Author: Jason Kendall / Editor: Jason Kendall / Reviewer: Liz Florey, Jolene Rosario / Codes: CC1, CC2, CP1, SLO1, SLO3 / Published: 21/10/2021

Context

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].

Acute coronary syndromes (ACS) encompass a broad range of presentations including:

  • Unstable angina (UA)
  • Non-ST segment elevation myocardial infarction (NSTEMI)
  • ST segment elevation myocardial infarction (STEMI)

A clear understanding of the pathophysiology, classification and clinical presentation of these conditions is a pre-requisite for effective subsequent risk stratification and therapy.

Definition of Myocardial Infarction

Myocardial infarction (MI) is defined pathologically as myocardial cell death following prolonged ischaemia. 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 MI [2] are listed in the panel on the right.

Classification

In the context of cardiac marker rise, ST segment changes on the ECG define either STEMI or NSTEMI.

At the time of presentation, however, cardiac marker status is unknown, so the 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 NSTEMI (marker rise) or UA (no marker rise) [3].

The image illustrates the classification of acute coronary syndromes. Click on the image to enlarge.

Introduction

ACS occurs 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 micro-embolisation.

Atherosclerotic plaque disruption initiates thrombosis with platelet activation and platelet aggregation.

Thrombus formation

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

A 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. This is the process that is thought to be occurring in infarction without ST elevation, i.e. NSTEMI.

Dynamic Pathophysiology

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. Which particular process predominates determines the clinical syndrome, i.e. STEMI, NSTEMI or UA, and, in turn, the most appropriate subsequent therapy.

The incidence of NSTE-ACS is higher than STEMI and it appears that the number of NSTE-ACSs 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]. In patients with NSTE-ACS, it is thought that greater age and higher incidence of co-morbidities, e.g. diabetes and renal impairment, contributes to the higher long term mortality.

Learning Bite

Short term mortality is higher with STEMI, but long term mortality is higher 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], dropped 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 since the 1960s.

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. 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 [7].

Click here to go to the British Heart Foundation website.

Classical Presentation

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

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

Likelihood ratios have been calculated that link features of the history with AMI [8-10].

Table of likelihood ratios

Table 1: Value of specific components of the chest pain history for the diagnosis of acute myocardial infarction
Historical factor Likelihood ratio
Ref 8 Ref 9 Ref 10
Increased likelihood of AMI:
Radiation to right arm/shoulder 4.7 2.9 2.6
Radiation to both arms/shoulders 4.1 7.1 4.1
Associated with exertion 2.4
Radiation to left arm 2.3 2.3 1.5
Associated with diaphoresis 2.0 2.0 2.1
Associated with nausea/vomiting 1.9 1.9 1.9
Worse than previous angina/similar to previous MI 1.8 1.3
Described as a pressure 1.3 1.4
Decreased likelihood of AMI:
Described as pleuritic 0.2 0.2 0.2
Described as positional 0.3 0.3 0.3
Described as sharp 0.3 0.3 0.3
Reproducible with palpation 0.3 0.2 – 0.4* 0.2
Inframammary location 0.8
Not associated with exertion 0.8

* In heterogenous studies, likelihood ratios are expressed as a range.

Learning Bite

No single factor in the history alone can confidently rule in or rule out AMI; characteristics of the pain with the highest likelihood for AMI are radiation of the pain to the right arm or shoulder, or to both arms or shoulders.

Risk Factors

Based on the analyses of the likelihood ratios for AMI, 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 enable 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 [3], which makes the diagnosis of ACS significantly more or less likely.

Atypical presentations of ACS are common, occurring in up to 33% of patients, mostly in the elderly, diabetics and women. 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.

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 causes for chest pain (i.e. not ischaemic cardiac) or are associated with the complications of AMI (see Table 2).

Table 2

Examination finding Likelihood ratio
Ref 9 Ref 10
Increased likelihood of AMI:
Third heart sound 3.2 3.2
Hypotension (systolic BP <80 mmHg) 3.1 3.1
Pulmonary crepitations 2.1 2.1
Decreased likelihood of AMI:
Chest pain reproducible by palpation 0.3 0.2-0.4*

* In heterogenous studies, likelihood ratios are expressed as a range.

Learning Bite

The finding of a third heart sound, hypotension or pulmonary crepitations makes AMI more likely.

Electrocardiography

Broadly speaking, the ECG will directly determine whether a patient’s further management follows:

  • An immediate fibrinoytic or mechanical reperfusion strategy, i.e. ST segment elevation and left bundle branch block
  • An anti-thrombotic and anti-platelet strategy (ST segment depression or T-wave inversion)
  • A ‘rule out’ strategy (normal ECG)

The image shows partial and complete coronary occlusion.

What ECG changes are indicative of myocardial ischaemia that may progress to AMI [2]?

ST segment changes, new conduction defects, Q waves and T wave changes may indicate AMI [2].

Example of a Non-STE ACS ECG:

Example of a STEMI ECG showing myocardial infarction:

Table 3 below shows the likelihood ratios for the association of various ECG changes with AMI [9,10]:

Table 3: Value of specific components of the ECG for the diagnosis of acute myocardial infarction [9,10]
ECG finding Likelihood ratio
Ref 9 Ref 10
Increased likelihood of AMI:
New ST segment elevation 5.7 – 53.9* 13.1
New Q wave formation 5.3 – 24.8* 5.0
New conduction deficit 6.3
New ST segment depression 3.0 – 5.2* 3.13
T wave peaking and/or inversion 3.1 1.9
Decreased likelihood of AMI:
Normal ECG 0.1 – 0.3 0.1

* In heterogenous studies, likelihood ratios are expressed as a range.

ST Segment Elevation

The presence of ST segment elevation, new Q wave formation or a new conduction deficit (e.g. left bundle branch block), in the context of acute ischaemic chest pain, is associated with such significantly positive likelihood ratios for AMI (see Table 1) that the diagnosis can usually be made with confidence and appropriate therapy commenced.

Table 4

Table 4: Value of specific components of the ECG for the diagnosis of acute myocardial infarction [9,10]
ECG finding Likelihood ratio
Ref 9 Ref 10
Increased likelihood of AMI:
New ST segment elevation 5.7 – 53.9* 13.1
New Q wave formation 5.3 – 24.8* 5.0
New conduction deficit 6.3
New ST segment depression 3.0 – 5.2* 3.13
T wave peaking and/or inversion 3.1 1.9
Decreased likelihood of AMI:
Normal ECG 0.1 – 0.3 0.1

* In heterogenous studies, likelihood ratios are expressed as a range.

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, such as:

  • ‘Aborted’ myocardial infarction where early reperfusion has occurred [11]
  • Coronary artery vasospasm with spontaneous resolution

Pitfall: There are occasional situations where ST elevation in the setting of ischaemic chest pain does not indicate that necrosis has or will occur.

ST segment elevation will typically be found in a ‘territorial’ distribution on the ECG that reflects, and is determined by, coronary artery anatomy

Click on the links below to view the ECGs.

Fig 1

Fig 2

ST Segment Depression and T Wave Changes

The presence of ST segment depression and/or T wave changes (see Fig 1), 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 1). Fig 1 Table 5

Table 5: Value of specific components of the ECG for the diagnosis of acute myocardial infarction [9,10]
ECG finding Likelihood ratio
Ref 9 Ref 10
Increased likelihood of AMI:
New ST segment elevation 5.7 – 53.9* 13.1
New Q wave formation 5.3 – 24.8* 5.0
New conduction deficit 6.3
New ST segment depression 3.0 – 5.2* 3.13
T wave peaking and/or inversion 3.1 1.9
Decreased likelihood of AMI:
Normal ECG 0.1 – 0.3 0.1

* In heterogenous studies, likelihood ratios are expressed as a range. Approximately 50% of patients with ST depression and 33% of patients with T wave inversion will subsequently be shown to have myocardial infarction [2,12]. This group of patients are presenting with an ACS (i.e. UA or NSTEMI).

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

  • Patients with inferior ST segment elevation because the majority of right-sided infarcts and posterior infarcts occur as extensions of inferior infarcts. This may affect management – patients with right sided MI 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.

Standard and posterior ECG lead placement

Figure 1: Standard and posterior ECG lead placement

Click on the links below to see standard-lead and posterior-lead ECG traces.

Standard chest lead

Additional posterior leads

Learning Bite

Be alert to the need for right sided or posterior leads when diagnosing STEMI – they should be performed as routine in all patients with inferior ST elevation or anteroseptal ST depression.

What About Left Bundle Branch Block?

Patients with ischaemic cardiac chest pain and left bundle branch block (LBBB) should be assumed to be having an AMI. These patients should be considered for immediate reperfusion therapy, because they have been shown to have amongst the highest mortality of patients with AMI, and they also gain the greatest benefit from thrombolysis [13].

Learning Bite

The default position for patients presenting with ischaemic chest pain and LBBB should be to assume that the presentation is due to AMI.

A normal ECG significantly reduces the probability of AMI [9,10]. It does not, however, reduce this probability enough to allow confident safe discharge based upon the history and ECG alone [15]. 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.

Pitfall

A normal ECG in a patient with chest pain does not allow safe discharge without further investigation.

References:

  1. Goodacre S, Cross E, Arnold J, et al. 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 Jun 24;320(7251):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. Eur Heart J. 2000 Sep;21(18):1502-13. doi: 10.1053/euhj.2000.2305. PMID: 10973764.
  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 acute myocardial infarction change during the past 30 years? A meta-analysis. J Am Coll Cardiol. 1991 Sep;18(3):698-706.
  6. Assessment of the 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 Aug 25;358(9282):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, 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, Müller-Bardorff M, Kurowski V, et al. Independent prognostic value of cardiac troponin T in patients with confirmed pulmonary embolism. Circulation. 2000 Jul 11;102(2):211-7.
  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 Committee. A comparison of pharmacologic 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 Jul;27(13):1530-8.
  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. Acute coronary syndromes [NICE guideline NG185]. 18 November 2020.
  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-Avilés F, Alonso JJ, Castro-Beiras A, Vázquez N, 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. 2004 Sep 18-24;364(9439):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. National Institute of Health and Clinical Excellence. Ticagrelor for the treatment of acute coronary syndromes. NICE Technology Appraisal Guidance [TA236]. 26 October 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. Yusuf S, Zhao F, Mehta SR, et al. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001 Aug 16;345(7):494-502.
  68. 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.
  69. 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.
  70. Low-molecular-weight heparin during instability in coronary artery disease, Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Lancet. 1996 Mar 2;347(9001):561-8. PMID: 8596317.
  71. 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.
  72. 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.
  73. 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.
  74. 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.
  75. ESPRIT. Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet 2000;356:2037-44.
  76. 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.
  77. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med. 1998 May 21;338(21):1498-505.
  78. 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.
  79. 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.
  80. Global Organization Network (PARAGON)-B Investigators. Randomized, placebo-controlled trial of titrated intravenous lamifiban for acute coronary syndromes. Circulation. 2002 Jan 22;105(3):316-21.
  81. 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.
  82. 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.
  83. 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.
  84. 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.
  85. 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.
  86. 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.
  87. Dellborg M, Gustafsson G, Swedberg K. Buccal versus intravenous nitroglycerin in unstable angina pectoris. Eur J Clin Pharmacol 1991;41:5-9.
  88. Yusuf S, Wittes J, Friedman L. Overview of results of randomised clinical Calcium channel blockerstrials in heart disease. Unstable angina, heart failure, primary prevention with aspirin, and risk factor modification. JAMA 1988;260:2259-63.
  89. 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.
  90. Held P, Furberg C. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. Br Med J 1989;299:1187-92.
  91. 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.
  92. 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.
  93. 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.
  94. Fox K, Poole-Wilson P, Henderson R et al. Randomized Intervention Trial of unstable Angina Investigators. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina. Lancet. 2002 Sep 7;360(9335):743-51.
  95. 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.
  96. Hochman JS, Sleeper LA, Webb JG et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med. 1999 Aug 26;341(9):625-34.
  97. 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.
  98. National Institute for Health and Clinical Excellence. Recent-onset chest pain of suspected cardiac origin: assessment and diagnosis [NICE guideline CG95]. Updated: 30 November 2016.
  99. Resuscitation Council (UK) May 2021 Advanced Life Support Course Provider Manual is in the 8th Edition.