PPCI and Ticagrelor is preferred in patients undergoing PPCI who have a contra-indication to Prasugrel. The remainder should receive clopidogrel (Grade A recommendation, level of evidence 1a).
  8. Weight adjusted Heparin should be given to patients with STEMI either unfractionated (in the pre-hospital setting) or LMWH (in the emergency department) (Grade A recommendation, level of evidence 1a).
  9. Many of the early complications of STEMI (e.g. cardiac failure, cardiogenic shock, arrythmias) can be treated by effective reperfusion. Mechanical complications (e.g. valvular regurgitation, tamponade) will usually require surgical intervention.

(c) Management NSTEMI and UA:

  1. Risk stratification should be performed within the ED as soon as a differential diagnosis of NSTE-ACS is considered. Risk stratification in patients with NSTE-ACS not only determines prognosis but also directly influences early treatment options (Grade A recommendation, level of evidence 1a).
  2. Aspirin should be given to all patients with NSTE-ACS (unless contraindications exist) at presentation at a dose of 150 300mgs (Grade A recommendation, levels of evidence 1a 1b).
  3. Where a heparin is to be used as the adjuvant anticoagulant, enoxaparin is superior to unfractionated heparin and should be administered to patients with NSTE-ACS and continued during the in-patient stay (Grade A recommendation, level of evidence 1a).
  4. Fondaparinux is the preferred anticoagulant because it has a superior efficacy / safety profile (Grade A recommendation, level of evidence 1a).
  5. Clopidogrel should be administered to patients with NSTE-ACS in the acute setting and continued for 12 months(Grade A recommendation, level of evidence 1b).
  6. Patients with NSTE-ACS undergoing PCI should receive GpIIb/IIIa receptor inhibitors as part of their anti-thrombotic regime (Grade A recommendation, level of evidence 1a).
  7. GpIIb/IIIa receptor inhibitors should be commenced in patients with higher risk NSTE-ACS (diabetes, troponin positive, high TIMI score or intermediate/high GRACE Score) even if they are not undergoing early PCI (Grade A recommendation, level of evidence 1a).
  8. Urgent angiography is indicated alongside maximal medical therapy in unstable patients with NSTE-ACS (Grade D recommendation, level of evidence 5).
  9. Early angiography (<96 hours) should be considered alongside medical therapy for high risk patients with NSTE-ACS (Grade A recommendation, level of evidence 1a).

References:

  1. Goodacre S, Cross E, Arnold J, Angelini K, Capewell S, Nichol J. The health care burden of acute chest pain.Heart 2005;91:229-30.
  2. Collinson PO, Premachandram S, Hashemi K. Prospective audit of incidence of prognostically important myocardial damage in patients discharged from emergency department. BMJ 2000;320:1702-5.
  3. Myocardial infarction redefined A consensus document of The Joint European Society of Cardiology / American College of Cardiology Committee for the Redefiniton of Myocardial Infarction. The Joint European Socitey of Cardiology / American College of Cardiology Committee. Eur Heart J 2000;21:1502-1513.
  4. Norris RM, Caughey DE, Mercer CJ et al. Prognosis after myocardial infarction. Six year follow-up. Br Heart J1974;36:786-790.
  5. de Vreede JJ, Gorgels AP, Verstraaten GM et al. Did prognosis after myocardial inarction change after the last 30 years? A meta-analysis. J Am Coll Cardiol 1991;18:698-706
  6. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. The Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Lancet 2001;358:605-13.
  7. Norris RM. Fatality outside hospital from acute coronary events in three British districts, 1994-5. United Kingdom Heart Attack Collaborative Study Group. BMJ1998;316:1065-70.
  8. Tunstall-Pedoe H, Kuulasmaa K, Mahonen M, et al. Contribution of trends in survival and coronary event rates to changes in coronary heart disease mortality: 10 year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet 1999;353:1547-57.
  9. Kainth A, Hewitt A, Sowden A et al. Systematic review of interventions to reduce delay in patients with suspected heart attack. Emerg Med J 2004;21:506-508.
  10. Swap CJ and Nagurney JT. Value and limitations of chest pain history in the evaluation of patients with suspected acute coronary syndromes. JAMA 2005;294(20):2623-29.
  11. Panju A, Hemmelgarn B, Guyatt G, and Simel D. Is this patient having a myocardial infarction? JAMA1998;280:1256-63.
  12. Mant J, McManus RJ, Oakes RAL, Delaney BC, Barton PM, Deeks JJ et al. Systematic review and modelling of the investigation of acute and chronic chest pain presenting in primary care. Health Technology Assessment 2004;Vol 8:No. 2.
  13. Jaeschke R, Guyatt GH, Sackett DL. Users guide to the medical literature. III. How to use an article about a diagnostic test. B. What are the results and will they help me cure my patients? The Evidence Based Medicine Working Group. JAMA 1994;271:703-7.
  14. Canto J, Shlipak M, Rogers W, et al. Prevalence, clinical characteristics, and mortality among patients with acute myocardial infarction presenting without chest pain. JAMA 2000;283:3223-3229.
  15. Verheugt F, Gersh B, Armstrong P. Aborted myocardial infarction: a new target for reperfusion therapy. Eur Heart J2006;27:901-904.
  16. Karlson B, Herlitz J, Wiklund O, Richter A, Hjalmarson A. Early prediction of acute myocardial infarction from clinical history, examination and electrocardiogram in the emergency room. Am J Cardiol 1991;68:171-5.
  17. 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 with more than 1000 patients. Lancet 1994;343:311-22.
  18. Newby KH, Pisano E, Rukoff MW, et al. Incidence and clinical relevance of the occurrence of bundle branch block in patients treated with thrombolytic therapy. Circulation 1996;94:2424-8.
  19. Sgarbossa EB, Pinski SL, Barbagelata A, et al. Electrocardiographic diagnosis of evolving myocardial infarction in the presence of left bundle branch block. N Engl J Med 1996;334:481-7.
  20. Reuben AD, Mann CJ. Simplifying thrombolysis decisions in patients with left bundle branch block. Emerg Med J2005;22:617-20.
  21. Bertrand M, Simoons M, Fox K, et al. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. The Task Force on the Management of Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J 2002;23:1809-40.
  22. Jaffe As, Ravkilde J, Roberts R et al. Its time for a change to a troponin standard. Circulation2000;102:1216-20.
  23. Hamm CW, Goldmann BU, Heeschen C, Kreymann G, Berger J, Meinertz T. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. New Engl J Med 1997;337:1648-53.
  24. Smith SC, Ladenson JH, Mason JW et al. Elevations of cardiac troponin I associated with myocarditis. Circulation1997;95:163-8.
  25. Giannitsis E, Muller-Bardorff M, Kurowski V et al. Independent prognostic value of cardiac troponin T in patients with confirmed pulmonary embolism. Circulation 1997;96:2953-8.
  26. Frankel WL, Herold DA, Ziegler TW et al. Cardiac troponin is elevated in asymptomatic patients with chronic renal failure. Am J Clin Path 1996;106:118-23.
  27. NICE. Unstable angina and NSTEMI: The early management of unstable angina and non-ST-segment-elevation myocardial infarction.. Clinical Guideline 94. National Institute of Health and Clinical Excellence. London, March 2010.
  28. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina / non-ST elevation MI. JAMA2000;284:835-42.
  29. Boersma E, Pieper KS, Steyerberg EW, et al. for the PURSUIT Investigators. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. Circulation 2000;101:2557-67.
  30. Granger CB, Goldberg RJ, Dabbous OH, et al. for the Global Registry of Acute Coronary Events Investigators. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med 2003;163:2345-53.
  31. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischaemic events in unstable angina/non-Q wave myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 11B trial.Circulation 1999;100:1593-601.
  32. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low molecular weight heparin with unfractionated heparin for unstable coronary disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. ESSENCE. N Engl J Med1997;337:447-52.
  33. Sabatine MS, Antmann EM. The Thrombolysis in Myocardial Infarction Risk Score in Unstable Angina / Non-ST-Segment Elevation Myocardial Infarction. J Am Coll Cardiol 2003;41:89S-95S.
  34. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the 6 month postdischarge death in an international registry. JAMA 2004;291:2727-2733.
  35. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003 ;361 :13-20.
  36. Gruppo Italiano per lo Studio della Streptochinasi nellInfarto Miocardio (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-401.
  37. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet1988;2:349-60.
  38. Keeley E, Boura J, Grines C. Comparison of primary and facilitated percutaneous coronary interventions for ST-segment elevation myocardial infarction: quantitative review of randomised trials. Lancet2006;367:579-88.
  39. Bonnefoy E, Lapostolle F, Leizorovicz A et al. Primary angioplasty versus prehospital fibrinolysis in acute myocardial infarction: a randomised study. Lancet 2002;360:825-29.
  40. Armstrong PW, WEST Steering Group Committee. A comparison of pharmacological therapy with/without timely coronary intervention vs. primary percutaneous intervention early after ST-elevation myocardial infarction: the WEST (Which Early ST-elevation myocardial infarction Therapy) study. Eur Heart J, 2006;
  41. Nallamothu B, Antman E, Bates E. Primary Percutaneous Coronary Intervention versus Fibrinolytic therapy in Acute Myocardial Infarction: Does the choice of fibrinolytic agent impact on the importance of time to treatment? Am J Cardiol 2004;94:772-4.
  42. Hochman JS, Sleeper LA, Webb JG et al, for the Should We Emergently Revascularise Occluded Coronaries for Cardiogenic Shock (SHOCK) Investigators. Early revascularisation in acute myocardial infarction complicated by cardiogenic shock. NEJM 1999;341:625-34.
  43. National Institute for Health and Clinical Excellence. Clinical Guideline 167: Myocardial infarction with ST-segment elevation. NICE Publication; NICE CG167, London, July 2013. View guideline
  44. ACC/AHA Guidelines for the Management of Patients with ST-elevation Myocardial Infarction. A report of the ACC/AHA Task Force on practice guidelines. Circulation 2004;110:588-636.
  45. The Task Force on the Management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation.Eur Heart J 2008;29:2909-45.
  46. Boersma E, Mass A, Deckers J et al. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996;348:771-75.
  47. Morrison LJ, Verbeek PR, McDonald AC et al. Mortality and pre-hospital thrombolysis for acute myocardial infarction: a meta-analysis. JAMA 2000;283:2686-92.
  48. MINAP Steering Group. How the NHS manages heart attacks. Sixth Public Report 2008.
  49. White H. Thrombolytic therapy in the elderly. Lancet 2000;356:2028-30.
  50. Gershlick AH, Stephens-Lloyd A, Hughes S et al for the REACT Trial Investigators. Rescue Angioplasty after failed Thrombolytic Therapy for Acute Myocardial Infarction. NEJM 2005;353:2758-68.
  51. Fernandez-Aviles F, Alonso J, Castro-Beiras A et al. Routine Invasive strategy within 24 hours of thrombolysis versus ischaemia-guided conservative approach for acute myocardial infarction with ST-segment elevation (GRACIA-1): a randomised controlled trial. Lancet 2994;364:1045-53.
  52. The Task Force for Percutaneous Coronary Interventions of The European Society of Cardiology. Guidelines for percutaneous coronary interventions. Eur Heart J 2005;26:804-47.
  53. Verheugt FW. Lyse now, stent later: the grace of GRACIA. Lancet 2004;364:1014-15.
  54. ASSENT-4 PCI Investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): randomised trial. Lancet2006;367:569-78.
  55. Anti-thrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of anti-platelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
  56. Sabatine MS, Cannon CP, Gibson M et al, for the CLARITY-TIMI 28 Investigators. Addition of Clopidogrel to Aspirin and Fibrinolytic Therapy for Myocardial Infarction with ST-Segment Elevation. N Engl J Med2005;352 (25):2647-57.
  57. COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: a randomised placebo-controlled trial. Lancet 2005;366:1607-21.
  58. NICE. Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention. NICE Technology Appraisal Guidance 182. National Institute of Health and Clinical Excellence. London, October 2009.
  59. NICE. Ticagrelor for the treatment of acute coronary syndromes. NICE Technology Appraisal Guidance 236. National Institute of Health and Clinical Excellence. London, September 2011.
  60. de Bono D, Simoons ML, Tijssen J et al. Effect of early intravenous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: results of a randomised double blind European Cooperative Study Group trial. Br Heart J 1992;67:122-8
  61. Antman EM, Morrow DA, McCabe C et al for the EXTRACT-TIMI 25 Investigators. Enoxaparin versus Unfractionated Heparin with Fibrinolysis for ST-Elevation Myocardial Infarction. NEJM 2006;354:1477-88.
  62. The Assessment of Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358:605-13.
  63. Wallentin L, Goldstein p, Armstrong P et al. Efficacy and Safety of Tenecteplase in Combination with the Low-Molecular-Weight Heparin Enoxaparin or Unfractionated Heparin in the Prehospital Setting. Circulation2003;108:135-42.
  64. Fondaparinux in patients with ST-segment elevation acute myocardial infarction not receiving reperfusion treatment. Eur Heart J 2008;29:315-23.
  65. The GUSTO V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combined reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet2001;375:1905-14.
  66. Theroux P, Ouimet H, McCans J et al. Aspirin, Heparin, or both to treat acute unstable angina.NEJM1988;319:1105-11.
  67. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial. Effects of
  68. Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation. NEJM2001;345(7):494-503.
  69. Budaj A, Yusuf S, Mehta S et al. Benefit of Clopidogrel in Patients with Acute Coronary Syndromes without ST-Segment Elevation in Various Risk Groups. Circulation 2002;106:1622-26.
  70. NICE. Unstable angina and NSTEMI The early management of unstable angina and non-ST-segment-elevation myocardial infarction. Clinical Guideline 94. National Institute of Health and Clinical Excellence. London, March 2010.
  71. Fragmin during Instability in Coronary Artery Disease (FRISC) study Group. Low molecular weight heparin during instability in coronary artery disease. Lancet 1996;347:561-68.
  72. Peterson MD, Mahaffey KW, Hasselblad V et al. Efficacy and Bleeding Complications among Patients Randomised to Enoxaparin or Unfractionated Heparin for Anti-thrombin Therapy in Non-ST-Segment Elevation Acute Coronary Syndromes. A Systematic Overview. JAMA 2004;292:89-96.
  73. Yusuf S, Mehta SR, Chrolavicius S et al . Efficacy and safety of fondaparinux compared to enoxaparin in 20,078 patients with acute coronary syndromes without ST segment elevation. The OASIS (Organisation to Assess Strategies in Acute Ischaemic Syndromes)-5 Investigators. N Engl J Med 2006;354:1464-76.
  74. EPIC Investigators. Use of a monoclonal antibody directed against the platelet Glycoprotein IIB/IIIA receptor inhibitor in high risk angioplasty. N Engl J Med 1994;330:956-61.
  75. EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with the use of platelet glycoprotein IIB/IIIA blockade. The EPISTENT Investigators. Evaluation of platelet IIB/IIIA Inhibitor for Stenting. Lancet 1998;352:87-92.
  76. ESPRIT. Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet 2000;356:2037-44.
  77. CAPTURE Investigators. Randomised placebo-controlled trial of Abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997;349:1429-35.
  78. PRISM. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. Platelet Receptor Inhibition in Ischaemic Syndrome Mangement (PRISM) Study Investigators. N Engl J Med1998;338:1498-505.
  79. PRISM-PLUS. Inhibition of the platelet Glycoprotein IIB/IIIA receptor with tirofiban in unstable angina and non-Q-wave-myocardial infarction. Platelet Receptor Inhibition in Ischaemic Syndrome Mangement in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med1998;338:1488-97.
  80. PARAGON Investigators. International, randomised, controlled trial of lamifiban (a platelet glycoprotein IIB/IIIA inhibitor), heparin, or both in unstable angina. The PARAGON Investigators. Platelet IIB/IIIA Antagonism for the Reduction of Acute coronary syndrome events in a Global Organisation Network. Circulation 1998;97:2386-95.
  81. PARAGON-B Investigators. Randomised, placebo-controlled trial of titrated IV lamifiban for acute coronary syndrome. Circulation 2002;105:316-21.
  82. PURSUIT Investigators. Inhibition of Platelet glycoprotein IIB/IIIA with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIB/IIIA in Unstable Angina: Receptor Suppression using Integrilin Therapy. N Engl J Med 1998;339:436-43.
  83. GUSTO-IV ACS Investigators. Effect of glycoprotein IIB/IIIA receptor blocker abciximab on outcome of patients with acute coronary syndromes without early revascularisation: The GUSTO-IV ACS randomised trial. Lancet2001;357:1915-24.
  84. Boersma E, Harrington R, Moliterno D et al. Platelet Glycoprotein IIB/IIIA inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 2002;359:189-198.
  85. Roffi M, Chew DP, Mukherjee D et al. Platelet glycoprotein IIB/IIIA inhibitors reduce mortality in diabetic patients with Non-ST segment elevation acute coronary syndromes. Circulation. 2002.;105:316-21.
  86. Technology Appraisal Guidance Number 47. National Institute for Clinical Excellence. Guidance on the use of GpIIB/IIIA receptor inhibitors in the treatment of acute coronary syndromes. September 2002.
  87. Curfman G, Heinsimir J, Lozner E et al. Intravenous nitroglycerin in the treatment of spontaneous angina pectoris: a prospective randomised trial. Circulation 1983;67:276-82.
  88. Dellborg M, Gustafsson G, Swedberg K. Buccal versus intravenous nitroglycerin in unstable angina pectoris. Eur J Clin Pharmacol 1991;41:5-9.
  89. Yusuf S, Wittes J, Friedman L. Overview of results of randomised clinical trials in heart disease. Unstable angina, heart failure, primary prevention with aspirin, and risk factor modification. JAMA 1988;260:2259-63.
  90. Theroux P, Taeymans Y, Morissette et al. A randomised study comparing proranolol and diltiazem in the treatment of unstable angina. J Am Coll Cardiol 1985;5:717-22.
  91. Held P, Furberg C. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. Br Med J 1989;299:1187-92.
  92. Mehta SR, Yusuf S, Peters RJ et al. Effects of pre-treatment with clopidogrel and aspirin followed by long term therapy in patients undergoing percutaneous coronary intervention: the PERI-CURE Study. Lancet2001;358:527-33.
  93. Cannon C, Weintraub W, Demopoulos L et al for the TACTICS-Thrombolysis in Myocardial Infarction 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with glycoprotein IIB/IIIA inhibitor tirofiban. N Engl J Med 2001;344:1879-87.
  94. FRISC II Investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomised multicentre study. Fragmin and Fast Revascularisation during InStability in Coronary artery disease investigators. Lancet 1999;354:708-15.
  95. Fox K, Poole-Wilson P, Henderson R et al for the Randomised Intervention Trial of unstable Angina (RITA) investigators. Intervention versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Lancet 2002;360:743-51.
  96. Hoenig MR, Doust JA, Aroney CN, et al. Early invasive versus conservative strategies for unstable angina and non-ST-elevation myocardial infarction in the stent era. Cochrane Database Syst Rev 2006;3:CD004815
  97. Hochman JS, Sleeper LA, Webb JG et al, for the Should We Emergently Revascularise Occluded Coronaries for Cardiogenic Shock (SHOCK) Investigators. Early revascularisation in acute myocardial infarction complicated by cardiogenic shock. NEJM 1999;341:625-34.
  98. Becker RC, Hochman JS, Cannon CP et al. Fatal cardiac rupture among patients treated with thrombolytic agents and adjunctive thrombin antagonists: observations from the TIMI 9 study. J Am Coll Cardiol 1999;33:479-87.
  99. Resuscitation Council (UK) 2005. Advanced Life Support Course Provider Manual (5th Edition). London: Resuscitation Council (UK).

5 Comments

  1. qazizu says:

    WONDERFULL , VERY EXTENSIVE

  2. abdelrehimmo says:

    nice one , great job

  3. solimankh says:

    Very good, enough for FRCEM exam

  4. flewittsh says:

    Excellent
    Logical and well ordered

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