Definitions according to 2015 ESC Guidelines for the management of NSTE-ACS

The leading symptom that initiates the diagnostic and therapeutic cascade in patients with suspected ACS is chest pain. Based on the ECG, two groups of patients should be differentiated:

(1) Patients with acute chest pain and persistent (>20 min) ST-segment elevation. This condition is termed ST-elevation ACS and generally reflects an acute total coronary occlusion. Most patients will ultimately develop an STEMI.

(2) Patients with acute chest pain but no persistent ST-segment elevation. ECG changes may include transient ST-segment elevation, persistent or transient ST-segment depression, T-wave inversion, flat T waves or pseudo-normalization of T waves or the ECG may be normal. The clinical spectrum of non-ST-elevation ACS (NSTE-ACS) may range from patients free of symptoms at presentation to individuals with ongoing ischaemia, electrical or haemodynamic instability or cardiac arrest. The pathological correlate at the myocardial level is cardiomyocyte necrosis [NSTE-myocardial infarction (NSTEMI)] or, less frequently, myocardial ischaemia without cell loss (unstable angina).

Anginal pain in NSTE-ACS patients may have the following presentations:
• Prolonged (>20 min) anginal pain at rest;
• New onset (de novo) angina (class II or III of the Canadian Cardiovascular Society classification);
• Recent destabilization of previously stable angina with at least Canadian Cardiovascular Society Class III angina characteristics (crescendo angina); or
• Post-MI angina.

Universal definition of myocardial infarction (2015 ESC Guideline)

A combination of criteria is required to meet the diagnosis of acute MI, namely the detection of an increase and/or decrease of a cardiac biomarker, preferably high-sensitivity cardiac troponin and at least one of the following: (1) Symptoms of ischaemia. (2) New or presumed new significant ST-T wave changes or LBBB on 12-lead ECG. (3) Development of pathological Q waves on ECG. (4) Imaging evidence of new or presumed new loss of viable myocardium or regional wall motion abnormality. (5) Intracoronary thrombus detected on angiography or autopsy.

Type 1 MI
Type 1 MI is characterized by atherosclerotic plaque rupture, ulceration, fissure, erosion or dissection with resulting intraluminal thrombus in one or more coronary arteries leading to decreased myocardial blood flow and/or distal embolization and subsequent myocardial necrosis. The patient may have underlying severe CAD but, on occasion (i.e. 5–20% of cases), there may be non-obstructive coronary atherosclerosis or no angiographic evidence of CAD, particularly in women.

Type 2 MI
Type 2 MI is myocardial necrosis in which a condition other than coronary plaque instability contributes to an imbalance between myocardial oxygen supply and demand. Mechanisms include coronary artery spasm, coronary endothelial dysfunction, tachyarrhythmias, bradyarrhythmias, anaemia, respiratory failure, hypotension and severe hypertension. In addition, in critically ill patients and in patients undergoing major non-cardiac surgery, myocardial necrosis may be related to injurious effects of pharmacological agents and toxins. The universal definition of MI also includes type 3 MI (MI resulting in death when biomarkers are not available) and type 4 and 5 MI (related to PCI and CABG, respectively)

Cardiac biomarkers
Cardiac troponins are more sensitive and specific markers of cardiomyocyte injury than CK, CK-MB and myoglobin. In patients with MI, levels of cardiac troponin rise rapidly (i.e. usually within 1 h if using high-sensitivity assays) after symptom onset and remain elevated for a variable period of time (usually several days). CK-MB shows a more rapid decline after MI as compared with cardiac troponin and may provide added value for the timing of myocardial injury and the detection of early reinfarction (e.g. suspected MI after CABG in hospital).

Rhythm monitoring
NSTEMI patients at low risk for cardiac arrhythmias require rhythm monitoring for ≤24 h or until coronary revascularization (whichever comes first) in an intermediate or coronary care unit, while individuals at intermediate to high risk for cardiac arrhythmia may require rhythm monitoring for >24 h in an intensive or coronary care unit or in an intermediate care unit, depending on the clinical presentation, degree of revascularization and early post-revascularization course.

DAPT
In patients with NSTE-ACS, DAPT with aspirin and clopidogrel has been recommended for 1 year over aspirin alone, irrespective of revascularization strategy and stent type, according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, while the TRITON-TIMI 38 and PLATO studies have demonstrated the superiority of a prasugrel- and ticagrelor-based regimen, respectively, over a clopidogrel-based one. Evidence to support the extension of DAPT after DES beyond 1 year in NSTE-ACS patients is limited.

Unstable angina (2015 ESC Guideline)

Unstable angina is defined as myocardial ischaemia at rest or minimal exertion in the absence of cardiomyocyte necrosis. Dual antiplatelet therapy comprising aspirin and clopidogrel has been shown to reduce recurrent ischaemic events in the NSTE-ACS setting compared with aspirin alone. Compared with NSTEMI patients, individuals with unstable angina do not experience myocardial necrosis, have a substantially lower risk of death and appear to derive less benefit from intensified antiplatelet therapy as well as early invasive strategy.

Revascularization in NSTE-ACS (2014 ESC Guidelines on myocardial revascularization)

Patients in cardiogenic shock, or after resuscitation, should undergo immediate angiography (within 2 hours) because of the high likelihood of critical CAD, but it is equally important to identify patients at low risk, in whom invasive and medical treatments provide little benefit or may even cause harm.

Early invasive vs. conservative strategy

A more recent meta-analysis, based on individual patient data from three studies that compared a routine invasive against a selective invasive strategy, revealed lower rates of death and myocardial infarction at 5-year follow-up, with the most pronounced difference in high-risk patients. Age, diabetes, previous myocardial infarction, ST-segment depression, hypertension, body mass index (<25 kg/m2 or >35 kg/m2), and treatment strategy were found to be independent predictors of death and myocardial infarction during follow-up. All results supported a routine invasive strategy but highlight the importance of risk stratification in the decision-making process management.

Timing of angiography and intervention (Also according to 2015 ESC Guidelines for the management of NSTE-ACS)

The timing of angiography and revascularization should be based on patient risk profile.

A) Patients at very high risk (i.e. those with refractory angina, severe heart failure or cardiogenic shock, life-threatening ventricular arrhythmias, marked ST depression or haemodynamic instability) should be considered for urgent coronary angiography (in less than 2 hours), regardless of ECG or biomarker findings.

B) In patients at high risk, with at least one of high-risk criterion (Tabl), an early invasive strategy within 24 hours appears to be the reasonable timescale.

C) Invasive strategy (<72 h) is the recommended maximal delay for angiography in patients with at least one intermediate risk criterion, recurrent symptoms or known ischaemia on non-invasive testing.

D) In other low-risk patients without recurrent symptoms, a noninvasive assessment of inducible ischaemia should be performed before hospital discharge and before deciding on an invasive strategy.

Type of revascularization

In stabilized patients, the choice of revascularization modality can be made in analogy to patients with SCAD. In multivessel disease the decision is more complex and the choice has to be made between culprit-lesion PCI, multivessel PCI,CABG, or a hybrid revascularization.

Culprit-lesion PCI is usually the first choice in most patients with NSTE-ACS and multivessel disease; however, there are no prospective studies comparing culprit-lesion PCI with early CABG. In stabilized patients with multivessel disease and a high SYNTAX score (>22), particularly when there is no clearly identified culprit lesion, a strategy of urgent CABG should be preferred. In a large database including 105 866 multivessel CAD patients with NSTE-ACS, multivessel PCI was compared with single-vessel PCI and was associated with lower procedural success but similar in-hospital mortality and morbidity. However, incomplete revascularization appears to be associated with more 1-year adverse event rates.

After culprit-lesion PCI, patients with scores in the two higher terciles of the SYNTAX score should be discussed by the Heart Team, in the context of functional evaluation of the remaining lesions. This also includes the assessment of patients' comorbidities and individual characteristics.

As there is no randomized study comparing an early with a delayed CABG strategy, the general consensus is to wait 48–72 hours in patients who had culprit-lesion PCI and have residual severe CAD. When there is continuing or recurrent ischaemia, ventricular arrhythmias, or haemodynamic instability, CABG should be performed immediately. Patients with LM or three-vessel CAD involving the proximal LAD should undergo surgery during the same hospital stay. Pre-treatment with a dual antiplatelet regimen should be considered only as a relative contraindication to early CABG.

New generation DES are preferred over BMS as the default option. Dual antiplatelet therapy (DAPT) should be maintained for 12 months, irrespective of stent type.

Revascularization in NSTE-ACS (from AHA/ACC Guideline 2014)

Ischemia-Guided Strategy Versus Early Invasive Strategies
Two treatment pathways have emerged for all patients with NSTE-ACS. The invasive strategy triages patients to an invasive diagnostic evaluation. In contrast, the initial ischemia-guided strategy calls for an invasive evaluation for those patients who 1) fail medical therapy (refractory angina or angina at rest or with minimal activity despite vigorous medical therapy), 2) have objective evidence of ischemia (dynamic electrocardiographic changes, myocardial perfusion defect) as identified on a noninvasive stress test, or 3) have clinical indicators of very high prognostic risk (e.g., high TIMI or GRACE scores). In both strategies, patients should receive optimal anti-ischemic and antithrombotic medical therapy. A subgroup of patients with refractory ischemic symptoms or hemodynamic or rhythm instability are candidates for urgent coronary angiography and revascularization.

Rationale and Timing for Early Invasive Strategy
This strategy seeks to rapidly risk stratify patients by assessing their coronary anatomy. The major advantages of invasive therapy when appropriate are 1) the rapid and definitive nature of the evaluation, 2) the potential for earlier revascularization in appropriate patients that might prevent occurrence of further complications of ACS that could ensue during medical therapy, and 3) facilitation of earlier discharge from a facility.

Routine Invasive Strategy Timing
The optimal timing of angiography has not been conclusively defined. In general, 2 options have emerged: early invasive (i.e., within 24 hours) or delayed invasive (i.e., within 25 to 72 hours). In most studies using the invasive strategy, angiography was deferred for 12 to 72 hours while antithrombotic and anti-ischemic therapies were intensified. The concept of deferred angiography espouses that revascularization may be safer once plaque is stabilized with optimal antithrombotic and/or anti-ischemic therapies. Conversely, early angiography facilitates earlier risk stratification and consequently speeds revascularization and discharge but can place greater logistic demands on a healthcare system.

Rationale for Ischemia-Guided Strategy
The ischemia-guided strategy seeks to avoid the routine early use of invasive procedures unless patients experience refractory or recurrent ischemic symptoms or develop hemodynamic instability. When the ischemiaguided strategy is chosen, a plan for noninvasive evaluation is required to detect severe ischemia that occurs at a low threshold of stress and to promptly refer these patients for coronary angiography and revascularization as indicated. The major advantage offered by the ischemia guided strategy is that some patients' conditions stabilize during medical therapy and will not require coronary angiography and revascularization. Consequently, the ischemia-guided strategy may potentially avoid costly and possibly unnecessary invasive procedures.

Early Invasive and Ischemia-Guided Strategies: Recommendations

CLASS I
1. An urgent/immediate invasive strategy (diagnostic angiography with intent to perform revascularization if appropriate based on coronary anatomy) is indicated in patients with NSTE-ACS who have refractory angina or hemodynamic or electrical instability (without serious comorbidities or contraindications to such procedures). 2. An early invasive strategy is indicated in initially stabilized patients with NSTE-ACS who have an elevated risk for clinical events (Table)

CLASS IIa
1. It is reasonable to choose an early invasive strategy (within 24 hours of admission) over a delayed invasive strategy (within 25 to 72 hours) for initially stabilized high-risk patients with NSTE-ACS. For those not at high/intermediate risk, a delayed invasive approach is reasonable.

CLASS IIb
1. In initially stabilized patients, an ischemia-guided strategy may be considered for patients with NSTE-ACS who have an elevated risk for clinical events. 2. The decision to implement an ischemia-guided strategy in initially stabilized patients may be reasonable after considering clinician and patient preference.

CLASS III: NO BENEFIT
1. An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is not recommended in patients with: a. Extensive comorbidities (e.g., hepatic, renal, pulmonary failure; cancer), in whom the risks of revascularization and comorbid conditions are likely to outweigh the benefits of revascularization. b. Acute chest pain and a low likelihood of ACS who are troponin-negative, especially women. Several studies and meta-analyses have concluded that a strategy of routine invasive therapy is generally superior to an ischemia-guided strategy or selectively invasive approach.

Comparison of Early Versus Delayed Angiography
In some studies, early angiography and coronary intervention have been more effective in reducing ischemic complications than delayed interventions, particularly in patients at high risk (defined by a GRACE score >140) A more delayed strategy is also reasonable in low- to intermediate-risk patients. The advantage of early intervention was achieved in the context of intensive background antithrombotic and anti-ischemic therapy. However, this question was also assessed by a meta-analysis of 11 trials. Meta-analysis of the RCTs was inconclusive for a survival benefit of the early invasive strategy, and there were no significant differences in MI or major bleeding; a similar result was found with the observational studies.

A meta-analysis suggests that in NSTE-ACS, an invasive strategy has a comparable benefit in men and high-risk women for reducing the composite endpoint of death, MI, or rehospitalization. In contrast, an ischemia guided strategy is preferred in low-risk women. An invasive strategy appeared to reduce recurrent nonfatal MI to a greater extent in patients with diabetes mellitus.

Patients with left main disease or multivessel CAD with reduced LV function are at high risk for adverse outcomes and are likely to benefit from CABG. Clinical evaluation and noninvasive testing aid in the identification of most patients at high risk because they often have $1 of the following high-risk features: advanced age (>70 years of age), prior MI, revascularization, ST deviation, HF, depressed resting LV function (i.e., LVEF #0.40) on noninvasive study, or noninvasive stress test findings. Any of these risk factors or diabetes mellitus may aid in the identification of high-risk patients who could benefit from an invasive strategy.

The goals of noninvasive testing in patients with a low or intermediate likelihood of CAD and high-risk patients who did not have an early invasive strategy are to detect ischemia and estimate prognosis.

Patient and clinician judgments about risks and benefits are important for patients who might not be candidates for coronary revascularization, such as very frail older adults and those with serious comorbid conditions (e.g., severe hepatic, pulmonary, or renal failure; active or inoperable cancer).

Compilation by Dr. Samad Ali Moradi; According to 2015 ESC Guidelines for the management of NSTE-ACS, 2014 ESC Guidelines on myocardial revascularization and AHA/ACC Guideline 2014.