Abstract

Cardiovascular diseases are currently the leading cause of death in industrialized

countries and are expected to become so in emerging countries by 2020.1 Among

these, coronary artery disease (CAD) is the most prevalent manifestation and is
associated with high mortality and morbidity. The clinical presentations of CAD include
silent ischaemia, stable angina pectoris, unstable angina, myocardial infarction (MI),
heart failure, and sudden death. Patients with chest pain represent a very substantial
proportion of all acute medical hospitalizations in Europe.
The present document deals with the management of patients with suspected
non-ST-elevation acute coronary syndrome (NSTE-ACS), replacing the document
published in 2007. The management of patients with ST-elevation MI (STEMI) is
addressed in the respective ESC Guidelines.

Definitions
The leading symptom that initiates the diagnostic and therapeutic cascade is chest pain,
but the classification of patients is based on the electrocardiogram (ECG). Two
categories of patients may be encountered:

1. Patients with acute chest pain and persistent (>20 min)

ST-segment elevation.
This is termed ST-elevation ACS (STE-ACS) and generally reflects an acute total
coronary occlusion. Most of these patients will ultimately develop an STEMI. The
therapeutic objective is to achieve rapid, complete, and sustained reperfusion by
primary angioplasty or fibrinolytic therapy.
2. Patients with acute chest pain but without persistent ST-segment
elevation
These patients have rather persistent or transient ST-segment depression or
T-wave inversion, flat T waves, pseudo-nomalization of T waves, or no ECG
changes at presentation. The initial strategy in these patients is to alleviate
ischaemia and symtomps, to monitor the patient with serial ECGs, and to repeat
measurements of markers of myocardial necrosis. At presentation, th working
diagnosis of NSTE-ACS, based on the measurement of troponins, will be further
qualified as non ST-elevation MI (NSTEMI) or unstable angina. In some patients,
coronary heart disease will subsequently be excluded as the cause of symtomps.
Diagnosis
Distinguishing patient with ACS within the very large proportion with suspected cardiac
pain represents a diagnostic challenge, especially in individuals without clear symtomps
or electrocardiographic features. Despite modern treatment, the rates of death, MI, and
readmission of patients with ACS remain high.
The leading symtptom of ACS is typically chest pain. The working diagnosis of NSTE
ACS is a rule-out diagnosis based on the ECS, i.e. lack of persistent ST elevation.
Biomarkers (troponins) further distinguish NSTEMI and unstable angina. Imaging
modalities are used to rule out or rule in differential diagnoses.

Clinical presentation
The clinical presentation of NSTE-ACS encompasses a wide variety of symptoms.
The typical clinical presentation of NSTE-ACS is retrosternal pressure ofr heaviness
(angina) radiating to the left arm, neck or jaw, which may be intermittent (usually lasting
for several minutes) or persistens.

These complaints may be accompanied by other symptoms such as diaphoresis,

nausea, abdominal pain, dyspnoea, and syncope. However, atypical presentations are
not uncommon. These include epigastric pain, indigeston, stabbing chest pain, chest
pain with some pleuritic features, or increasing dyspnonea, in women, and in patients
with diabetes, chronic renal failure, or dementia. Absence of chest pain leads to under-
recognition and under treatment of disease.
Traditionally, several clinical prenstations have been distinguished :
 Prolonged (> 20 min) anginal pain at rest
 New onset (de novo) angina 9CCS class II or III)
 Recent destabilization of previously stable angina with at least CCS class III
angina charateristics (crescendo angina)
 Post MI angina

Diagnostic tools
Physical Examination : The physical examination is frequently normal. Signs of heart
failure or haemodynamic instability must prompt the physician to expedite diagnosis
and treatment. An important goal of the physical examination is to exclude non-
cardiac causes of chest pain and non-ischaemic cardiac disorders (e.g. pulmonary
embolism, aortic dissection, pericarditis, valvular heart disease) or potentially
extra-cardiac causes such as acute pulmonary diseases (e.g. pneumothorax,
pneumonia, or pleural effusion).

ECG : The resting 12-lead ECG is the first-line diagnostic tool in the assess- ment of
patients with suspected NSTE-ACS. It should be obtained within 10 min after first
medical contact and immediately interpreted by a qualified physician. The characteristic
ECG abnormalities of NSTE-ACS are ST-segment depression or transient elevation
and/or T-wave changes. The finding of persistent (>20 min) ST-elevation suggests
STEMI, which mandates different treatment
 Normal ECG does not exclude possibility of NSTE-ACS

Biomarkers : Cardiac troponins play a central role in establishing a diagnosis and

stratifying risk, and make it possible to distinguish between NSTEMI and unstable
angina. Troponins are more specific and sensitive than the traditional cardiac enzymes
such as creatine kinase (CK), its isoenzyme MB (CK-MB). A test with high ability to rule
out (negative predictive value) and correctly diagnose ACS (positive predictive value) is of
paramount interest. The diagnostic cut off for MI is defined as a cardiac population
(upper reference limit) using an assay with an imprecision (coefficient of variation) of
< 10% at the upper reference limit. In NSTE-ACS, minor troponin elevations usually
resolve within 48 – 72 h. There is no fundamental difference between troponin T and
troponin I. With recently introduced high sensitivity assays MI cn be detected more
frequently protocol 3 hous. In order to differentiate chronic from acute troponin
elevation the magnitude of change depending on the initial value gains importance at
borderline level.(table 3)
 The diagnosis of NSTE-ACS should never be made only on the basis of cardiac
biomarkers whose levation should be interpreted in hte context of other clinical
findings. For differential diagnoses of troponin elevations
Prognosis assessment
NSTE-ACS is an unstable coronary condition prone to ischaemic recurrences and
other complications that may lead to death or MI in the short and long term. The
management, which includes anti- ischaemic and antithrombotic pharmacological
treatments as well as various strategies for coronary revascularization, is directed to
prevent or reduce such complications and to improve outcomes.

Clinical risk assessment

In addition to some universal clinical markers of risk, such as advanced age,
diabetes, renal failure, or other co-morbidities, the initial clinical presentation is highly
predictive of early prognosis. Symptoms at rest carry a worse prognosis than
symptoms elicited only during physical exertion. In patients with intermittent symptoms,
an increasing number of episodes preceding the index event also has an impact on
outcome. The presence of tachycardia, hypotension, or heart failure upon presentation
indicates a poor prognosis and calls for rapid diagnosis and management.

ECG Indicators
The initial ECG presentation is predictive of early risk. The number of leads showing
ST depression and the magnitude of ST depression are indicative of the extent and
severity of ischaemia and correlate with prognosis.ST-segment depression ≥0.05 mV
in two or more contiguous leads, in the appropriate clinical context, is suggestive
of NSTE-ACS and linked to prognosis. Minor (0.1 mV) and particularly ST
depression of > 2 mm. ST depression of > 1 mm with transient ST-elevation also
identifies a high risk subgroup. Deep related to a significant stenosis of the proximal left
anterior descending coronary artery or main stem. Continous ST segment monitoring
adds independent prognostic information to that trovided by the ECG at rest, troponins,
and other clinical variables.

Biomarkers
Biomarkers reflect different pathophysiological aspects of NSTE-ACS, such as
myocardial cell injury, inflammation, platelet activation, and neurohormonal activation.
Troponin T or I are the preferred biomarkers to predict short-term (30 days)
outcome with respect to MI and death. The prognostic value of troponin
measurements has also been confirmed for the long term (1 year and beyond). Any
troponin elevation is associated with an adverse prognosis.

NSTEMI patients with elevated troponin levels but no rise in CK-MB (who comprise
approximately one third of the NSTEMI ), although undertreated, have a higher risk
profile and lower in-hospital mortality than patients with both markers elevated.
The increased risk associated with elevated troponin levels is independent of and
additive to other risk factors, such as ECG changes at rest or on continuous
monitoring, or markers of inflammatory activity. Furthermore, the identification of
patients with elevated troponin levels is also useful for selecting appropriate treatment
in patients with NSTE-ACS. However, troponins should not be used as the sole
decision criterion, because in-hospital mortality may be as high as in certain high risk
troponin-negative subgroups

Due to low sensitivity for MI, a single negative test on first contact with the
patient is not sufficient for ruling out NSTE-ACS, as in many patients an
increase in troponins can be detected only in the subsequent hours. Therefore,
repeated measurements after 6 – 9 h have been advocated. The recently introduced
high-sensitivity troponin assays better identify patients at risk and provide reliable and
rapid prognosis prediction allowing a fast track rule-out protocol (3 h).

Hyperglycaemia on admission is a strong predictor of mortality and heart failure even

in non-diabetic patients. More recently it became apparent that fasting glucose levels,
obtained early during the hospital course, may predict mortality even better than
admission levels.
Furthermore, fluctuations of fasting glucose during hospital stay are strongly
predictive of outcome and persistently abnormal fasting glucose levels carry a
particularly ominous prognosis.
A number of routine haematological variables are also predictors of worse prognosis.
Patient with anaemi have consistently been shown to be at higher risk. Similary
higher risk, similarly, higher white blood cell counts or lower platelet counts on
admission are associated with worse outcomes.
Impaired renal function is a strong independent predictor of long-term mortality in
ACS patients. Serum creatinine concen- tration is a less reliable indicator of renal
function than creatinine clearance (CrCl) or estimated glomerular filtration rate
(eGFR) because it is affected by a multitude of factors including age, weight,
muscle mass, race, and various medications. Several formulae have been devised
to improve the accuracy of the serum creatinine level as a surrogate for eGFR,
including the Cockcroft – Gault and the abbreviated Modification of Diet in Renal
Disease (MDRD) equations. Long-term mortality increases exponentially with
decreasing eGFR/CrCl

Risk scores
Quantitative assessment of risk is useful for clinical decision making. Several
scores have been developed from different populations to estimate ischaemic and
bleeding risks, with different outcomes and time frames. In clinical practice, simple risk
scores may be more convenient and preferred.

Risk scores of outcome

Among several risk scores predicting short- or mid-term risk of ischaemic events, the
GRACE and the TIMI risk scores are the most widely used. There are some
differences with respect to populations, outcomes, and time frames, as well as
predictors derived from baseline characteristics, history, clinical or haemodynamic
presentation, ECG, laboratory measures, and treatment. Based on direct comparisons,
the GRACE risk score provides the most accurate stratification of risk both on
admission and at discharge due to its good discriminative power.
Treatment

Antiplatelet agents
Platelet activation and subsequent aggregation play a dominant role in the propagation
of arterial thrombosis and consequently are the key therapeutic targets in the
management of ACS. Antiplatelet therapy should be instituted as early as possible
when the diagnosis of NSTE-ACS is made in order to reduce the risk of both acute
ischaemic complications and recurrent atherothrombotic events. Platelets can be
inhibited by three classes of drugs : aspirin, P2Y12 inhibitors, and glycoprotein Iib/IIIa
inhibitors.
 Anticoagulants
Anticoagulants are used in the treatment of NSTE-ACS to inhibit thrombin generation
and/or activity, thereby reducing thrombus- related events. There is evidence that
anticoagulation is effective in addition to platelet inhibition and that the combination of
the two is more effective than either treatment alone. Several anticoagulants, which
act at different levels of the coagulation cascade, have been investigated or are
under investigation in NSTE-ACS:

Indirect inhibitors of coagulation (need antithrombin for their full action)

Indirect thrombin inhibitors: UFH LMWHs
Indirect factor Xa inhibitors: LMWHs fondaparinux
Direct inhibitors of coagulation
Direct factor Xa inhibitors: Apixaban, rivaroxaban, otamixaban
Direct thrombin inhibitors (DTIs) : Bivalirudin, dabigatran
Coronary revascularization
Revascularization for NSTE-ACS relieves symptoms, shortens hos- pital stay, and
improves prognosis. The indications and timing for myocardial revascularization and
choice of preferred approach (PCI or CABG) depend on many factors including the
patient’s condition, the presence of risk features, co-morbidities, and the extent and
severity of the lesions as identified by coronary angiography.
Management strategy
This section summarizes the diagnostic and therapeutic steps as discussed in detail in
the previous sections and translates the key elements into checklists and a workflow.
This allows standardization of the clinical routine work-up and thereby improves
quality of care. However, specific findings in individual patients may result in
appropriate deviations from the proposed strategy since NSTE-ACS encompasses a
heterogeneous spectrum of patients with different levels of risk in terms of death, MI, or
recurrence of MI. For every patient, the physician must make an individ- ual decision,
taking into account the patient’s history (co-morbid illnesses, age, etc.), his/her clinical
condition, findings during the initial assessment on first contact, and the available
pharmacological and non-pharmacological treatment options.

Step one: initial evaluation

A patient with suspected NSTE-ACS must be evaluated in a hospital and seen
immediately by a qualified physician. Specialized chest pain units or coronary care
units provide the best and most expeditious care.
Diagnosis on which the treatment strategy will be based. The assessment criteria
are the following:
 Quality of chest pain and a symptom-orientated physical examination
 Assessment of the likelihood of CAD (e.g. age, risk factors, previous MI,
CABG, PCI)
 ECG (to detect ST-segment deviation or other abnormality)

On the basis of these findings, which should be available within 10 min of first
medical contact, the patient can be assigned to one of the three major working
diagnoses:
 STEMI
 NSTE-ACS;
 ACS (highly) unlikely.

The treatment of patients with STEMI is covered in the respective guidelines.2 The
assignment to the category ‘unlikely’ must be done with caution and only when another
explanation is obvious (e.g. thorax trauma). The initial treatment measures are
summarized in Table.
Blood is drawn on arrival of the patient in hospital and the results should be
available within 60 min to be used in the second step. Initial blood tests must at
least include: troponin T or I, creatinine, haemoglobin, blood glucose, and blood
cell count, in addition to standard biochemistry tests.
Assignment of the patient to the NSTE-ACS category will lead on to step two
diagnosis validation and risk assessment.

Step two: diagnosis validation and risk assessment

After the patient is assigned to the group NSTE-ACS, i.v. and oral antithrombotic
treatments will be started according to Table . Further management of the patient
will be based on additional information/data:
 Responsiveness to antianginal treatment.
 Routine clinical chemistry, particularly troponins (on presen- tation and after
6 – 9 h) and other markers, according to working diagnoses (e.g. D-dimers,
BNP, NT-proBNP); if highly sensitive troponin assays are available, a fast
track rule-out protocol (3 h) may be implemented (Figure 5).
 Repeat or continuous ST-segment monitoring (when available).
 Ischaemic risk score assessment (GRACE score).
 Echocardiogram;
 Optional: chest X-ray, CT, MRI or nuclear imaging for differen- tial diagnoses (e.g.
aortic dissection, pulmonary embolism, etc.).

During step two, other diagnoses may be confirmed or excluded, such as

pulmonary embolism and aortic aneurysm Treatment of the individual patient is tailored
according to their risk for subsequent events, which should be assessed early at the
initial presentation as well as repeatedly thereafter in the light of continuing or
repetitive symptoms and additional information from clinical chemistry or imaging
modalities.
Risk assessment is an important component of the decision- making process and is
subject to constant re-evaluation. It encompasses assessment of both ischaemic
and bleeding risk. The risk factors for bleeding and ischaemic events overlap
considerably, with the result that patients at high risk of ischaemic events are
also at high risk of bleeding.
Therefore, the choice of pharmacological environment (dual or triple anti- platelet
therapy, or anticoagulants) is important, as is the dosage of the drugs and the
access site in the case of angiography. Particular attention has to be paid to
renal dysfunction, shown to be particularly frequent in elderly patients and
diabetic patients. The pharmacological options are summarized in Table
Step three: invasive strategy
Cardiac catheterization followed by revascularization has been shown to prevent
recurrent ischaemia and/or improve short-
and long-term outcomes. Several risk factors (troponin elevation, diabetes, ST-
segment depression, renal insufficiency, etc.) have been identified to predict the long-
term benefit of an invasive strategy. Depending on the acuteness of risk, the timing
of angiography can be tailored, according to four categories
 invasive (,72 h);
– urgent invasive (,120 min);
– early invasive (,24 h);
 primarily conservative.
The optimal timing depends on the risk profile of the individual patient and can be
assessed by several variables.

Urgent invasive strategy (<120 min after first medical contact) This should be
undertaken for very high risk patients. These patients are characterized by:
 Refractory angina (indicating evolving MI without ST abnormalities).
  Recurrent angina despite intense antianginal treatment, associ- ated with ST
depression (2 mm) or deep negative T waves.
 Clinical symptoms of heart failure or haemodynamic instability (‘shock’).
 Life-threatening arrhythmias (ventricular fibrillation or ventricu- lar tachycardia).

A GP IIb/IIIa receptor inhibitor (eptifibatide or tirofiban) may be considered in patients

with such features in order to bridge the prior to PCI is given in Table

Early invasive strategy (<24 h after first medical contact) Most patients initially
respond to the antianginal treatment, but are at increased risk and need angiography
followed by revascu- larization. High risk patients as identified by a GRACE risk
score >140 and/or the presence of at least one primary high risk criterion
should undergo invasive evaluation within 24 h.

Invasive strategy (<72 h after first medical contact)

In patients with less acute risk, according to Table 9, and without recurrence of
symptoms, angiography may be performed within a time window of 72 h. Thus, such
patients should undergo elective invasive evaluation at the first opportunity depending
on the local circumstances.
Conservative strategy (no or elective angiography)
Patients that fulfil all of the following criteria may be regarded as low risk and should
not routinely be submitted to early invasive evaluation :
 No recurrence of chest pain
 No signs of heart failure
 No abnormalities in the initial ECG or a second ECG (at 6 – 9 h)
 No rise in troponin level (at arrival and at 6 – 9 h)
 No inducible ischaemia

Low risk as assessed by a risk score (see Section 4.4) should support the
decision-making process for a conservative strategy. The further management of
these patients is according to the evaluation of stable CAD. Before discharge from hospital,
a stress test for inducible ischaemia is useful for treatment planning and required
before elective angiography.

Step four: revascularization modalities

If the angiogram shows atheromatous burden but no critical cor- onary lesions,
patients will be referred for medical therapy. The diagnosis of NSTE-ACS may be
reconsidered and particular attention paid to other possible reasons for symptoms
at pres- entation, before the patient is discharged. However, the absence of critical
coronary lesions does not rule out the diagnosis if the clinical presentation was
suggestive of ischaemic chest pain and if biomarkers were positive.In this situation,
patients should receive treatment according to the recommendations for NSTE-
ACS.
Recommendations for the choice of a revascularization modality in NSTE-ACS are
similar to those for elective revascularization procedures. In patients with single-
vessel disease, PCI with stenting of the culprit lesion is the first choice. In patients with
multivessel disease, the decision for PCI or CABG must be made individually,
according to institutional protocols designed by the ‘Heart Team’. A sequential
approach, consisting of treating the culprit lesion with PCI followed by elective CABG
with proof of ischaemia and/or functional assessment (FFR) of the non-culprit
lesions, may be advantageous in some patients.

The anticoagulant should not be changed during PCI. In patients pre-treated

with fondaparinux, UFH must be added before PCI. A GP IIb/IIIa inhibitor should be
considered if tropo- nins are elevated or on angiographic presence of thrombus. If
CABG is planned, P2Y12 inhibitors should be stopped and surgery deferred
only if the clinical condition and the angio- graphic findings permit.
If angiography shows no options for revascularization, owing to the extent of the
lesions and/or poor distal run-off, freedom from angina at rest should be achieved by
intensified medical therapy, and secondary preventive measures should be instituted.

Step five: hospital discharge and post-discharge management

Although in NSTE-ACS most adverse events occur in the early phase, the risk for
MI or death remains elevated over several months. Patients treated with early
revascularization are at low (2.5%) risk for developing life-threatening arrhythmias,
with 80% occurring during the first 12 h after onset of symptoms. Accordingly, routine
monitoring of the patients beyond 24 – 48 h is not warranted. Patients with NSTE-
ACS should be hospitalized for at least 24 h after successful stenting of the culprit
lesion.
Intense risk factor modification and lifestyle change are warranted in all patients following
the diagnosis of NSTE-ACS . Enrolment in a cardiac rehabilitation programme after
discharge can enhance patient adherence to the medical regimen and may be sup-
portive in risk factor modification. A checklist of measures necessary at discharge from
hospital is given in Table
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