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Ischaemic heart disease
Clinical implications of the Third Universal Definition of Myocardial Infarction
  1. Harvey D White1,
  2. Kristian Thygesen2,
  3. Joseph S Alpert3,
  4. Allan S Jaffe4
  1. 1Cardiology Department, Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
  2. 2Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
  3. 3Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona, USA
  4. 4Cardiovascular Division, Department of Medicine, Laboratory Medicine and Pathology, Mayo Clinic and Medical School, Rochester, Minnesota, USA
  1. Correspondence to Professor Harvey D White, Cardiology Department, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92024, Victoria St West, Auckland 1142, New Zealand; HarveyW{at}adhb.govt.nz

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The definition of myocardial infarction (MI) continues to evolve as refined ECG criteria, more advanced imaging, and more sensitive and specific biomarkers are developed. The acceptance globally of a clinically practical standard definition for everyday practice would allow for better comparisons across clinical experiences and further facilitate research in this critical area. Because of the evolution of better diagnostic tools and more information about the value and limitations of previous definitions, there was a need to update the Universal Definition of MI published in 20071 and this has recently been accomplished.2 Great efforts were made by the taskforce that developed these guidelines to establish clinical criteria which correspond to the contemporary management of patients suspected of having MI. Therefore, a combination of clinical symptoms, cardiac biomarkers, and ECG changes indicative of myocardial ischaemia are central to the 2012 Third Universal Definition of MI. It stresses the importance of a careful clinical history of 20 min of ischaemic symptoms which may not be classical chest discomfort in all instances, an appreciation of the clinical setting (eg, in the critically ill), and careful interpretation of the ECG. Biomarkers are central to the diagnosis, and imaging has received more emphasis (box 1).

Box 1

Definition of myocardial infarction (MI)

  • Criteria for acute myocardial infarction

  • The term acute myocardial infarction (AMI) should be used when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischaemia. Under these conditions, any one of the following criteria meets the diagnosis for MI:

  • Detection of a rise and/or fall of cardiac biomarker values (preferably cardiac troponin) with at least one value above the 99th centile upper reference limit (URL) and with at least one of the following:

      – Symptoms of ischaemia

      – New or presumed new significant ST segment-T wave (ST-T) changes or new left bundle branch block (LBBB)

      – Development of pathological Q waves in the ECG

      – Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

      – Identification of an intracoronary thrombus by angiography or autopsy

  • Cardiac death with symptoms suggestive of myocardial ischaemia and presumed new ischaemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were obtained, or before biomarker values would be increased.

  • Percutaneous coronary intervention related MI is arbitrarily defined by elevation of troponin values >5× the 99th centile URL for troponin if the preprocedure value is normal (<99th centile URL). If baseline values are elevated but are stable or falling, an increase of >20% is required. In addition, patients should have either (1) symptoms suggestive of myocardial ischaemia, or (2) new ischaemic ECG changes, or (3) angiographic findings consistent with procedural complication, or (4) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality.

  • Stent thrombosis associated with MI when detected by coronary angiography or autopsy in the setting of myocardial ischaemia and with a rise and/or fall of cardiac biomarker values with at least one value above the 99th centile URL.

  • Coronary artery bypass grafting related MI is arbitrarily defined by elevation of cardiac biomarker values (>10× 99th centile URL) in patients with normal baseline troponin values (<99th centile URL). In addition either (1) new pathological Q waves or new LBBB, or (2) angiographic documented new graft or new native coronary artery occlusion, or (3) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality are required.

Myocardial injury, necrosis and infarction

There is controversy about the best term to describe the processes that cause the release of biomarkers. The Concise Oxford Dictionary defines injury as physical harm or damage, necrosis as the death of tissue caused by disease or injury, and infarction as dead tissue caused by an inadequate blood supply. Since all damage to the heart is not due to inadequate blood supply, and some would even question whether release of biomarkers requires cell death (see below), the new document suggests the term myocardial injury is preferred to myocardial necrosis (figure 1).

Figure 1

Various clinical entities that can be associated with myocardial injury with cell death and troponin elevation. If this occurs in the setting of clinical ischaemia with rise and/or fall of troponins the diagnosis becomes myocardial infarction. Adapted with permission from Thygesen et al2.

The Third Universal Definition of MI document carefully defines myocardial injury and states: “Small amounts of myocardial injury with necrosis may be detected which are associated with heart failure, renal failure, myocarditis, arrhythmias, pulmonary embolism or otherwise uneventful percutaneous or surgical coronary procedures. These should not be labelled as MI or a complication of the procedures, but rather as myocardial injury.”

and “It is recognized that the complexity of clinical circumstances may sometimes render it difficult to determine where individual cases may lie (with respect to myocardial injury vs myocardial infarction).”

In the document, acute MI (AMI) is defined as myocardial cell death due to prolonged myocardial ischaemia.

Preference for troponins

The Universal Definition of MI has emphasised the use of biomarkers as a cornerstone for the diagnosis of AMI since its first publication in 2000.3 Thus, there must be elevated concentrations of a biomarker of myocardial injury in the appropriate ischaemic clinical setting to meet this criterion.

Troponins are recommended in the 2012 document, as in the previous documents,1 ,3 as the preferred biomarkers for the detection of overall MI and for each individual subcategory of MI. This is because they are more specific than the isoenzyme creatine phosphokinase MB (CK-MB) and they are substantially more sensitive.4

There should be a rise and/or fall of cardiac troponin I or cardiac troponin T (cTnI or cTnT) with at least one value above the 99th centile of the upper reference limit (URL). Optimal assays have high precision at the 99th centile value as measured by a coefficient of variation (CV) ≤10%. When cardiac troponins are not available, the use of CK-MB mass (but not activity) is acceptable with detection of a rise and/or fall with at least one value above the 99th centile of the URL measured with a CV ≤10%. Sex specific cutoff values should be used with CK-MB. However, it is unclear if there is any situation in which CK-MB is superior to cardiac troponin (cTn).4

Causes for elevations of cTn values due to myocardial injury are tabulated in box 2.

Box 2

Causes of elevated troponin values. Adapted with permission from Thygesen et al2

  • Injury related to supply/demand imbalance of myocardial ischaemia

  • Tachy-/bradyarrhythmias

  • Aortic dissection or severe aortic valve disease

  • Hypertrophic cardiomyopathy

  • Cardiogenic, hypovolaemic, or septic shock

  • Severe respiratory failure

  • Severe anaemia

  • Hypertension with or without left ventricular hypertrophy

  • Coronary spasm

  • Coronary embolism or vasculitis

  • Coronary endothelial dysfunction without significant coronary artery disease

  • Injury not related to myocardial ischaemia

  • Cardiac contusion, surgery, ablation, pacing or defibrillator shocks

  • Rhabdomyolysis with cardiac involvement

  • Myocarditis

  • Cardiotoxic agents, for example, anthracyclines, trastuzumab (Herceptin)

  • Multifactorial or indeterminate myocardial injury

  • Heart failure

  • Stress (takotsubo) cardiomyopathy

  • Severe pulmonary embolism or pulmonary hypertension

  • Sepsis and critically ill patients

  • Renal failure

  • Severe acute neurological diseases, for example, stroke, subarachnoid haemorrhage

  • Infiltrative diseases, for example, amyloidosis, sarcoidosis

  • Strenuous exercise

Potential mechanisms of causes of troponin elevation

There are various potential mechanisms that may cause troponin elevation other than myocyte necrosis (table 1).5 Apoptosis as well as necrosis can lead to the release of troponin. Although controversial, there is an argument to be made that even reversible myocardial injury may lead to the release of biomarkers. Regardless of the specific mechanism, the concept of an elevated troponin in the appropriate clinical setting leading to the diagnosis of MI is strongly endorsed. However, if the elevation is due to some other aetiology, such as myocarditis, heart failure, renal failure, or uneventful percutaneous or surgical procedures, the term myocardial injury is preferred. It is recognised that the distinction may be difficult at times. Increases in troponin values found in patients with renal failure are due to myocardial injury and not impaired renal excretion.6 w1

Table 1

Pathobiological classification of types of mechanisms causing troponin elevations. Adapted with permission from White5

Relevant troponin cutoff values

In the 2000 document, the 99th centile of a normal reference population was mandated for use as the decision limit for MI.3 The 2012 redefinition of MI reaffirms that advocacy.2 This is termed the URL. The exact limit to use varies from troponin assay to assay.7 The choice of the 99th centile was related to the fact that this value is approximately three standard deviations from the mean value. It was thought that such an approach would protect against false positive elevations.8 However, this has not transpired to be as major a concern as initially thought, because these values for most conventional troponin assays (with the exception of the newer high sensitivity assays) are not close to the normal range. The use of this cutoff value maximises the identification of patients with MI.

Precision of troponin assays

All the troponin assays have imprecision due to both preanalytic and analytic issues. It was thought that an increased imprecision might lead to false positive values. This is not correct. It simply makes the assay less sensitive.w2 Defining a rising pattern is related to the precision around any given value and thus such an evaluation is helped by better precision. Assays that do not reach the level of 10% imprecision at the 99th centile are usable. Assays with CVs >20% are not recommended to be used.8

Reporting of troponin values

As the assays have become more sensitive, the numbers of zeros has increased and this may lead to an inadvertent error either in the reporting and/or in the interpretation of troponin concentrations. The 2012 Universal Definition of MI2 suggests that values should be reported in whole numbers in nanograms per litre (ng/l).

Value of serial troponin sampling

Serial sampling allows for the demonstration of a rising and/or falling pattern which is essential to distinguish acute elevations from chronic elevations that may be associated with structural heart disease. Measurement of troponins should be made at time zero and repeated 3–6 h later.9–11 If there is a high index of suspicion, and/or ongoing or new ischaemic symptoms, even later sampling may be necessary.

The presence of a changing pattern of troponin release, however, only shows that a given elevation is of an acute cause and does not define the aetiology. It is the elevation of troponin values in an ischaemic setting that is required for the diagnosis of AMI. Patients who have elevated troponin values early in the absence of MI nonetheless are at substantial risk for mortality over time.w3 Therefore, follow-up with ongoing assessments of all patients who have elevated troponin values is recommended.

Troponin release not associated with AMI

If troponin values are elevated but the clinical setting is not one of acute ischaemia, a diagnosis of MI should not be made. This distinction may be difficult at times. For example, a patient presenting with heart failure may have a rising pattern of troponin values that could be due to either type 1 MI, due to plaque rupture if the underlying aetiology for the heart failure is coronary artery disease (CAD), or to type 2 MI (box 4) if there is substantial supply–demand imbalance related to the presentation. On the other hand, elevations of troponin values can occur due to acute ventricular stretch alone or be present chronically.5 Thus, in the absence of ischaemic symptoms or new ECG changes indicative of ischaemia, or new wall motion abnormality or new loss of viable myocardium, patients with these elevations should not be diagnosed as having an MI.

ECG

The ECG is an important and integral part of the diagnostic work-up of patients with suspected MI. It should be recorded and interpreted within 10 min of presentation. Rapid classification with ST elevation MI (STEMI) and non-ST elevation MI (NSTEMI) is important to determine treatment, including the appropriateness of reperfusion therapy. Age and sex dependent ECG criteria for the degree of ST elevation are advocated (box 3). This is extremely important as the normal ST elevation in women in ECG leads V2–V3 is 0.15 mV (≥0.2 mV in men ≥40 years; ≥0.25 mV in men <40 years) and thus many thousands of women may be denied reperfusion therapy worldwide if the criteria for reperfusion requires >2.0 mm in these leads.12 Although the suggested criteria requires ST changes in two contiguous ECG leads, occasionally the criteria for ST elevation may be found in just one lead. This suggests the need for serial recordings and clinical judgement.

The importance of the ECG findings of circumflex coronary artery ischaemia is stressed as circumflex occlusion and an inferobasal MIw4 are often overlooked.w5 There is a recommendation to record leads V7, V8, and V9 in patients with a high clinical suspicion of acute circumflex coronary occlusion (ST depression in V1–V3 or a non-diagnostic ECG with symptoms of ischaemia), for which acute reperfusion therapy is indicated. A cut point of 0.05 mV elevation is recommended and 0.1 mV in males <40 years of age.w6

Box 3

ECG manifestations of acute myocardial ischaemia. Adapted with permission from Thygesen et al2

  • ST elevation

  • New ST elevation at the J point in two contiguous leads with the cut points:

  •  ≥0.1 mV in all leads other than leads V2–V3 where the following cut points apply: ≥0.2 mV in men ≥40 years; ≥0.25 mV in men <40 years, ≥0.15 mV in women.

  • ST depression and T wave changes

  • New horizontal or downsloping ST depression ≥0.05 mV in two contiguous leads and/or T inversion ≥0.1 mV in two contiguous leads with prominent R wave or R/S ratio >1.

Right ventricular (RV) recordings (V3R and V4R) are recommended in patients with inferior MI to detect RV MI. Criteria for RV MI include ST elevation >0.05 mV and >0.1 mV in men <30 years old.w7 Supplemental leads as well as serial ECG recordings (to detect dynamic changes) are recommended in patients who present with ischaemic chest discomfort but have an initial non-diagnostic ECG.

In patients with left bundle branch block (LBBB) concordant ST segment elevation can fulfil the criteria for MI.w8 Comparison with a former ECG is helpful to determine if the LBBB is new or old.

Imaging

The 2012 definition requires either imaging evidence of new loss of viable myocardium, a new regional wall motion abnormality, or the identification of intracoronary thrombus by angiography in a setting of clinical ischaemia and a rise and/or fall of troponins to fulfil criteria for the diagnosis of MI. Loss of viability meets the criteria for the diagnosis of MI when biomarkers are not available. However, if biomarkers are measured appropriately and not elevated above the MI decision limit, the diagnosis of MI is excluded.

MRI has a capability similar to echocardiography in AMI and is particularly useful in detecting myocarditis and other myocardial abnormalities which can mimic MI.w9

Types of MI

The new definition defines five types of MI based on pathological, clinical and prognostic differences. Each type has a different treatment strategy (box 4). This has proven to be very useful in clinical practice and in trials.12–14 w10

Box 4

Universal classification of myocardial infarction (MI). Adapted with permission from Thygesen et al2

  • Type 1: spontaneous MI

  • Spontaneous MI related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary arteries leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. The patient may have underlying severe coronary artery disease (CAD) but on occasion non-obstructive or no CAD.

  • Type 2: MI secondary to an ischaemic imbalance

  • In instances of myocardial injury with necrosis where a condition other than CAD contributes to an imbalance between myocardial oxygen supply and/or demand, for example, coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachy-/bradyarrhythmias, anaemia, respiratory failure, hypotension, and hypertension with or without left ventricular hypertrophy.

  • Type 3: MI resulting in death when biomarker values are unavailable

  • Cardiac death with symptoms suggestive of myocardial ischaemia and presumed new ischaemic ECG changes or new left bundle branch block (LBBB), but death occurring before blood samples could be obtained, before cardiac biomarkers could rise, or in rare when cardiac biomarkers were not collected.

  • Type 4a: MI related to percutaneous coronary intervention (PCI)

  • MI associated with PCI is arbitrarily defined by elevation of cardiac troponin (cTn) values >5× 99th centile upper reference limit (URL) in patients with normal baseline values (<99th centile URL) or a rise of cTn values >20% if the baseline values are elevated and are stable or falling. In addition, either (1) symptoms suggestive of myocardial ischaemia, or (2) new ischaemic ECG changes or new LBBB, or (3) angiographic loss of patency of a major coronary artery or a side branch or persistent slow- or no-flow or embolisation, or (4) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality are required.

  • Type 4b: MI related to stent thrombosis

  • MI associated with stent thrombosis is detected by coronary angiography or autopsy in the setting of myocardial ischaemia and with a rise and/or fall of cardiac biomarker values with at least one value above the 99th centile URL.

  • Type 4c: MI related to restenosis

  • MI associated with restenosis defined as ≥50% stenosis at coronary angiography or a complex lesion associated with a rise and/or fall of cTn values >99th centile URL and no other significant obstructive CAD of greater severity following: (1) initially successful stent deployment, or (2) dilatation of a coronary artery stenosis with balloon angioplasty (<50%).

  • Type 5: MI related to coronary artery bypass grafting (CABG)

  • MI associated with CABG is arbitrarily defined by elevation of cardiac biomarker values >10× 99th centile URL in patients with normal baseline cTn values (<99th centile URL). In addition, either (1) new pathological Q waves or new LBBB, or (2) angiographic documented new graft or new native coronary artery occlusion, or (3) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality are required.

Distinguishing between type 2 and type 1 MI

Differentiation between type 2 and type 1 MI is challenging and requires careful clinical assessment and judgement. The determination that needs to be made is whether the myocardial injury is likely to be due to plaque rupture, which would make it a type 1 MI, or whether it is due to an imbalance in myocardial oxygen supply or demand (type 2 MI). The distinction is important as the approaches to investigation and management may differ. For type 1 MI, the management may include (in the absence of major contraindications or patient preferences) antithrombotic therapy, angiography, and revascularisation as appropriate.w11 The treatment response to a patient with type 2 MI will likely be more heterogeneous. For example, if a patient becomes hypotensive after a hysterectomy and develops ischaemic symptoms with ischaemic ECG changes and a rise in troponin values, the management may be to treat the underlying cause (for example, transfusion for blood loss and the hypotension) and then to decide subsequently on the need for angiography. Often a subsequent test for inducible ischaemia may be helpful. Similarly, a patient with known severe three-vessel CAD not suitable for revascularisation, who develops an MI after prostrate surgery, may be best treated medically with β-blockers and nitrates. There may, at times, be patients in whom a type 2 MI unmasks severe CAD, so in some instances angiography may be necessary. It is often very difficult to distinguish between type 1 and type 2 MI without performing angiography (figure 2).

Figure 2

Differentiation between myocardial infarction (MI) types 1 and 2 according to the condition of the coronary arteries. Adapted with permission from Thygesen et al2.

It is recommended to document the type of MI in the clinical records and to designate the pathobiological mechanism leading to the event—for example, type 2 MI secondary to hypotension and anaemia secondary to blood loss at surgery.

Type 4a MI: percutaneous coronary intervention related

The implications for clinical practice of the previous definition of a type 4a MI have been controversial as new data have been published challenging the idea that type 4a MIs (percutaneous coronary intervention (PCI) related MI) are prognostically important. The 2007 universal definition required increases of cardiac biomarkers greater than 3× 99th centile URL without a need for associated ischaemic features or angiographic complications. Since myocardial injury occurs commonly after PCI15 ,16w12–w14 the 2007 definition resulted in large numbers of patients being defined as having had a procedure related MI, with approximately 15% of patients undergoing PCI having an MI,w15 and higher rates in patients undergoing complex procedures. Therefore, this definition was not embraced enthusiastically by the interventional community.

This has led to a more strict definition of type 4a MI in the 2012 definition,2 in which PCI related MI is defined by an elevation of the cTn values >5× 99th centile URL occurring within 48 h after the procedure, as well as either: (1) symptoms suggestive of myocardial ischaemia; or (2) new ischaemic ECG changes; or (3) angiographic findings consistent with a procedural complication with loss of a major artery or side branch, decreased coronary flow, embolisation; or (4) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality.

Troponins should be measured before PCI to assess whether the baseline is stable, and measured 3–6 h afterwards and optionally 12 h after PCI. If the baseline is not stable or values are not falling, increasing biomarker values cannot be interpreted as being related to PCI.w14 If baseline biomarkers are elevated but not stable or declining, a rise of >20% is required for the diagnosis of MI. If biomarker values are not elevated >5× 99th centile URL, then the term myocardial injury should be used.

The increase from 3× to 5× 99th centile from the 2007 definition was chosen arbitrarily, given the increasing sensitivity of troponin assays. The need for the addition of ischaemic features and/or various angiographic complications was a consensus decision based on clinical judgment and societal implications of patients being labelled as having had a periprocedural MI. However, there are no studies available that have evaluated whether the additional use of angiographic data is useful in defining the prognostic importance of type 4a MIs. Other factors that were considered were the lack of convincing data that biomarker elevations of 3× 99th centile are prognostically important.w12 Consideration was also given to making the definition more symmetric with the coronary artery bypass grafting (CABG) definition, which requires more than just biomarker elevations and includes features such as the new development of Q waves, new LBBB or imaging evidence of loss of viability of the myocardium, or new wall motion abnormalities.

It is expected that raising the biomarker threshold by 66% and requiring other factors will significantly decrease the number of periprocedural MIs; time will tell whether they are related to an adverse prognosis.

The recommendation that biomarkers should be measured 3–6 h after PCI should be possible with day case procedures. However, documentation of angiographic complications will be challenging.

MI related to stent thrombosis (MI type 4b) is defined by coronary angiography and/or autopsy in the setting of myocardial ischaemia, with a rise and/or fall of cardiac biomarkers with at least one value >99th centile URL as for type 1 MI.

Type 5 MI: CABG related

Elevation of cardiac biomarker values after CABG is inevitable due to myocardial trauma, with dissection of the coronary arteries and manipulation of the heart. In addition, biomarkers may increase if there is inadequate cardiac protection, reperfusion injury, or graft failure after the operation.

Any increase in cardiac biomarker values >99th centile URL is defined as myocardial injury. By arbitrary convention, values of biomarkers >10× 99th centile URL during the first 48 h (changed from 72 h in the 2007 definition) occurring from a normal baseline, plus additional features of new Q waves or new LBBB, angiographic documentation of new graft or new native coronary artery occlusion, or imaging evidence of new regional wall motion abnormality or new loss of viable myocardium, fulfil the criteria for type 5 MI.

After 48 h following surgery, the existing principles from the universal definition may be applied. Further data are required to validate these criteria and to determine their impact on prognosis.

Persistence of troponin elevations and reinfarction

Values of troponin may remain elevated for 2 weeks.10 ,11 There was initially concern that there may be difficulty diagnosing reinfarction when troponin concentrations are elevated. This is not the case and data suggest that reinfarction can be detected if there is a >20% change in valuesw16 and this is the recommendation of the 2012 definition.

Application of the Third Universal Definition of MI in clinical trials

It is useful in clinical trials to include only patients who may benefit from a potential therapy—for example, the impact of antithrombotic therapy on plaque rupture—and thus to include only patients who have had a previous type 1 MI. The standardised definition proposed in the 2012 document should facilitate that. In addition, the effects of a therapy can and should be determined separately for each type of MI as was done in TRITON-TIMI 38 (Prasugrel Trial to Assess Improvement in Therapeutic Outcomes by Optimising Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38).13 A template for the spectrum of biomarker elevations is recommended to be available from all trials, either in the primary manuscript or in an appendix. However, this recommendation has been implemented only sporadically across clinical trials.17w17

A new category of MI type 4c has been created for reporting in clinical trials, for the not uncommon situation where a patient presents with an MI (rise and/or fall in troponins in the setting of ischaemia), with ECG changes in the territory of previous successful stent deployment or balloon angioplasty, and when the only angiographic finding is restenosis ≥50%. This designation will be very useful for adjudication committees in clinical trials where an event is clearly neither a type 1 MI (plaque rupture in a native coronary artery segment) nor a type 4b MI related to stent thrombosis.

Myocardial injury or infarction associated with heart failure

This is a new section of the 2012 definition. As with other syndromes, elevated cardiac biomarker values alone do not make the diagnosis of MI. In the setting of acutely decompensated heart failure, elevations of troponins, often with background known prior elevations due to multiple processes, are common. However, even if there is a rising pattern of values, only if there are ischaemic symptoms, new ischaemic ECG changes or imaging evidence of loss of myocardial function should the diagnosis of MI be made. It may be difficult at times to distinguish a type 1 MI from a type 2 MI due to elevated left ventricular end diastolic pressure, myocardial stretch, endothelial dysfunction, anaemia or hypotension.

Impact of the previous definitions

A number of studies have evaluated the impact of the 2000 definition of MI and shown an increase in the frequency of MI due to the more sensitive criteria advocated by the use of troponins. Increases in the incidence of MI have varied from 41% in Omsted County, Minnesotaw18 to 83% in a Finnish study.w19 Importantly, the additional patients with MI had a substantial risk of cardiovascular death, and in the Finnish study the 1 year prognosis was worse for those patients than patients who met the WHO Monica definition of MI (HR 1.6, 95% CI 1.1 to 2.2).

Although other studies have provided different estimates, it is clear that, despite progressively more sensitive troponin assays, individuals identified with MI have an adverse prognosis, both short term as in GRACE (Global Registry of Acute Coronary Events) (OR 2.8, 95% CI 2.2 to 3.5)w20 and long term (HR 1.58, 95% CI l.07 to 2.40, p=0.03).w21 Importantly, in the latter study the definition of MI based on CK-MB was not associated with an increase in 10  year mortality. If less standard definitions of MI are used in clinical trials, it is possible that they may bias the results.

The universal definition has also been used for the reanalysis of data from prior trials with illuminating results. The long term outcome of the Occluded Artery Trial (OAT) has been reported using the universal definition,14 compared with the original trial definition of MI. It was shown that reinfarction was more common in the PCI group using the universal definition, raising further questions concerning the advisability of opening occluded arteries late after MI in the absence of clear clinical indications. Further, in a pooled analysis of two large negative phase III trials with the P2Y12 antagonist cangrelor, it became clear that with the universal definition of MI, instead of the protocol definition of MI, there was a reduction in the primary end point which included MI as opposed to a null result.18 This has led to the design of a further large phase III trial, the (CHAMPION PHOENIX) Cangrelor versus standard therapy to achieve optimal management of platelet inhibition trial, with cangrelor using the universal definition of MI in the primary end point.w10 The trial showed a significant 20% reduction in MI.19

Some clinicians have questioned the value of the clinical typing of MIs in relation to prognosis, but doing so will make these studies more applicable to direct patient care. Several studies have shown that type 1 MIs have a worse prognosis than type 4a MIs.17w22 Also the TRITON trial showed that, overall, patients who had an MI defined by the universal definition had higher mortality compared with patients without an MI (HR 5.2, 95% CI 3.8 to 7.1).w23 The higher risk of mortality was present across all subtypes of MI including type 4a (3.2% vs 1.3%, p<0.001) and type 4b (15.4% vs 1.3%, p<0.001). Also, in a combination of the early ACS (Acute Coronary Syndrome) and SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularisation and Glycoprotein IIb/IIIa Inhibitors) datasets, type 1 MIs had a different prognosis than type 4a MIs with an approximate four times higher 1 year mortality.17 These data begin what will likely be a beneficial process of standardising the definitions used for clinical trials.

Implications for patients

By continuing the advocacy for the use of troponin and as the assays become progressively more sensitive, the universal definition likely will increase the incidence of MI and decrease the diagnosis of unstable angina. This has been well shown in a series of TIMI trials: in the TIMI IIIB trialw24 in 1996, the cut point for URL of troponin I was 0.4 ng/ml; in the TIMI IIB trialw25 w26 in 2000 the URL cut point with a newer assay was ≥0.10 ng/ml; and in the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction (MERLIN-TIMI) 36 trial in 2010 the URL was 0.04 ng/ml. The numbers of patients with unstable angina in these three trials with similar populations and different assays reduced progressively from 65.5% to 49.4% to 35.0%.w27 Also, in a small study of 50 patients with unstable angina (rest pain and serial negative cTnI), the use of an ultrasensitive nanoparticle assay for cTnI measured at 0, 2, and 8 h found, respectively, 44%, 62%, and 82% of patients had values ≥ the 99th centile decision limit.w28 This indicates that ischaemia with rest pain without myocardial injury may be uncommon with the new assays. The use of higher sensitivity troponins will decrease the number of patients with unstable angina even further. Negative high sensitivity troponin values measured over 3–6 h can rule out acute coronary syndrome9 and many of these patients may have normal coronary arteries.

In 2013 the diagnosis of MI has different implications for patients than the diagnosis did 10 years ago, which clearly has social, psychological and epidemiological impacts.w29 At present, the prognosis for many patients is excellent with early return to work and normal activities, but the group is still very heterogeneous. Prognosis is affected not only by the type of MI but also by other factors such as the ejection fraction, whether reperfusion and revascularisation has been successful or not, whether there is associated CAD, and whether there are associated risk factors such as diabetes, dyslipidaemia, hypertension, smoking or renal failure. In addition, prescribing and adherence to evidence based therapies is very important.

The diagnosis of an MI may affect insurability and much work is required to be done with insurance companies to define the different prognoses with the different types of MI. For example, a small type 2 MI with normal left ventricular function that occurred in conjunction with a severe haemodynamic challenge will have an excellent prognosis (eg, MI related to hypotension following hysterectomy).

Further work is also required in relation to diagnosis-related coding so that the types of MI are coded appropriately on discharge from hospital and reimbursed accordingly. In addition, an applicable code for myocardial injury should be established in collaboration with the World Health Organization to be included in the International Classification of Diseases.

Global implications

The rates of cardiovascular events are exploding worldwide and a standardised definition will be useful for epidemiological comparisons. From the epidemiological point of view the incidence of MI is very important for monitoring CAD prevalence,w30 and changes in diagnostic criteria will affect trend data. Changing criteria may also shift the clinical spectrum of MI.

It is recognised that in countries with limited economic resources that biomarkers and imaging modalities (and sometimes ECGs) may not be available and hence more flexible standards are required.20

The new MI definition has important changes, which have been achieved by international consensus. It is hoped that the new definition will be embraced worldwide and be used to improve patient care.

Clinical implications of the Third Universal Definition of Myocardial Infarction: key points

  • Troponins remain a core part of the diagnosis, along with clinical history, ECG criteria, imaging, and identification of intracoronary thrombus by angiography as additional criteria when troponins are elevated.

  • Five types of myocardial infarction (MI) are defined, based on pathological, clinical, and prognostic differences.

  • As a result, there will be more MIs and fewer cases of unstable angina.

  • The prognosis of patients with MI will be better than for patients with previous definitions of MI because small MIs will be diagnosed.

  • The clinical spectrum of MI will change.

  • Distinction between type 1 and type 2 MI is often difficult.

  • The criteria for percutaneous coronary intervention (PCI) related MI (type 4a) have been made more strict, requiring associated ischaemia or angiographic complications and greater elevation of troponins (>5× vs >3× URL). A normal or unchanging baseline value is key to this diagnosis.

  • Change in the type 4a MI criteria will result in fewer PCI related MIs and these may be more closely related to prognosis.

  • Changes in the criteria for the diagnosis of MI will have social and psychosocial implications for patients as well as an impact on epidemiology with effects on trend data.

  • The standard definition will facilitate comparison across clinical studies and registries.

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Acknowledgments

We would like to thank Charlene Nell, Team Support Administrator, Green Lane Cardiovascular Research Unit, for excellent secretarial assistance.

References

  1. The universal definition of MI re-emphasised the importance of troponins and recommended that five types of MI be defined.
  2. The Third Universal Definition of MI consensus statement defined clinical criteria for the diagnosis of MI corresponding to contemporary management. New ECG and imaging criteria are added, the definitions for the five types of MI are refined, and the presence of angiographic intracoronary thrombus is added as a criterion.
  3. The first international consensus for a new definition of MI, recommending troponins as central to the diagnosis.
  4. A classification of the six potential pathobiological causes of troponin elevations is defined. Potential mechanisms include myocyte necrosis, apoptosis, normal myocyte turnover, cellular release of troponin degradation products, increased cell wall permeability, and release of membranous blebs.
  5. A publication by the European Biochemical Working Group with recommendations on how to use high sensitivity troponins for the diagnosis of MI.
  6. An editorial discussing why CK-MB should no longer be used for the diagnosis of MI associated with PCI (type 4a)
  7. An editorial discussing many of the issues in relation to a type 4a MI including the need for a stable baseline and the need for more data with respect to prognosis using troponins and associated ischaemia and/or angiographic complications.
  8. A pooled analysis of two large negative clinical trials testing the intravenous P2Y12 inhibitor cangrelor compared with clopidogrel. On re-analysis using the universal definition of MI there was a significant reduction in ischaemic events leading to a new large trial.
  9. The WHO has a played a leading role in developing standard criteria for the diagnosis of MI since the early 1970s. This article presents a revision of the WHO definition taking into account the universal definition and the common situation in resource constrained settings where biomarkers and ECGs may not be available.
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Footnotes

  • Contributors All authors have made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data. All authors have been involved in drafting the article or revising it critically for important intellectual content, and all authors have given final approval of the version to be published.

  • Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. HW has received research grants from: Sanofi Aventis; Eli Lilly; Medicines Company; NIH; Pfizer; Roche; Johnson & Johnson; Schering Plough; Merck Sharpe & Dohme; Astra Zeneca; GlaxoSmithKline; Daiichi Sankyo Pharma Development and Bristol-Myers Squibb, and has served on advisory boards for Merck Sharpe & Dohme, Roche and Regado Biosciences. KT has received lecture honoraria from Roche Diagnostics. JSA has received Consultation and Data Safety and Monitoring honoraria from Servier pharma, Johnson & Johnson, Bayer, Daiichi Sankyo Pharma, Sanofi Aventis, Bristol Myers Squibb, Elsevier Publishers, and UptoDate. AJ has consulted or presently consults for most of the major diagnostic companies. At present these include Roche, Alere, Abbott Ortho, Critical Diagnostics, and Radiometer. He also consults for Amgen.

  • Provenance and peer review Commissioned; externally peer reviewed.

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