2023 ESC Guidelines for the management of acute coronary syndromesESC Clinical Practice Guidelines
Introduction
ACS, acute coronary syndrome; involves performing an electrocardiogram (ECG) to assess for Abnormalities or evidence of ischaemia, taking a targeted clinical history to assess the clinical Context of the presentation, and carrying out a targeted clinical examination to assess for clinical and haemodynamic Stability. Based on the initial assessment, the healthcare provider can decide whether immediate invasive management is required.
Patients with ST-elevation myocardial infarction (STEMI) require primary percutaneous coronary intervention (PPCI) (or fibrinolysis if PPCI within 120 min is not feasible); patients with non-ST-elevation ACS (NSTE-ACS) with very high-risk features require immediate angiography ± PCI if indicated; patients with NSTE-ACS and high-risk features should undergo inpatient angiography (angiography within 24 h should be considered). A combination of antiplatelet and anticoagulant therapy is indicated acutely for patients with ACS. The majority of patients with ACS will eventually undergo revascularization, most commonly with PCI.
Once the final diagnosis of ACS has been established, it is important to implement measures to prevent recurrent events and to optimize cardiovascular risk. This consists of medical therapy, lifestyle changes and cardiac rehabilitation, as well as consideration of psychosocial factors.
Definitions
Acute coronary syndromes (ACS) encompass a spectrum of conditions that include patients presenting with recent changes in clinical symptoms or signs, with or without changes on 12-lead electrocardiogram (ECG) and with or without acute elevations in cardiac troponin (cTn) concentrations (Figure 2). Patients presenting with suspected ACS may eventually receive a diagnosis of acute myocardial infarction (AMI) or unstable angina (UA). The diagnosis of myocardial infarction (MI) is associated with cTn release and is made based on the fourth universal definition of MI.1 UA is defined as myocardial ischaemia at rest or on minimal exertion in the absence of acute cardiomyocyte injury/necrosis.
It is characterized by specific clinical findings of prolonged (>20 min) angina at rest; new onset of severe angina; angina that is increasing in frequency, longer in duration, or lower in threshold; or angina that occurs after a recent episode of MI. ACS are associated with a broad range of clinical presentations, from patients who are symptom free at presentation to patients with ongoing chest discomfort/symptoms and patients with cardiac arrest, electrical/haemodynamic instability, or cardiogenic shock (CS)
Table 3
Definitions of terms related to invasive strategy and reperfusion therapy commonly used in this document
Term | Definition |
First medical contact (FMC) | The time point when the patient is initially assessed by a physician, paramedic, nurse, or other trained emergency medical services worker who can obtain and interpret the ECG and deliver initial interventions (e.g. defibrillation). FMC can be either in the pre-hospital setting or upon patient arrival at the hospital (e.g. the emergency department) |
STEMI diagnosis | The time at which a patient with ischaemic symptoms is interpreted as presenting with ACS and ST-segment elevation (or ST-segment elevation equivalent) |
Primary PCIa | Emergent PCI with balloon, stent, or other approved device, performed on the IRA without previous fibrinolytic treatment |
Primary PCI strategya | Emergency coronary angiography and PCI of the IRA if indicated |
Rescue PCIa | Emergency PCI performed as soon as possible in cases of failed fibrinolytic treatment |
Routine early PCI strategy after fibrinolysisa | Coronary angiography, with PCI of the IRA if indicated, performed between 2 h and 24 h after successful fibrinolysis |
Pharmaco-invasive strategya | Fibrinolysis combined with rescue PCI (in cases of failed fibrinolysis) or routine early PCI strategy (in cases of successful fibrinolysis) |
Immediate invasive strategy | Emergency coronary angiography (i.e. as soon as possible) and PCI/CABG of the IRA if indicated |
Early invasive strategy | Early coronary angiography (<24 h from diagnosis of ACS) and PCI/CABG of the IRA if indicated |
Selective invasive strategy | Coronary angiography ± PCI/CABG based on clinical assessment and/or non-invasive testing |
ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; ECG, electrocardiogram; IRA, infarct-related artery; PCI, percutaneous coronary intervention; STE-ACS, ST-segment-elevation acute coronary syndrome.
CABG may also be indicated instead of PCI in certain circumstances.
What is new
New/revised concepts
ACS should be considered a spectrum, which encompasses both non-ST-elevation (NSTE)-ACS and ST-elevation MI (STEMI).
A section on the management of ACS in patients with cancer is provided.
A section on patient perspectives is provided.
3.1. Clinical presentation and physical examination
3.1.1. Clinical presentation
Acute chest discomfort—which may be described as pain, pressure, tightness, heaviness, or burning—is the leading presenting symptom prompting consideration of the clinical diagnosis of ACS and the initiation of testing aligned with specific diagnostic algorithms (Figure 4).
Chest pain descriptors should be classified as cardiac, possibly cardiac, and likely non-cardiac. Further information on the suggested use of these terms. The use of the descriptor ‘atypical’ should be avoided. Chest pain-equivalent symptoms include dyspnoea, epigastric pain, and pain in the left or right arm or neck/jaw.
Misdiagnosis or delayed diagnosis is sometimes due to an incomplete history or difficulty in eliciting symptoms from the patient. In order to understand the complexity of ACS-related symptomatology, careful history taking and comprehensive interaction with the patient are crucial and may help to facilitate an early and accurate diagnosis. It is necessary to recognise the most common symptoms of ACS in women and men.
It is important that awareness of the symptoms associated with ACS is high among the general population, in particular red flag symptoms such as prolonged chest pain (>15 min) and/or recurrent pain within 1 h, which should prompt patients or other members of the public to seek urgent medical help. Continuous education, promotion, and advocacy efforts are important to make sure that this information is as widely available as possible to the general population.
History taking and physical examination
Patients with suspected ACS present in a broad range of clinical scenarios, including in the community, at the emergency department (ED), or in the inpatient setting. It is crucial to take a focused medical history and accurately characterize the presenting symptoms in order to manage the patient via the appropriate care pathway as soon as possible.
Prompt assessment of vital signs is recommended at first medical contact (FMC), at the same time as acquisition of an initial ECG . In patients presenting with suspected ACS, physical examination is recommended and is useful both to eliminate differential diagnoses and to identify very high-risk and high-risk ACS features. This may be particularly relevant for patients presenting with cardiac arrest, signs of CS, and/or haemodynamic or electrical instability.4 Focused physical examination should include checking for the presence of all major pulses, measurement of blood pressure in both arms, auscultation of the heart and lungs, and assessing for signs of HF or circulatory compromise.
Diagnostic tools | Electrocardiogram
The resting 12-lead ECG is the first-line diagnostic tool in the assessment of patients with suspected ACS. It is recommended that an ECG is obtained immediately upon FMC and interpreted by a qualified emergency medical technician or physician within 10 min.4,5 It should be repeated as necessary, especially if symptoms have waned at FMC. Based on the initial ECG, patients with suspected ACS can be differentiated into two working diagnoses:
Patients with acute chest pain (or chest pain-equivalent signs/symptoms) and persistent ST-segment elevation (or ST-segment elevation equivalents) on ECG (working diagnosis: ST-segment elevation MI: STEMI). The vast majority of these patients will sustain myocardial necrosis and troponin elevation, fulfilling the criteria for an MI, but MI will not be the final diagnosis in all patients with a working diagnosis of STEMI.
Patients with acute chest pain (or chest pain-equivalent signs/symptoms) but without persistent ST-segment elevation (or ST-segment elevation equivalents) on ECG (working diagnosis: non-ST-elevation [NSTE]-ACS). These patients may exhibit other ECG alterations, including transient ST-segment elevation, persistent or transient ST-segment depression, and T wave abnormalities, including hyperacute T waves, T wave inversion, biphasic T waves, flat T waves, and pseudo-normalization of T waves. Alternatively, the ECG may be normal. The majority of patients in this category who subsequently display a typical rise and fall in cardiac troponin levels (i.e. fulfilling MI criteria as per the fourth universal definition of MI) will receive a final diagnosis of non-ST-elevation MI (NSTEMI). In other patients, the troponin level will remain below the 99th centile and they will receive a final diagnosis of UA, although with high-sensitivity troponin assays this diagnosis has become less common. It is also important to recognize that NSTEMI or UA will not be the final diagnosis in all patients with an initial working diagnosis of NSTE-ACS.
Acute coronary syndrome with persistent ST-segment elevation (suspected ST-elevation myocardial infarction)
The priority for these patients is the implementation of reperfusion therapy as soon as possible. In the appropriate clinical context, ST-segment elevation (measured at the J-point) is considered suggestive of ongoing coronary artery acute occlusion in the following cases:
New ST elevation at the J-point in at least two contiguous leads:
≥2.5 mm in men <40 years, ≥2 mm in men ≥40 years, or ≥1.5 mm in women regardless of age in leads V2–V3
and/or ≥1 mm in the other leads (in the absence of left ventricular [LV] hypertrophy or left bundle branch block [LBBB]).
In patients with suspected inferior STEMI, it is recommended to record right precordial leads (V3R and V4R) in order to assess for ST-segment elevation. Posterior leads (V7–V9) can also be recorded to investigate for posterior STEMI, particularly in patients with ongoing symptoms and an inconclusive standard 12-lead ECG.
The diagnosis of ongoing acute coronary artery occlusion on ECG can sometimes be challenging, and some cases may warrant prompt management and triage for immediate reperfusion therapy despite the absence of ST-segment elevation. It is also important to recognize that while the most sensitive sign for ongoing acute coronary artery occlusion is ST-segment elevation, there are other ECG findings that can be suggestive of ongoing coronary artery occlusion (or severe ischaemia). If these findings are present, prompt triage for immediate reperfusion therapy is indicated .
-ST-segment depression in leads V1–V3 (especially when the terminal T wave is positive) and/or ST-segment elevation in V7–V9 are highly suggestive of posterior coronary artery occlusion (often the left circumflex artery).
-ST-segment elevation in V3R and V4R is highly suggestive of ongoing RV ischaemia.
ST depression ≥1 mm in ≥6 surface leads (inferolateral ST depression), coupled with ST-segment elevation in aVR and/or V1, suggests multivessel ischaemia or left main coronary artery obstruction, particularly if the patient presents with haemodynamic compromise.9–11
-Bundle branch block (BBB). In patients with a high clinical suspicion of ongoing myocardial ischaemia, the presence of LBBB, right bundle branch block (RBBB), or a paced rhythm precludes an accurate assessment of the presence or absence of ST-segment elevation. Therefore, patients presenting with these ECG patterns in combination with signs/symptoms that are highly suspicious for ongoing myocardial ischaemia should be managed similarly to those with clear ST-segment elevation, regardless of whether the BBB is previously known
.
Acute coronary syndrome without persistent ST-segment elevation (non-ST elevation acute coronary syndrome)
While the ECG in the setting of NSTE-ACS may be normal in more than one-third of patients, characteristic ECG abnormalities are frequently present and increase the diagnostic probability of ACS.12–16 These ECG abnormalities include ST depression and T wave changes (especially biphasic T waves or prominent negative T waves [Wellens’ sign, related to severe proximal left anterior descending artery stenosis]),
Recommendation Table 1
Recommendations for clinical and diagnostic tools for patients with suspected acute coronary syndrome
. Diagnostic tools | Biomarkers
High-sensitivity cardiac troponins
After excluding clinical and ECG signs suggestive of STEMI or very high-risk NSTE-ACS, biomarkers play a complementary role in the diagnosis, risk stratification, and management of patients with suspected ACS. Measurement of a biomarker of cardiomyocyte injury, preferably high-sensitivity cardiac troponin (hs-cTn), is recommended in all patients with suspected ACS.15,17,25–27,53,54 If the clinical presentation is compatible with myocardial ischaemia, then a rise and/or fall in cTn above the 99th percentile of healthy individuals points to a diagnosis of MI as per the criteria in the fourth universal definition of MI.1 In patients with MI, levels of cTn 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).1,15,26,53,55–58
Confounders of cardiac troponin concentration
In patients presenting with suspected NSTE-ACS, four clinical variables affect hs-cTn concentrations beyond the presence or absence of MI. These variables are: age (concentrations in healthy very young vs. ‘healthy’ very old individuals differ by up to 300%); renal dysfunction (differences between otherwise healthy patients with very high vs. very low estimated glomerular filtration rate [eGFR] of up to 300%); time from chest pain onset (>300%); and, to a lesser extent, sex (≈40%). Despite the potential baseline differences in hs-cTn values based on these four variables, absolute changes in hs-cTn levels are still of diagnostic and prognostic value. Current data on the use of sex-specific hs-cTn values in the diagnosis of MI have been controversial and failed to demonstrate a clear clinical benefit.Therefore, until automated tools (i.e. risk assessment calculators) incorporating the effect of all four clinical variables (age, eGFR, time from chest pain onset, and sex) are available, the use of uniform cut-off concentrations should remain the standard of care for the early diagnosis of MI.
Rapid ‘rule-in’ and ‘rule-out’ algorithms
Due to their higher sensitivity and diagnostic accuracy for the detection of MI at presentation, the time interval to the second cTn assessment can be shortened with the use of hs-cTn assays. This substantially reduces the delay to diagnosis, translating into shorter stays in the ED, lower costs, and less diagnostic uncertainty for patients. It is recommended to use the 0 h/1 h algorithm (best option) or the 0 h/2 h algorithm (second-best option) . These algorithms have been derived and validated in large multicentre diagnostic studies using central adjudication of the final diagnosis for all currently available hs-cTn assays. Optimal thresholds for rule-out were selected to allow a sensitivity and NPV of at least 99%. Optimal thresholds for rule-in were selected to allow a positive predictive value (PPV) of at least 70%. These algorithms were developed from large derivation cohorts and then validated in large independent validation cohorts. The previous ESC 0 h/3 h algorithm was considered as an alternative, but three recent large diagnostic studies suggested that the ESC 0 h/3 h algorithm appears to balance efficacy and safety less well than more rapid protocols using lower rule-out concentrations, including the ESC 0 h/1 h algorithm. The very high safety and high efficacy of applying the ESC 0 h/1 h algorithm was recently confirmed in three real-life implementation studies, including one randomized controlled trial (RCT).
Therefore, the ESC 0 h/3 h algorithm is an alternative for cases where the ESC 0 h/1 h or 0 h/2 h algorithms are not available. Of note, patients assigned to the ‘rule-out’ pathway using the ESC 0 h/1 h or 0 h/2 h algorithms have a very low rate of clinical events through to 30 days.
European Society of Cardiology 0 h/1 h and 0 h/2 h algorithms
The ESC 0 h/1 h and 0 h/2 h algorithms are based on two underlying concepts: firstly, hs-cTn is a continuous variable and the probability of MI increases with increasing hs-cTn values. Secondly, early absolute changes in the levels within 1 h or 2 h can be used as surrogates for absolute changes over 3 h or 6 h and provide incremental diagnostic value to the single cTn assessment at presentation.The cut-off concentrations within the 0 h/1 h and 0 h/2 h algorithms are assay specific .
Rule out
The NPV for MI in patients assigned to the ‘rule-out’ pathway has exceeded 99% in several large validation cohorts. Assignment to the rule-out pathway does not always equal outpatient management. However, when used in conjunction with clinical and ECG findings, the 0 h/1 h and 0 h/2 h algorithms will enable the identification of appropriate candidates for early discharge and outpatient management. Even after the ruling out of MI, elective non-invasive or invasive imaging may be appropriate according to clinical and risk assessment, and an alternative diagnosis to MI should be identified.
Rule-in
The PPV for MI in patients meeting the ‘rule-in’ pathway criteria in several studies has been ∼70–75%. Most of the ‘rule-in’ pathway patients with diagnoses other than MI still have conditions that require specialist cardiology input and either coronary angiography or non-invasive imaging in order to establish an accurate final diagnosis. Therefore, the vast majority of patients triaged towards the ‘rule-in’ pathway by these algorithms will require hospital admission and invasive coronary angiography (ICA).
Observe
Patients who do not qualify for the ‘rule-out’ or ‘rule-in’ pathways are assigned to the ‘observe’ pathway. These patients represent a heterogeneous group and have been shown to have a mortality rate that is comparable to rule-in patients. Therefore, an individual assessment based on the particular risk profile of the patient (i.e. risk scores) is of paramount importance for patients in this group. Additionally, a third measurement of cTn at 3 h (± echocardiography) is recommended as the next step in order to guide further management.
Most patients in the observe zone with a high degree of clinical suspicion of ACS (e.g. relevant increase in cTn from presentation to 3 h) are candidates for ICA. Conversely, most patients with a low to intermediate likelihood for ACS according to clinical judgment are candidates for non-invasive imaging after transfer from the ED to the ward. Computed tomography (CT) angiography can be used to aid diagnosis and, in particular, to identify patients with non-obstructed coronary arteries who can be discharged if other relevant diseases have been excluded. CT angiography can also identify patients with obstructive coronary disease in whom revascularization may be considered. In the appropriate clinical context, if alternative conditions have been identified that explain the cTn values (i.e. rapid ventricular rate response to atrial fibrillation [AF], marked anaemia, or a hypertensive emergency), further diagnostic testing (i.e. ICA) may not be required.
Initial measures for patients presenting with suspected acute coronary syndrome | Initial treatment
Pre-hospital logistics of care
Individuals experiencing acute chest pain in the community represent an undifferentiated population, often presenting ad hoc to first medical responders in the pre-hospital setting. These patients should undergo immediate risk assessment and triage following local protocols established within the emergency medical service (EMS)
Modes of presentation and pathways to invasive management and myocardial revascularization in patients presenting with STEMI.
ACS, acute coronary syndrome; ECG, electrocardiogram; EMS, emergency medical services; FMC, first medical contact; PCI, percutaneous coronary intervention; PPCI, primary percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.
Selection of invasive strategy and reperfusion therapy in patients presenting with NSTE-ACS.
ACS, acute coronary syndrome; CS, cardiogenic shock; ECG, electrocardiogram; FMC, first medical contact; GRACE, Global Registry of Acute Coronary Events; hs-cTn, high-sensitivity cardiac troponin; NSTE-ACS, non-ST-elevation acute coronary syndrome; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; UA, unstable angina. This figure summarizes the selection of invasive strategy and reperfusion therapy in patients presenting with ACS. aRisk criteria: Patients who meet any one of the ‘very high-risk’ NSTE-ACS criteria should undergo an immediate invasive strategy; these very high-risk criteria include haemodynamic instability or CS, recurrent or refractory chest pain despite medical treatment, life-threatening arrhythmias, mechanical complications of MI, HF clearly related to ACS, and recurrent dynamic ST-segment or T wave changes, particularly with intermittent ST-segment elevation. Patients with NSTE-ACS who meet any of the ‘high-risk’ criteria (confirmed NSTEMI as per the hs-cTn-based ESC algorithm, NSTE-ACS with GRACE score >140, dynamic ST-segment or T wave changes, or transient ST-segment elevation) should be considered for early invasive angiography (i.e. within 24 h) and should undergo an inpatient invasive strategy. An invasive strategy during hospital admission is recommended in NSTE-ACS patients with high-risk criteria or with a high index of suspicion for UA. In selected patients a selective invasive strategy can also be an option.
. Emergency care
. Initial diagnosis and monitoring
Management of ACS starts from the point of FMC, when a working diagnosis of ACS is established. The working diagnosis of ACS is usually based on symptoms consistent with myocardial ischaemia and the signs on a 12-lead ECG (see Section 3.2). It is recommended to initiate ECG monitoring as soon as possible in all patients with suspected ACS in order to detect life-threatening arrhythmias and to allow prompt defibrillation if indicated.
Acute pharmacotherapy
Oxygen
Oxygen supplementation is recommended in ACS patients with hypoxaemia (oxygen saturations <90%). Oxygen supplementation in patients who are not hypoxic (oxygen saturations >90%) is not associated with clinical benefits and is therefore not recommended.148,149
Nitrates
Sublingual nitrate may be helpful to relieve ischaemic symptoms. However, a reduction in chest pain after nitroglycerine administration can be misleading and is not recommended as a diagnostic manoeuvre.150 In patients with an ECG compatible with ongoing STEMI and symptom relief after nitroglycerine administration, it is recommended to obtain another 12-lead ECG. Complete normalization of ST-segment elevation, along with relief of symptoms, after nitroglycerine administration is suggestive of coronary spasm, with or without associated MI. Nitrates should not be given to patients with hypotension, marked bradycardia or tachycardia, RV infarction, known severe aortic stenosis, or phosphodiesterase 5 inhibitor use within the previous 24–48 h.
Pain relief
Intravenous opioids (e.g. morphine 5–10 mg) should be considered for the relief of severe chest pain. Other forms of pain relief (e.g. nitrous oxide/oxygen plus i.v. acetaminophen/paracetamol) have been reported to be inferior to morphine.However, morphine may enhance nausea and vomiting and slow the gastrointestinal absorption of oral medicines, which may delay the onset of action of orally administered antiplatelet therapy.Evidence from small-scale trials suggests that i.v. morphine may also reduce myocardial and microvascular damage when given to patients with ongoing acute coronary artery occlusion, though co-administration with metoclopramide appears to negate this effect. Conversely, morphine has also been reported to reduce antiplatelet activity after administration of ticagrelor, though this effect was rescued by metoclopramide administration.The positive effects of morphine on myocardial damage may potentially be related to reduced oxygen consumption as a result of decreased preload and negative inotropy and chronotropy.
Platelet inhibition induced by oral P2Y12 receptor antagonists may be delayed in patients with ongoing MI. Morphine may also further reduce absorption, delay the onset of action, and decrease the antiplatelet effect of oral P2Y12 receptor inhibitors in MI patients, although this effect may vary between the different P2Y12 inhibitors.Further research is ongoing in this area, but at present it should be noted that currently available clinical data have not demonstrated any increase in the risk of adverse clinical outcomes as a result of any interaction between morphine and antiplatelet agents in the setting of ACS.
Intravenous beta-blockers
Few RCTs testing early i.v. beta-blockers have been performed in the era of invasive management for patients with a working diagnosis of STEMI. Not all beta-blockers appear to exert the same cardio-protective effect in the context of ongoing acute coronary occlusion, with metoprolol demonstrating the greatest protective effect in experimental studies.Intravenous metoprolol is also the most widely tested beta-blocker in trials enrolling patients undergoing PPCI. While the long-term clinical benefits associated with early i.v. metoprolol administration are not clear, it is safe when used in patients without signs of acute HF and has been consistently associated with a reduction in the incidence of VF and microvascular obstruction (MVO). Based on these data, i.v. beta-blockers (preferably metoprolol) should be considered at the time of presentation in patients with a working diagnosis of STEMI undergoing PPCI with no signs of acute HF, a systolic blood pressure (SBP) >120 mmHg, and without other contraindications. Administration of i.v. beta-blockers in patients with suspected NSTE-ACS has not been tested.
Recommendation Table 3
Recommendations for the initial management of patients with acute coronary syndrome
Primary percutaneous coronary intervention strategy for ST-elevation myocardial infarction
In patients with a working diagnosis of STEMI, a PPCI strategy (i.e. immediate angiography and PCI as needed) is the preferred reperfusion strategy, provided it can be performed in a timely manner (i.e. within 120 min of the ECG-based diagnosis. RCTs have shown that if the delay to treatment is similar, PPCI is superior to fibrinolysis in reducing mortality, non-fatal reinfarction, and stroke.However, in some circumstances, PPCI is not an immediate option and fibrinolysis should be initiated expeditiously as part of a pharmaco-invasive strategy, provided the patient has presented within 12 h of symptom onset.
For patients who undergo fibrinolysis, rescue PCI is indicated if fibrinolysis fails (i.e. ST-segment resolution <50% within 60–90 min of fibrinolytic administration) or in the presence of haemodynamic or electrical instability, worsening ischaemia, or persistent chest pain.
Invasive strategy in ST-elevation myocardial infarction late presenters
While routine immediate angiography and PCI (if indicated) are clearly associated with clinical benefit in patients presenting within 12 h of symptom onset, the value of a routine PPCI strategy in STEMI patients presenting later than 12 h after symptom onset is less well established.
A small RCT in 347 STEMI patients presenting 12–48 h after symptom onset and without persistent symptoms reported that a routine PPCI strategy improved myocardial salvage and long-term survival compared with conservative treatment
Summary of invasive strategies for patients with non-ST elevation acute coronary syndrome
In summary, very high-risk NSTE-ACS patients are recommended to undergo an immediate invasive strategy with emergency angiography and PCI if required. High-risk NSTE-ACS patients are recommended to undergo an inpatient invasive strategy and should be considered for an early invasive strategy (i.e. within 24 h).
5.3. Fibrinolysis and pharmaco-invasive strategy in patients with ST-elevation myocardial infarction
5.3.1. Benefit and indication of fibrinolysis
Fibrinolytic therapy is an important reperfusion strategy for STEMI patients presenting within 12 h of symptom onset when PPCI cannot be performed in a timely manner; it prevents 30 early deaths per 1000 patients treated within 6 h of symptom onset.205 The largest absolute treatment benefit is seen among those patients at the highest risk, including the elderly. Successful reperfusion is generally associated with significant improvement in ischaemic symptoms, ≥50% ST-segment resolution, and haemodynamic stability.
Pre-hospital fibrinolysis
If trained medical or allied health staff can interpret the ECG on site, or transmit the ECG for remote interpretation, it is recommended to initiate fibrinolytic therapy in the pre-hospital setting. A fibrin-specific agent (i.e. tenecteplase, alteplase, or reteplase) is the preferred agent. The goal is to start fibrinolytic therapy within 10 min of the STEMI diagnosis.
6. Antithrombotic therapy
Antithrombotic treatment is an important component of the management of all patients presenting with ACS. The specific choice and combination of therapy, the time of its initiation, and the treatment duration depend on various patient and procedural factors. Treatment decisions must be made weighing the benefits of antithrombotic therapy against the risk of bleeding, including severe, life-threatening bleeding. Recommended anticoagulant and antiplatelet drugs and their dosing
Table 6
Dose regimen of antiplatelet and anticoagulant drugs in acute coronary syndrome patients
I. Antiplatelet drugs | |
Aspirin | LD of 150–300 mg orally or 75–250 mg i.v. if oral ingestion is not possible, followed by oral MD of 75–100 mg o.d.; no specific dose adjustment in CKD patients. |
P2Y12 receptor inhibitors (oral or i.v.) | |
Clopidogrel | LD of 300–600 mg orally, followed by an MD of 75 mg o.d.; no specific dose adjustment in CKD patients. Fibrinolysis: at the time of fibrinolysis an initial dose of 300 mg (75 mg for patients older than 75 years of age). |
Prasugrel | LD of 60 mg orally, followed by an MD of 10 mg o.d. In patients with body weight <60 kg, an MD of 5 mg o.d. is recommended. In patients aged ≥75 years, prasugrel should be used with caution, but a MD of 5 mg o.d. should be used if treatment is deemed necessary. No specific dose adjustment in CKD patients. Prior stroke is a contraindication for prasugrel. |
Ticagrelor | LD of 180 mg orally, followed by an MD of 90 mg b.i.d.; no specific dose adjustment in CKD patients. |
Cangrelor | Bolus of 30 mcg/kg i.v. followed by 4 mcg/kg/min infusion for at least 2 h or the duration of the procedure (whichever is longer). In the transition from cangrelor to a thienopyridine, the thienopyridine should be administered immediately after discontinuation of cangrelor with an LD (clopidogrel 600 mg or prasugrel 60 mg); to avoid a potential DDI, prasugrel may also be administered 30 min before the cangrelor infusion is stopped. Ticagrelor (LD 180 mg) should be administered at the time of PCI to minimize the potential gap in platelet inhibition during the transition phase. |
GP IIb/IIIa receptor inhibitors (i.v.) | |
Eptifibatide | Double bolus of 180 mcg/kg i.v. (given at a 10-min interval) followed by an infusion of 2.0 mcg/kg/min for up to 18 h. For CrCl 30–50 mL/min: first LD, 180 mcg/kg i.v. bolus (max 22.6 mg); maintenance infusion, 1 mcg/kg/min (max 7.5 mg/h). Second LD (if PCI), 180 mcg/kg i.v. bolus (max 22.6 mg) should be administered 10 min after the first bolus. Contraindicated in patients with end-stage renal disease and with prior ICH, ischaemic stroke within 30 days, fibrinolysis, or platelet count <100 000/mm3. |
Tirofiban | Bolus of 25 mcg/kg i.v. over 3 min, followed by an infusion of 0.15 mcg/kg/min for up to 18 h. For CrCl ≤60 mL/min: LD, 25 mcg/kg i.v. over 5 min followed by a maintenance infusion of 0.075 mcg/kg/min continued for up to 18 h. Contraindicated in patients with prior ICH, ischaemic stroke within 30 days, fibrinolysis, or platelet count <100 000/mm3. |
II. Anticoagulant drugs | |
UFH | Initial treatment: i.v. bolus 70–100 U/kg followed by i.v. infusion titrated to achieve an aPTT of 60–80 s. During PCI: 70–100 U/kg i.v. bolus or according to ACT in case of UFH pre-treatment. |
Enoxaparin | Initial treatment: for treatment of ACS 1 mg/kg b.i.d. subcutaneously for a minimum of 2 days and continued until clinical stabilization. In patients whose CrCl is below 30 mL per minute (by Cockcroft–Gault equation), the enoxaparin dosage should be reduced to 1 mg per kg o.d. During PCI: for patients managed with PCI, if the last dose of enoxaparin was given less than 8 h before balloon inflation, no additional dosing is needed. If the last s.c. administration was given more than 8 h before balloon inflation, an i.v. bolus of 0.3 mg/kg enoxaparin sodium should be administered. |
Bivalirudin | During PPCI: 0.75 mg/kg i.v. bolus followed by i.v. infusion of 1.75 mg/kg/h for 4 h after the procedure. In patients whose CrCl is below 30 mL/min (by Cockcroft–Gault equation), maintenance infusion should be reduced to 1 mg/kg/h. |
Fondaparinux | Initial treatment: 2.5 mg/d subcutaneously. During PCI: A single bolus of UFH is recommended. Avoid if CrCl <20 mL/min. |
ACS, acute coronary syndrome; ACT, activated clotting time; aPPT, activated partial thromboplastin time; b.i.d., bis in die (twice a day); CKD, chronic kidney disease; CrCl, creatinine clearance; DDI, drug–drug interactions; ICH, intracranial haemorrhage; i.v. intravenous; LD, loading dose; MD, maintenance dose; o.d., once a day; PPCI, primary percutaneous coronary intervention; s.c. subcutaneous; UFH, unfractionated heparin.
Antiplatelet therapy in the acute phase
Oral antiplatelet therapy
Antiplatelet drugs play a key role in the acute phase of treatment for ACS. Table 6 summarizes the dosing regimens of the available oral and i.v. antiplatelet drugs.
The choice of antiplatelet regimen should take the bleeding risk of the patient into account. Factors associated with an elevated bleeding risk have been detailed by the Academic Research Consortium on High Bleeding Risk (ARC-HBR).The presence of one major or two minor ARC-HBR risk factors indicates high bleeding risk (HBR). Of note, the presence of multiple major risk factors is associated with a progressive increase in the bleeding risk.
Aspirin treatment is started with a loading dose (LD) as soon as possible, followed by maintenance treatment) Current evidence supports an aspirin maintenance dose (MD) of 75–100 mg once a day (o.d.).
Based on the results of the phase III PLATelet inhibition and patient Outcomes (PLATO) and TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38) studies, dual antiplatelet therapy (DAPT) including aspirin and a potent P2Y12 receptor inhibitor (prasugrel or ticagrelor) is recommended as the default DAPT strategy for ACS patients.
Clopidogrel, which is characterized by less effective and more variable platelet inhibition, should only be used when prasugrel or ticagrelor are contraindicated/not available, or in some patients considered otherwise at HBR
Prasugrel should be considered in preference to ticagrelor for ACS patients who proceed to PCI.
Anticoagulant treatment in the acute phase
Anticoagulation is an important component of the initial treatment of ACS and of the peri-procedural treatment for ACS patients managed with an invasive strategy. Therefore, parenteral anticoagulation is recommended for all ACS patients at the time of diagnosis.255 Table 6 provides an overview of the relevant anticoagulant drugs and their dosing in ACS patients.
In general, a crossover between anticoagulants should be avoided in patients with ACS (especially between unfractionated heparin [UFH] and low-molecular-weight heparin [LMWH]), with the exception of adding UFH to fondaparinux when a patient presenting with NSTE-ACS proceeds to PCI after a period of fondaparinux treatment (see below for further detail).256,257 Anticoagulants should generally be discontinued immediately after PCI, except in specific clinical settings such as the confirmed presence of LV aneurysm with thrombus formation or AF requiring anticoagulation. In addition, for bivalirudin in patients with STEMI undergoing PCI, a full dose post-PCI infusion is recommended.
In this section of the guideline, we summarize the recommendations for anticoagulant treatment in the acute phase for patients with STEMI undergoing PPCI and for patients with NSTE-ACS undergoing angiography (and PCI if indicated).
To summuarise
Antithrombotic therapy is indicated in all ACS patients, regardless of the management strategy. This consists of both antiplatelet and anticoagulant therapy. Aspirin is recommended for all ACS patients at an initial loading dose and a longer-term maintenance dose. In addition to aspirin, a P2Y12 receptor inhibitor is recommended, and should be maintained over 12 months unless there are concerns regarding HBR. Regarding P2Y12 receptor inhibitor choice, prasugrel and ticagrelor are recommended in preference to clopidogrel, and prasugrel should be considered in preference to ticagrelor for ACS patients who undergo PCI. Pre-treatment (i.e. treatment with a P2Y12 receptor inhibitor prior to coronary angiography) in patients with NSTE-ACS is not recommended routinely but may be considered for patients with STEMI undergoing PPCI. Parenteral anticoagulation is recommended for all patients at the time of diagnosis. Discontinuation of parenteral anticoagulation should be considered immediately after the invasive procedure. Some patients with ACS will also have an indication for long-term OAC, most commonly AF. In these patients, TAT for up to 1 week, followed by DAT using a NOAC at the recommended dose for stroke prevention and a single oral antiplatelet agent (preferably clopidogrel), is recommended as the default strategy.
Anticoagulation in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention
Unfractionated heparin has been established as the standard of care in patients with STEMI undergoing PPCI due to its favourable risk/benefit profile. In these patients, anticoagulation should be given during the invasive procedure. High-quality evidence with respect to the benefit of administering anticoagulation at an earlier time point in patients undergoing a PPCI strategy is lacking.
. Anticoagulation in patients with non-ST-elevation acute coronary syndrome undergoing angiography and percutaneous coronary intervention if indicated
Patients with NSTE-ACS are also recommended to receive parenteral anticoagulation. In patients with NSTE-ACS who are anticipated to undergo immediate or early (i.e. <24 h from the time of diagnosis)
Intravenous enoxaparin should also be considered as an anticoagulant for PCI in patients with NSTE-ACS in whom subcutaneous (s.c.) enoxaparin was used while awaiting coronary angiography.261
In summary, parenteral anticoagulation is recommended for patients with NSTE-ACS. For patients with NSTE-ACS undergoing immediate or early angiography (± PCI if indicated), UFH is recommended but enoxaparin should be considered as an alternative to UFH. For patients with NSTE-ACS who are not anticipated to undergo early angiography, fondaparinux (with a UFH bolus at time of PCI) is recommended in preference to enoxaparin, although enoxaparin should be considered if fondaparinux is not available.
Long-term treatment
By default, DAPT consisting of a potent P2Y12 receptor inhibitor in addition to aspirin is recommended for a minimum of 12 months after an ACS event; exceptions include patients for whom surgery is urgently needed, patients in whom OAC is indicated, and patients in whom the risk of bleeding is too high for other reasons. After PCI for ACS, ischaemic and bleeding events both markedly decrease over time. Further information regarding long-term antithrombotic strategies (i.e. beyond 12 months) is provided in the
Prolonging antithrombotic therapy beyond 12 months
Prolonged antithrombotic therapy options:
Antiplatelet therapy in patients requiring oral anticoagulation
Acute coronary syndrome patients requiring anticoagulation
In 6–8% of patients undergoing PCI, long-term OAC is indicated and should also be continued during the invasive procedure. Interruption of the long-term OAC and bridging with parenteral anticoagulants may lead to an increase in thrombo-embolic episodes and bleeds. In patients undergoing PCI, it is unknown whether it is safer to bridge non-vitamin K antagonist (VKA) OACs (NOACs) with parenteral anticoagulants or to continue NOACs without additional parenteral anticoagulation. In VKA-treated patients, no parenteral anticoagulation is needed if the international normalized ratio (INR) is >2.5. Strategies to minimize PCI-related complications in patients on OAC are listed in Table 7.
Table 7
Suggested strategies to reduce bleeding risk related to percutaneous coronary intervention
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GP, glycoprotein; INR, international normalized ratio; i.v., intravenous; NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulation/anticoagulant; PCI, percutaneous coronary intervention; UFH, unfractionated heparin; VKA, vitamin K antagonist.
© ESC 2023
Evidence on the management of ACS patients with an indication for long-term OAC undergoing PCI is derived from subgroups of RCTs. Patients with STEMI (who generally carry a higher atherothrombotic risk) were under-represented (∼10% of the study populations) in the major RCTs. Pivotal trials testing the benefit of NOACs as part of the antithrombotic regimen in patients with an indication for long-term anticoagulation undergoing PCI ar.
All of these trials were individually powered to address the safety of the tested strategy with regard to bleeding events, but not to reliably assess differences in individual ischaemic endpoints. In a meta-analysis of all four NOAC-based RCTs comparing dual antithrombotic therapy (DAT) with triple antithrombotic therapy (TAT) in AF patients undergoing PCI (encompassing 10 234 patients), the primary safety endpoint (International Society on Thrombosis and Haemostasis major or clinically relevant non-major bleeding) was significantly lower with DAT vs. However, DAT was associated with a borderline increased risk of MI and a significant increase in stent thrombosis. This translates into an absolute reduction in major bleeding events of 2.3% compared with an absolute increase in stent thrombosis of 0.4%, without an effect on overall MACE. When interpreting the results of these studies, an important general point is that the treatment effect is confounded by the use of NOACs in the DAT treatment arms and VKAs in the TAT arms.
In patients with ACS, the indication for OAC should be re-assessed and treatment continued only if a compelling indication exists (e.g. paroxysmal, persistent, or permanent AF with a CHA2DS2-VASc [Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke or transient ischaemic attack, Vascular disease] score ≥1 in men and ≥2 in women; mechanical heart valve; or recent/a history of recurrent or unprovoked deep vein thrombosis or PE). Although they have been tested in a minority of patients in the major RCTs, in the absence of robust safety and efficacy data, the use of prasugrel or ticagrelor as part of TAT is not recommended. The intensity of OAC should be carefully monitored, with a target INR of 2.0–2.5 in patients treated with VKA (with the exception of individuals with a mechanical prosthetic valve in the mitral position).
Overall, in patients with AF without mechanical prosthetic valves or moderate to severe mitral stenosis, the evidence supports the use of NOACs over VKAs as they reduce bleeding risk. DAT with a NOAC at the recommended dose for stroke prevention and SAPT (preferably clopidogrel, which was used in >90% of patients in the major RCTs) is recommended as the default strategy for up to 12 months after up to 1 week of TAT (with NOAC and DAPT consisting of aspirin and clopidogrel) —the up to 1 week duration of TAT is based on the median treatment duration in the investigational arm of the AUGUSTUS trial.Although none of the available RCTs were designed to detect differences in ischaemic events, the numerically higher risk of stent thrombosis and MI is offset by the lower risk of bleeding, with a resultant neutral effect on total mortality.
Patients requiring vitamin K antagonists or undergoing coronary artery bypass surgery
In patients for whom a VKA is mandated (e.g. patients with mechanical prosthetic valves), DAT with a VKA and SAPT (preferably clopidogrel) is indicated after an up to 1-week period of TAT (with aspirin and clopidogrel) A network meta-analysis has reported that compared with TAT (consisting of VKA plus aspirin and clopidogrel), DAT (VKA plus clopidogrel) was associated with a trend towards a reduction in TIMI major bleeding, with no significant difference observed in MACE.
In ACS patients undergoing CABG with an established indication for OAC, anticoagulation in combination with SAPT should be resumed after CABG as soon as possible and TAT should be avoided.
Antithrombotic therapy as an adjunct to fibrinolysis
ISIS-2 (Second International Study Of Infarct Survival) demonstrated that the benefits of aspirin and fibrinolytics (i.e. streptokinase) were additive.The first dose of aspirin (162–325 mg) should be chewed or given i.v. and a low dose (75–100 mg) given orally daily from the next day thereafter. Clopidogrel added to aspirin reduces the risk of CV events and overall mortality in patients treated with fibrinolysis and should be added to aspirin following lytic therapy. Based on the available RCTs, there is insufficient evidence to support or refute improved outcomes with ticagrelor or prasugrel in patients with STEMI treated with thrombolytics. There is no evidence that administration of GP IIb/IIIa receptor inhibitors improves myocardial perfusion or outcomes in patients treated with fibrinolysis, and it may increase the risk of bleeding events.
Parenteral anticoagulation is recommended until revascularization, if performed. Despite an increased risk of major bleeding, the net clinical benefit favoured enoxaparin over UFH in the ASsessment of the Safety and Efficacy of a New Thrombolytic 3 (ASSENT 3) trial (n = 6095).347 In the large Enoxaparin and Thrombolysis Reperfusion for Acute myocardial infarction Treatment–Thrombolysis In Myocardial Infarction 25 (ExTRACT–TIMI 25) trial (n = 20 506), a lower dose of enoxaparin was given to patients ≥75 years old and to those with impaired renal function (estimated creatinine clearance <30 mL/min). Enoxaparin was associated with a reduction in the risk of death and re-infarction at 30 days when compared with a weight-adjusted UFH dose, but at the cost of a significant increase in non-cerebral bleeding complications. The net clinical benefit (i.e. absence of death, non-fatal infarction, and intracranial haemorrhage) favoured enoxaparin
In the large OASIS-6 trial, fondaparinux was superior to placebo or UFH in preventing death and re-infarction, especially in patients who received streptokinase. In a large trial with streptokinase, significantly fewer re-infarctions were seen with bivalirudin given for 48 h compared with UFH, although at the cost of a modest non-significant increase in non-cerebral bleeding complications.351 Bivalirudin has not been studied with fibrin-specific agents, and there is no evidence to support direct thrombin inhibitors as an adjunct to fibrinolysis.
Weight-adjusted i.v. tenecteplase, low-dose aspirin, clopidogrel given orally, and enoxaparin i.v. followed by s.c. administration until the time of PCI (revascularization) represents the most extensively studied antithrombotic regimen as part of a pharmaco-invasive strategy
Antithrombotic therapy in patients not undergoing reperfusion
Patients with a final diagnosis of ACS who do not undergo reperfusion should receive a P2Y12 receptor inhibitor in addition to aspirin, maintained over 12 months unless there is HBR. Among ACS patients who are medically managed without revascularization, the combination of aspirin and ticagrelor for up to 12 months has demonstrated a benefit in comparison to aspirin and clopidogrel.238,361 The combination of aspirin and prasugrel can also be justified in preference to aspirin and clopidogrel if coronary angiography has been performed and CAD is confirmed.239,362 As such, potent P2Y12 inhibitor-based DAPT is a reasonable option for patients with a final diagnosis of ACS not undergoing reperfusion, unless concerns over the bleeding risk prevail (e.g. based on ARC-HBR criteria).238,361 A DAPT regimen based on clopidogrel and aspirin may provide a good net clinical benefit among older ACS patients
Unstable patients
Out-of-hospital cardiac arrest in acute coronary syndrome
While a small minority of all patients with ACS present as OHCA, ACS is the most common cause of OHCA. In patients with OHCA, resuscitation efforts should follow the European Resuscitation Council Guidelines.
The majority of adult cardiac arrest cases are associated with obstructive CAD and ACS should be included in the differential diagnosis.Therefore, ICA can be part of the post-resuscitation management for patients who are estimated to have a high probability of acute coronary occlusion (e.g. persistent ST-segment elevation or equivalents and/or haemodynamic and/or electrical instability).
Neurological status (e.g. comatose vs. non-comatose) and survival probability (i.e. favourable benefit/risk ratio vs. futility) should also be included in the decision-making algorithm.
Despite the lack of dedicated trials, patients with return of spontaneous circulation (ROSC) and persistent ST-segment elevation should, in general, undergo a PPCI strategy (immediate ICA and PCI if indicated), based on the overall clinical situation and a reasonable benefit/risk ratio. Based on registry reports, emergent ICA and PCI are associated with good outcomes in this setting, particularly in patients who are non-comatose at initial assessment.
The management of patients with ROSC without evidence of ST-segment elevation should be individualized according to haemodynamic and neurological status. In OHCA with an initial shockable rhythm and without ST-segment elevation or equivalents and without CS, routine immediate ICA is not superior to a delayed invasive strategy based on data from the COACT (Coronary Angiography after Cardiac Arrest) and TOMAHAWK (Immediate Unselected Coronary Angiography Versus Delayed Triage in Survivors of Out-of-hospital Cardiac Arrest Without ST-segment Elevation) RCTs.
Smaller, underpowered trials (EMERGE [EMERGEncy versus delayed coronary angiogram in survivors of out-of-hospital cardiac arrest with no obvious non-cardiac cause of arrest], PEARL [A Pilot Randomized Clinical Trial of Early Coronary Angiography Versus No Early Coronary Angiography for Post-Cardiac Arrest Patients Without ECG ST Segment Elevation], and COUPE [Coronariography in OUt of hosPital Cardiac arrEst]) have also pointed to the same conclusion.
Based on data from the COACT and TOMAHAWK trials, it appears reasonable to delay ICA in haemodynamically stable patients with resuscitated OHCA without ST-segment elevation or equivalents. Initial evaluation in the ED or intensive cardiac care unit (ICCU) should focus on excluding non-coronary causes (cerebrovascular events, respiratory failure, non-cardiogenic shock, PE, or intoxication). Echocardiography is also useful in the evaluation of these patients. The decision to perform selective coronary angiography (and PCI if indicated) should also consider factors associated with poor neurological outcome and the likelihood of ACS.
In patients who remain unresponsive after ROSC, monitoring of core temperature and actively preventing fever (defined as a temperature >37.7°C) is recommended to improve neurological outcome.
A recent study compared device-based temperature control of 36°C for 24 h followed by targeting of 37°C for either 12 or 48 h (for total intervention times of 36 and 72 h, respectively) or until the patient regained consciousness in 789 patients with OHCA of a presumed cardiac cause (∼45% with ST segment elevation on ECG; immediate coronary angiography performed in 92% and PCI in 43%). This study reported comparable outcomes with both strategies with respect to the primary endpoint (death, severe disability, or coma) at 90 days.384 In all comatose survivors, evaluation of neurological prognosis no earlier than 72 h after admission is recommended.
Systems of care
There is increasing evidence suggesting that specialized hospitals for patients following OHCA (referred to as cardiac arrest centres) may be associated with clinical benefits.
Cardiogenic shock complicating acute coronary syndrome
Early revascularization with either PCI or CABG is recommended for patients with AMI complicated by CS, based on the results of the SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial. While most patients will proceed to PCI at the time of diagnostic angiography if myocardial revascularization is indicated, surgical revascularization represents a valuable treatment option in patients in whom attempted PCI of the IRA has failed or if the coronary anatomy is not amenable to PCI In the presence of CS due to AMI-related mechanical complications, surgical or percutaneous treatment may also be indicated and the strategy should be decided based on discussion between members of the Heart Team.
In the IABP-SHOCK II (Intraaortic Balloon Pump in Cardiogenic Shock II) trial, intra-aortic balloon pump (IABP) use was not associated with lower 30-day mortality. Therefore, in the absence of mechanical complications, the routine use of an IABP is not recommended for CS complicating AMI. The role of mechanical circulatory devices (veno-arterial extracorporeal membrane oxygenation [VA-ECMO], micro-axial pump) in the AMI setting is not well established and large-scale randomized trials are warranted.
The Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock trial randomized 122 patients (51% with STEMI) with rapidly deteriorating or severe CS to either immediate implementation of VA-ECMO or an initially conservative strategy (which allowed for downstream use of VA-ECMO). The immediate implementation of VA-ECMO did not result in improved clinical outcomes. However, the interpretation of this trial is challenging because of the ∼40% crossover rate to VA-ECMO in the conservative arm, the inclusion of heterogenous phenotypes of CS, and inclusion of crossover in the combined primary endpoint. As a result of these limitations, this trial cannot adequately answer if mechanical circulatory support (MCS) is able to reduce mortality in this setting.
It is important to note that while there is still a lack of high-quality randomized data supporting the use of MCS in ACS patients presenting with CS, some recent observational analyses have reported that the use of intravascular LV assist devices may be associated with an increased risk of adverse events in comparison to IABP in this setting, including mortality and bleeding. Therefore, while MCS may be considered in selected patients with ACS and severe/refractory CS, caution should be exercised in this regard until further randomized data are available
Management of acute coronary syndrome during hospitalization
Coronary care unit/intensive cardiac care unit
Following reperfusion, it is recommended to admit high-risk ACS patients (including all STEMI patients) to a coronary care unit (CCU) or ICCU. Conditions in patients with ACS that act as acute risk modifiers include ongoing myocardial ischaemia (e.g. failed reperfusion), acute HF and/or hypoperfusion, CS, cardiac arrest with coma, malignant (life-threatening) cardiac arrhythmias, high-degree atrioventricular block, and acute renal failure (with oliguria). All ICCUs must have appropriate diagnostic facilities to guide the delivery of pharmacological and invasive treatment. The staff should be thoroughly familiar with the management of all aspects of ACS, including: arrhythmias, HF, mechanical circulatory support, invasive and non-invasive haemodynamic monitoring (arterial and pulmonary artery pressures), respiratory monitoring, mechanical ventilation, and temperature control. The CCU/ICCU should also be able to manage patients with renal and pulmonary disease. The desirable organization, structure, and criteria of CCU/ICCUs have been detailed in an ESC–Acute CardioVascular Care Association position paper.
Monitoring
It is recommended to initiate ECG monitoring as soon as possible in all patients with ACS in order to detect life-threatening arrhythmias and allow prompt defibrillation if indicated. ECG monitoring for arrhythmias and new ST-segment elevation/depression is recommended for at least 24 h after symptom onset in all high-risk patients with ACS, including all STEMI patients.409 Longer monitoring could be considered in patients at intermediate to high risk of cardiac arrhythmias (i.e. those with more than one of the following criteria: haemodynamically unstable, presenting with major arrhythmias, left ventricular ejection fraction [LVEF] <40%, failed reperfusion, additional critical coronary stenoses of major vessels, or complications related to PCI). Further monitoring for arrhythmias will be dependent on the estimated risk. When a patient leaves the ICCU or equivalent, monitoring may be continued by telemetry. It is recommended that personnel adequately equipped and trained to manage life-threatening arrhythmias and cardiac arrest accompany patients who are transferred between facilities during the time window in which they require continuous rhythm monitoring.
. Ambulation
Early ambulation (i.e. out of bed on day 1) is recommended in the majority of patients with ACS. This is facilitated by using radial access for invasive management. Patients with extensive myocardial damage, HF, hypotension, or arrhythmias may initially rest in bed before assessment of myocardial function and clinical stabilization. Prolongation of bed rest and limitation of physical activity may occasionally be required in patients with large infarcts or severe complications.
. Length of stay in the intensive cardiac care unit
The optimal length of stay in the ICCU and hospital should be individualized according to the patient’s clinical situation, taking into account their baseline cardiac risk and comorbidities, baseline mental/functional status, and social support. Of note, the majority of adverse in-hospital events occur early after admission and the initiation of treatment.
In-hospital care
. Length of hospital stay
The impact of both successful reperfusion and knowledge of the coronary anatomy (due to increasing rates of ICA) has resulted in progressive reductions in the length of stay after ACS, alongside significant reductions in 30-day mortality, suggesting that discharge within 72 h is not associated with late mortality.Candidates for early discharge after PCI can be identified using simple criteria.413,414 In one study, patients meeting the following criteria were considered to be ‘low risk’ and suitable for early discharge: age <70 years, LVEF >45%, one- or two-vessel disease, successful PCI, and no persistent arrhythmias. A recently published consensus document also presents a template and flow chart to support reasonable decision-making regarding post-procedural length of stay for a broad spectrum of patients undergoing PCI.
Early (i.e. same day) transfer to a local hospital following successful PPCI is routine practice. This can be done safely under adequate monitoring and supervision in selected patients (i.e. patients without signs or symptoms consistent with ongoing myocardial ischaemia, without arrhythmias, who are haemodynamically stable, who are not requiring vasoactive or mechanical support, and who are not scheduled for further revascularization).419
Risk assessment
Early and late risk stratification soon after presentation is useful to aid decision-making in patients presenting with ACS.
Clinical risk assessment
All patients with ACS (in particular, patients with STEMI) should have an early assessment of short-term risk, including an evaluation of the extent of myocardial damage, the achievement of successful reperfusion, and the presence of clinical markers of high risk of further events (i.e. older age, tachycardia, hypotension, Killip class >I, anterior MI, previous MI, elevated initial serum creatinine, history of HF, peripheral arterial disease or anaemia). Several risk scores have been developed based on readily identifiable parameters in the acute phase before reperfusion.420,421 A number of prognostic models that aim to estimate the longer-term risk of all-cause mortality, or the combined risk of all-cause mortality or MI, have also been developed. These models have been formulated into clinical risk scores and, among these, the GRACE risk score offers the best discriminative performance and is therefore recommended for risk assessment.
Imaging risk assessment
LV dysfunction is a key prognostic factor for patients with ACS. It is recommended that the LVEF is determined before hospital discharge in all patients with ACS. Routine echocardiography after PPCI is recommended to assess resting LV, RV, and valvular function. In addition, echocardiography can be used to exclude early post-infarction mechanical complications and LV thrombus. In the limited number of cases in which echocardiography is suboptimal or inconclusive, CMR may be a valuable alternative.
In patients presenting days after an acute ACS event with a completed MI, the presence of recurrent angina or documented ischaemia and proven viability in a large myocardial territory may help to guide the strategy of planned revascularization of an occluded IRA.
In patients with a pre-discharge LVEF of ≤40%, re-evaluation of the LVEF 6–12 weeks after complete revascularization and optimal medical therapy is recommended to assess the potential need for primary prevention implantable cardioverter defibrillator (ICD) implantation. Additional parameters that are measured by imaging in these patients and that have been used as endpoints in clinical trials include: (i) infarct size (CMR, SPECT, and positron emission tomography); (ii) myocardium at risk (SPECT, CMR); (iii) MVO (CMR); and (iv) intra-myocardial haemorrhage (CMR). Infarct size, MVO and intra-myocardial haemorrhage are predictors of both long-term mortality and HF in STEMI survivors.
Biomarkers fro Risk assessment
Beyond diagnostic utility, initial cTn levels add prognostic information in addition to clinical and ECG variables in terms of predicting the risk of short- and long-term mortality. While hs-cTn T and I have comparable diagnostic accuracy, hs-cTn T has slightly greater prognostic accuracy regarding mortality.Serial measurements are useful to identify peak levels of cTn for risk stratification purposes in patients with established MI. The higher the hs-cTn levels, the greater the risk of death.However, evidence is limited regarding the optimal time points of serial hs-cTn measurement.
Serum creatinine and eGFR should also be determined in all patients with ACS because they affect prognosis and are key elements of the GRACE risk score. Similarly, natriuretic peptides (brain natriuretic peptide [BNP] and N-terminal pro-BNP [NT-pro BNP]) provide prognostic information in addition to cTn regarding the risk of death and acute HF, and the development of AF.
. Bleeding risk assessment
Major bleeding events are associated with increased mortality in patients with ACS.
Integrating ischaemic and bleeding risks
Major bleeding events affect prognosis in a similar way to spontaneous ischaemic complications.Given the trade-off between ischaemic and bleeding risks for any antithrombotic regimen, risk scores may be useful to tailor antithrombotic duration and intensity, in order to maximize ischaemic protection and minimize bleeding risk in the individual patient. Specific risk scores have been developed for patients on DAPT following PCI, in the settings of both CCS and ACS.
Technical aspects of invasive strategies
Percutaneous coronary intervention
Vascular access
Timely PCI with concomitant antithrombotic drugs has reduced the ischaemic risk in patients with ACS. However, this strategy is also associated with an increased bleeding risk, which affects prognosis at least as much as ischaemic complications and is associated with impaired survival. Among patients undergoing PCI, access-related bleeding accounts for 30–70% of total bleeding events There is strong evidence demonstrating that reducing access-site bleeding events with the use of radial access translates into significant clinical benefits. The largest randomized trials on this topic in patients with ACS are the RadIal Vs femorAL access for coronary intervention (RIVAL) trial with 7021 ACS patients and the Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) trial with 8404 ACS patients (47.6% with STEMI).
These trials have demonstrated significantly lower rates of access site-related bleeding, surgical access site repair, and blood transfusion with radial compared with femoral access. In the MATRIX trial, no significant interaction was observed between the type of ACS and the benefit associated with the radial approach, suggesting that the results of this trial can be extended to patients across the entire spectrum of ACS. In a cost-effectiveness analysis of the MATRIX trial, radial access was also associated with significant savings in terms of quality-adjusted life years and PCI-related costs.
Therefore, radial access is recommended as the preferred approach in ACS patients undergoing invasive assessment with or without PCI. However, femoral access may still be selectively chosen instead of radial access in certain patients (i.e. depending on the haemodynamic situation and other technical aspects during the index PCI procedure).
Intravascular imaging/physiology of the infarct-related artery
Intravascular imaging
As a diagnostic tool, intravascular imaging is useful in ACS patients without significant obstructive CAD on coronary angiography. Excluding an atherothrombotic cause in the main coronary arteries for the ACS may have important clinical implications, not only for immediate invasive management but also for potentially lifelong antithrombotic therapies. Intravascular imaging is also useful in cases where there is ambiguity regarding the culprit lesion. Culprit lesion ambiguity can be present in more than 30% of patients with suspected NSTE-ACS and over 10% of patients may have multiple culprit lesions.
9.1.2.2. Intravascular physiology
Intracoronary physiology is increasingly being used in patients with ACS to assess the haemodynamic significance of intermediate severity non-IRA stenoses (see Section 10). However, PCI of the IRA should not be deferred based on invasive epicardial functional assessment in patients with ACS. The coronary microcirculation begins to recover within 24 h of PPCI and acute functional assessment of the IRA may underestimate the true haemodynamic severity of the coronary stenosis.461 Beyond 1 week from the acute event, fractional flow reserve (FFR) measurement has been reported to reliably predict abnormal nuclear imaging results.
Timing of revascularization with percutaneous coronary intervention
In some patients with ACS undergoing ICA, an initial conservative management strategy with optimized guideline-directed medical therapy may be considered on a case-by-case basis. The specific circumstances include ACS patients with small calibre vessels, an occluded small side branch, or concerns regarding non-compliance with antithrombotic therapy. In the context of complex CAD and anticipated complex PCI, an initial conservative strategy in medically stabilized patients without ongoing symptoms allows time for Heart Team discussion regarding the optimal revascularization strategy.
Balloons and stents
New-generation DES are associated with superior safety and improved efficacy compared with bare metal stents (BMS) and first-generation DES. The Norwegian Coronary Stent Trial (NORSTENT)—the largest clinical trial comparing outcomes of patients treated with new-generation DES or BMS—reported that the primary endpoint of death or MI was comparable in both treatment groups. Both target lesion revascularization (TLR) and stent thrombosis were reduced in the DES group and there was no treatment effect by ACS presentation interaction for the primary endpoint.463 The COMFORTABLE-AMI (Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST-Elevation Myocardial Infarction) and EXAMINATION (Everolimus-Eluting Stents Versus Bare-Metal Stents in ST Segment Elevation Myocardial Infarction) trials have also reported the clinical superiority of DES over BMS in terms of lower rates of re-infarction, target lesion revascularization, and stent thrombosis.This clinical benefit was preserved at longer-term follow-up.
Embolic protection and microvascular salvage strategies
Thrombus aspiration
Large RCTs have failed to demonstrate a clinical benefit with routine manual thrombus aspiration in comparison to conventional PPCI. In an individual patient data meta-analysis, thrombus aspiration was associated with fewer CV deaths and with more strokes or transient ischaemic attacks in the subgroup of patients with high thrombus burden (TIMI thrombus Grade 3).However, in a sub-analysis from TOTAL (a Trial of routine aspiration ThrOmbecTomy with PCI vs. PCI ALone in patients with STEMI), routine thrombus aspiration did not improve outcomes at 1 year and was also associated with an increased rate of stroke in patients with high thrombus burden. In patients with NSTE-ACS and thrombus-containing lesions, PCI with adjunctive thrombus aspiration was not associated with a reduction in MVO 4 days after the index procedure or with fewer MACE after up to 1 year of follow-up. Based on these data, routine thrombus aspiration is not recommended, but in cases of large residual thrombus burden after opening the vessel with a guide wire or a balloon, thrombus aspiration may be considered.
9.1.5.2. Interventions to protect the microcirculation
The damage inflicted on the myocardium during AMI is the result of ischaemia and subsequent reperfusion (ischaemia/reperfusion injury). In patient-level pooled analyses, infarct size and MVO are independent predictors of long-term mortality and HF in survivors of STEMI.
Strategies to reduce ischaemia/reperfusion injury in general (and MVO in particular) remain an unmet clinical need. Further information regarding interventions to protect the microcirculation that are under clinical or experimental investigation is presented in the Supplementary data online.
Coronary artery bypass grafting
Indication and timing of coronary artery bypass grafting in acute coronary syndrome patients
There are no dedicated RCTs comparing percutaneous vs. surgical revascularization in patients with ACS. In the setting of STEMI, CABG should be considered only when PPCI is not feasible, particularly in the presence of ongoing ischaemia or large areas of jeopardized myocardium.479
In patients requiring immediate revascularization in the setting of very high-risk NSTE-ACS, PCI is usually preferred for reasons of timeliness, unless concomitant mechanical complications dictate a preference for surgical intervention.
In other patients with ACS, the choice of revascularization modality should be made according to the number of diseased vessels and the general principles of myocardial revascularization.
Technical considerations specific to acute coronary syndrome patients
The patient profile, including the need for emergency or extremely expeditious revascularization, may influence both the technique of CABG (including on-pump beating heart CABG) and the choice and use of CABG conduits. The need for prompt surgical revascularization in emergency circumstances does not facilitate the use of full arterial revascularization due to the prolonged period required for graft harvesting. Accordingly, the use of total venous graft-based CABG or the use of single left internal mammary artery plus additional venous grafts may be useful in this setting.
Spontaneous coronary artery dissection
Spontaneous coronary artery dissection (SCAD) is an infrequent cause of ACS in general but accounts for a significant proportion of ACS cases in young/middle-aged women. The pathophysiology underlying SCAD is different to that of Type 1 MI and there are some differences in its management and outcomes. For these reasons, it is of paramount importance that an accurate diagnosis is established. Until evidence from ongoing prospective trials becomes available, patients with SCAD should receive the same pharmacological therapy as other ACS patients.
Intravascular imaging
There are no RCTs to guide management strategies in patients with SCAD. The use of intravascular imaging is based on observations reported from clinical cohort studies and expert opinion.
In cases of diagnostic uncertainty after angiography, the use of intracoronary imaging with OCT or IVUS has to be carefully considered. There should be sufficient diagnostic uncertainty to justify coronary instrumentation, and even if this is the case, other factors like vessel tortuosity, vessel diameter, and a distal lesion location may prohibitively increase the risk.If the decision is made to perform intravascular imaging, it is imperative to ensure the guide wire is located within the true lumen of the coronary artery before advancing the imaging catheter. In patients with a diagnosis of SCAD on angiography and a plan for medical therapy, additional coronary instrumentation and intravascular imaging is not recommended on safety grounds.
Revascularization
Conservative medical management, as opposed to PCI, is generally recommended for patients with SCAD. In an international case series, coronary complications following PCI occurred in >30% of patients. In a pooled analysis of three SCAD-PCI cohorts including 215 patients (94% female) drawn from Dutch, Spanish, and UK registries, and a matched cohort of conservatively managed SCAD patients (n = 221), PCI was associated with complications in ≈40% of cases (including 13% with serious complications). PCI is recommended only for SCAD with associated symptoms and signs of ongoing myocardial ischaemia, a large area of myocardium in jeopardy, and reduced antegrade flow. Useful strategies for these patients may include minimal plain balloon angioplasty to restore flow, followed by a conservative strategy, targeted stenting to seal the proximal and distal ends of the dissection, and/or extended stent lengths to prevent propagation of the haematoma. In patients with SCAD, CABG is recommended when dissection affects the left main or two proximal vessels, if PCI is not feasible or unsuccessful, and if there are symptoms and signs of ongoing myocardial ischaemia. In a small observational study, patients with SCAD treated with CABG had favourable early clinical outcomes, with an event rate up to 5 years similar to that of patients treated conservatively, despite a significant (68%) rate of graft occlusion at 5 years.
The rate of graft occlusion over time can be explained by the fact that CABG in these patients may be technically challenging as the dissected coronary artery is more prone to anastomosis failure, and because spontaneous healing over time may restore the flow in the anastomosed vessel. For this reason, vein grafts should be considered in these patients in order to preserve arterial conduits for future use.
Timing of non-infarct-related artery revascularization in acute coronary syndrome
Patients presenting with ST-elevation myocardial infarction and multivessel coronary artery disease
The previous ESC STEMI Guidelines recommended non-IRA PCI during the index procedure. The primary rationale for this recommendation was that all trials available until then had performed MVD PCI in that time frame. However, in the COMPLETE trial, non-IRA PCI in patients allocated to complete revascularization was performed either during hospitalization (67% of cases) or after discharge (33% of cases), at a mean time of 23 days after discharge but always within 45 days. No treatment effect by timing of PCI interaction was observed. Given that the optimal timing of revascularization (immediate vs. staged) has still not been investigated in adequately sized randomized trials with a superiority design, no recommendation in favour of an immediate vs. a staged (i.e. either during index hospitalization or within 45 days of discharge) non-IRA PCI strategy can be formulated. No surgical studies have specifically investigated non-IRA revascularization.
Patients presenting with non-ST-elevation acute coronary syndrome and multivessel coronary artery disease
While there are a large number of studies providing evidence for patients presenting with STEMI and MVD, there are fewer data guiding the management of patients presenting with NSTE-ACS and MVD.513 Currently, there is no dedicated trial comparing complete revascularization against IRA-only PCI for these patients. Observational studies and meta-analyses of non-randomized studies suggest that complete revascularization is associated with fewer deaths and MACE during follow-up in comparison to IRA-only PCI. However, given that these are analyses of treatment effects based on non-randomized studies, the results should be considered as hypothesis-generating at best and this remains a gap in evidence.
Evaluation of non-infarct-related artery stenosis severity (angiography vs. physiology)
Overestimation of the severity of non-IRA lesions during the PPCI procedure when assessed by quantitative coronary angiography as compared with a repeated angiogram performed within 9 months has been reported. Microvascular constriction may also occur in the non-IRAs, leading to some variation in functional measurements between baseline and follow-up, although the impact on decision-making may be modest.
Hybrid revascularization
Hybrid coronary revascularization (HCR) is defined as combined or consecutive procedures consisting of an internal mammary artery graft to the left anterior descending artery (LAD) and PCI to the other non-LAD vessels for the treatment of MVD.529 The preferred surgical technique for HCR is a minimally invasive left anterior mini-thoracotomy or robotic-assisted left internal mammary artery (LIMA)-LAD. The rationale for HCR is to combine the prognostic benefits of a LIMA for grafting of the LAD with the potential benefits of contemporary PCI with DES for disease in arteries that would otherwise be revascularized using vein grafts (which are prone to occlusion).
Special situations
Type 2 myocardial infarction
Pathological processes other than atherothrombosis commonly underlie the presentation of patients with acute chest pain with troponin elevation. These include Type 2 MI and myocardial injury as defined in the fourth universal definition of MI. Type 2 MI is an ischaemic myocardial injury in the context of a mismatch between oxygen supply and demand that is not related to acute coronary atherothrombosis. This may occur in the context of atherosclerosis and an oxygen supply/demand imbalance, with an oxygen supply/demand imbalance alone, secondary to vasospasm or coronary microvascular dysfunction, or secondary to non-atherosclerotic coronary dissection.
These causes of Type 2 MI can be divided into those with underlying coronary (e.g. coronary embolus, dissection, spasm, microvascular dysfunction) or non-coronary mechanisms (supply demand mismatch due to hypoxia, hypotension, anaemia, tachycardia, bradycardia).Type 2 MI is common and associated with a prognosis similar to Type 1 MI.
acute myocardial injury
Myocardial injury is characterized by myocyte necrosis and troponin elevation due to mechanisms other than myocardial ischaemia and can be acute (e.g. sepsis, myocarditis, takotsubo) or chronic (e.g. HF, cardiomyopathies, severe valve heart disease). Myocardial injury is increasingly appreciated in the era of hs-cTn assays, which are not specific for MI. In patients who have elevated hs-cTn values and do not have evidence of acute myocardial ischaemia, a diagnosis of myocardial injury can be made. It is important to recognize that this diagnosis can change if subsequent investigations indicate that the patient meets the criteria for MI.
Despite some common risk factors, the pathophysiology of Type 2 MI is different to that of Type 1 MI. Therefore, the natural history and appropriate management strategy of these two conditions also differs in some important respects. Type 2 and Type 1 MI require diagnostic distinction, which is best achieved by following an algorithmic approach.1Once patients with suspected Type 2 MI and myocardial injury have been stabilized and any precipitating illnesses have been treated, targeted echocardiography and/or coronary angiography (invasive or CCTA) can be used to identify contributory (and prognostically important) cardiac conditions and to guide appropriate long-term cardiovascular treatments.
Due to the lack of robust scientific evidence investigating management strategies and the wide range of precipitating causes, there are currently no specific recommended pharmacological interventions for patients with Type 2 MI. Therefore, management should instead focus on identifying and treating any precipitating conditions (e.g. anaemia, hypoxia) alongside strict control of CV risk factors.
Complications
Heart failure
Acute HF may occur as a complication of ACS. Acute HF as a result of ACS significantly increases the risk of other in-hospital complications, including worsening of renal function, respiratory failure, pneumonia, and death. De novo acute HF complicating ACS should be distinguished from pre-existing HF exacerbated by ACS. This can be challenging and the presence of acute HF may impede the straightforward diagnosis of ACS. Patients with ACS and acute HF are more likely to present with resting dyspnoea and clinical signs/symptoms of fluid overload. In some clinical scenarios, increased troponin levels in patients with acute HF may reflect myocardial injury due to HF rather than myocardial necrosis due to ischaemia.
Patients with ACS complicated by acute HF require urgent and co-ordinated management of both conditions. The management of acute HF should follow current recommendations included in the ESC Guidelines on HF and ancillary documents.
The use of diuretics, vasodilators, inotropic agents, and vasopressors should be considered according to the established algorithms. Mechanical circulatory support may also be considered in selected cases. Invasive respiratory support and/or renal replacement therapy may be required in some circumstances.
Patients presenting with acute HF (including patients with CS) complicating ACS require immediate ICA.These patients should also undergo emergency echocardiography/chest ultrasonography to gather information about LV and RV function, regional wall motion abnormalities, valvular function, and possible mechanical complications.
In patients with ACS, CS may occur as a result of extensive ischaemia due to MVD, acute severe mitral regurgitation, and mechanical complications. Patients with ACS and CS should be transferred as soon as possible to a PCI centre where immediate coronary angiography, and PCI of the IRA if needed, can be performed.404,505 In patients with CS complicating ACS in whom the coronary anatomy is not suitable for PCI, emergency CABG is recommended.
The clinical benefit of percutaneous MCS devices and/or VA-ECMO in the context of ACS remains unclear. Micro-axial MCS devices have not been associated with lower 30-day mortality in comparison to IABP in observational studies. In a large retrospective registry of 48 306 patients (>80% ACS) undergoing PCI with MCS, micro-axial MCS support was associated with higher mortality and bleeding rates in comparison to IABP. Similar results were observed in another propensity-matched registry analysis confined to patients with CS, where micro-axial MCS support was also associated with more complications and higher mortality than IABP. In the IABP-SHOCK II trial, the routine use of IABP in patients with ACS and CS did not reduce 30-day, 1-year, or 6-year mortality.
Based on these data, a benefit of LVAD in patients with ACS has not been demonstrated, and given that observational data have suggested that this may be associated with harm, caution is advised in this regard until further RCT evidence is available.
Mechanical complications
Mechanical complications may occur in the first days following MI, most commonly in patients presenting with STEMI. The incidence of mechanical complications has fallen significantly in the era of PPCI. A recent large epidemiological investigation including almost 9 million ACS patients reported an overall prevalence of mechanical complications in 0.27% of STEMI cases and 0.06% of NSTEMI cases, with in-hospital mortality rates of 42.4% and 18%, respectively. Mechanical complications are life-threatening and therefore require prompt identification and management.
Sudden hypotension, the recurrence of chest pain, new cardiac murmurs suggestive of acute mitral regurgitation or a ventricular septal defect, pulmonary congestion, or jugular vein distension should raise suspicion of a mechanical complication. Immediate echocardiographic assessment is indicated when mechanical complications are suspected.
The use of temporary MCS for mechanical complications, either to improve pre-operative clinical/haemodynamic status or prophylactically, represents a new trend in management. However, this approach requires more data and evidence in order to determine if it provides a clinical benefit.
Surgery is currently regarded as the treatment of choice for patients with ACS and mechanical complications, although percutaneous strategies are occasionally used in selected candidates with a prohibitive risk profile or contraindications to a surgical approach. A multidisciplinary approach to the management of these patients is of paramount importance, and should apply to all stages of care, from the initial stabilization of the patient to discussion and application of the therapeutic strategy, including palliative care. Patients with ACS-related mechanical complications should be considered for IABP while awaiting surgery.
Left ventricular thrombus
While the incidence of LV thrombus following AMI has declined due to advances in reperfusion and antithrombotic therapies, it remains relatively common, particularly following anterior STEMI, where it can be present in >9% of patients according to a large meta-analysis.
Echocardiography remains the first-line imaging test for the detection of LV thrombus. In patients where the apex is not well visualized on regular echocardiography, contrast echocardiography may be considered for improved image quality. CMR is the gold standard imaging modality for the diagnosis and assessment of LV thrombi. Contemporary CMR data report LV thrombi in up to 6.3% of all STEMI patients and in 12.2% of those with anterior STEMI, suggesting that the incidence of LV thrombi may be underestimated with echocardiography. Patients with LV thrombi that were not evident on echocardiography but were detected by CMR appear to have similar clinical outcomes to patients with LV thrombi that were evident on echocardiography. Therefore, CMR should be considered in patients with equivocal echocardiographic images or in patients considered to be at a particularly high risk of LV thrombus.
The timing of imaging for LV thrombus may also be relevant, given that the identification of LV thrombus has been reported to increase in the first 2 weeks post-MI. While more contemporary data are required, these data suggest that a high proportion of LV thrombi may develop following hospital discharge, indicating that delayed imaging at 2 weeks in high-risk patients may be of value.
Once an LV thrombus has been diagnosed, OAC therapy (warfarin or NOAC) should be considered for 3–6 months, guided by repeated echocardiography or CMR and with consideration of bleeding risk and the need for concomitant antiplatelet therapy. However, there are a lack of prospective randomized data on the optimal anticoagulation regimen, anticoagulation duration, and the combination of oral anticoagulation with antiplatelet agents in patients with LV thrombus following MI. The choice of therapy should be tailored to the patient’s clinical status and the results of follow-up investigations.
Post-acute coronary syndrome pericarditis
Pericardial complications that may develop after an AMI include early infarct-associated pericarditis (occurring from a few hours to 4 days after AMI, mostly transient), late pericarditis or post-cardiac injury (Dressler) syndrome (typically occurring 1–2 weeks after AMI), and pericardial effusion
Arrhythmias
Atrial fibrillation
Atrial fibrillation is the most frequent supraventricular arrhythmia in patients with ACS. AF may be pre-existing, first time detected, or of new onset during ACS management. Patients with AF have a greater number of comorbidities compared with patients without AF and are at higher risk of complications. In most cases, AF is well tolerated and no specific treatment is required, apart from anticoagulation Prompt treatment is required for AF causing acute haemodynamic instability, with electrical cardioversion being the preferred approach. Adequate rate control can be achieved by administration of beta-blockers depending on the presence of HF and low ejection fraction. For patients with depressed LVEF, amiodarone or digoxin could be used (preferably amiodarone). In cases of hypotension, digoxin is preferred over amiodarone or beta-blockers. Patients with AF and risk factors for thrombo-embolism should be adequately treated with chronic oral anticoagulation. ACS patients with documented AF of any length have worse short- and long-term prognoses when compared with patients in sinus rhythm. There is some evidence to suggest that transient, self-terminating AF during STEMI may be a predictor of an increased risk of stroke during long-term follow-up.
Ventricular arrhythmias
With the widespread increased uptake of emergency reperfusion therapies for patients with STEMI, the incidence of malignant arrhythmias (ventricular tachycardia [VT] and ventricular fibrillation [VF]) has significantly declined. Nevertheless, 6–8% of patients with STEMI develop haemodynamically significant VT or VF. The typical arrhythmia presentation is unstable, frequently polymorphic, and relatively fast VT, often degenerating into VF. Urgent reperfusion is most important as ischaemia is often the trigger for these arrhythmias. Early administration of i.v. or oral beta-blockers reduces the incidence of malignant arrhythmias.
Beta-blockers or amiodarone are recommended if malignant arrhythmias occur and lidocaine may be considered if these are contraindicated. The prognostic role of early VT/VF within the first 48 h of STEMI is still controversial. Several studies have suggested that patients with early VT/VF have increased 30-day mortality but no increase in long-term arrhythmic risk
Another study has suggested that while malignant ventricular arrhythmias occurring at the time of reperfusion do not confer poor prognosis, sustained VT or VF occurring during ongoing ischaemia or late after reperfusion (>48 h) is associated with an increase in long-term mortality. Sustained VT/VF late after reperfusion (>48 h) requires an evaluation for ICD implantation for secondary prevention of sudden cardiac death. Ventricular premature beats are very frequent during the first 24 h after reperfusion for STEMI and no specific therapy is required.
Primary prevention of sudden cardiac death with ICD implantation within 40 days after MI is generally not indicated. Patients should be re-evaluated for ICD implantation post-revascularization after a period of 6–12 weeks on evidence-based treatments, although patients with a pre-existing impaired LVEF may be considered for ICD implantation for primary prevention even within the early post-infarction period. Some patients may develop electrical storm and/or incessant VT despite complete revascularization and treatment with anti-arrhythmic drugs. Overdrive stimulation may help to control this situation; however, recurrence of VT/VF upon cessation of stimulation is frequent and catheter ablation of such triggers appears to be the preferred treatment option in centres with that expertise. Successful radiofrequency ablation has been shown to abolish recurrent VT/VF .
Non-sustained monomorphic VT is the most common form of ventricular arrhythmia in the early phase of ACS, and usually does not require anti-arrhythmic treatment. Accelerated idioventricular rhythm at reperfusion is frequent and does not require intervention given its benign nature.
.Bleeding
Bleeding is associated with a poor prognosis in ACS patients. The mechanisms by which bleeding increases the risk of death are complex and multifactorial . While intracranial or massive haemorrhage directly threatens life through fatal brain damage or sudden cardiocirculatory collapse, other less severe forms of haemorrhage may increase the risk of death through indirect mechanisms. Blood transfusion may increase systemic inflammation and represents one of the possible links between bleeding and subsequent mortality. Bleeding is also a major driver of unplanned DAPT discontinuation and the interruption of other medication (e.g. statins, beta-blockers).
Management of bleeding
Comorbid conditions
Patients at high bleeding risk and with blood disorders (anaemia and thrombocytopaenia)
Anaemia is more prevalent in elderly/frail ACS patients and in patients with multimorbidity (i.e. HF, chronic kidney disease [CKD], diabetes mellitus, cancer, and autoimmune diseases). In some cases, severe anaemia may precipitate Type 2 MI. Persistent or worsening anaemia in patients with ACS is associated with an increased risk of recurrent ischaemic events, death, and major bleeding. According to the ARC-HBR, haemoglobin <11 g/dL at the time of PCI constitutes a major criterion for HBR, whereas haemoglobin between 11 and 13 g/dL (12 g/dL for women) is a minor criterion.
There is no established strategy for treating anaemia in patients with ACS. The efficacy and safety of blood transfusion in this clinical scenario remains unknown. In the majority of studies investigating different transfusion protocols, a liberal blood transfusion strategy has been defined as any red blood cell transfusion at a haemoglobin level <9–10 g/dL, while a restrictive blood transfusion strategy has been defined as any transfusion at a haemoglobin level <7–8 g/dL. Observational data suggest that a liberal blood transfusion strategy may be associated with an increase in all-cause mortality.The open-label Restrictive and Liberal Transfusion Strategies in Patients With Acute Myocardial Infarction (REALITY) trial enrolled 668 ACS patients who were randomized to management with a restrictive (triggered by haemoglobin ≤8) or a liberal (triggered by haemoglobin ≤10) transfusion strategy. The composite outcome (all-cause death, stroke, recurrent MI, or emergency revascularization) at 30 days occurred in a comparable number of patients in both arms (11% vs. 14%, RR 0.79, with a one-sided 97.5% CI of 0.00–1.19), meeting the pre-specified non-inferiority criterion. All components of the composite endpoint were numerically higher in the liberal transfusion strategy arm. The trial was not powered to detect superiority of the restrictive strategy, and the CI included what may be a clinically important harm. The pre-specified 1-year follow-up of the REALITY trial yielded contradictory conclusions to the 30-day outcomes: at 1 year, the restrictive transfusion strategy (vs. a liberal approach) did not achieve non-inferiority in terms of MACE. In addition, a post-hoc analysis of MACE between day 30 and 1 year demonstrated an increased risk in the restrictive transfusion strategy group.Therefore, no formal recommendation as to the optimal transfusion strategy (liberal vs. restrictive) in patients with ACS can be made at present.
Although there are several classifications to grade the severity of thrombocytopaenia, clinically relevant thrombocytopaenia can be defined as a platelet count <100 000/μL or a relative drop in platelet count of 50% from baseline in the context of ACS. Thrombocytopaenia increases the risk of death, major bleeding events, and life-threatening thrombotic events.The ARC-HBR criteria define a platelet count <100 000/μL as a major criterion for HBR.
Chronic kidney disease
Moderate to severe CKD (stages III–V) is present in more than 30% of ACS patients. Patients with ACS and concomitant CKD receive less interventional and pharmacological treatment and have a worse prognosis than patients with normal kidney function. Likely contributing factors to this worse prognosis include a larger number of comorbidities and an increased risk of in-hospital complications, including serious bleeding complications.Although evidence from RCTs is lacking, data from observational and registry-based studies indicate that ACS patients with moderate to severe CKD have a better prognosis with early revascularization than with medical therapy alone.
The type and dose of antithrombotic agent and the amount of contrast agent should be considered based on kidney function. In relation to supplementary i.v. hydration during and after revascularization, the evidence around choice, timing, and duration of treatment is somewhat conflicting. Taking the clinical circumstances and patient characteristics into consideration, i.v. hydration should be considered as part of the management of ACS patients with a low eGFR undergoing invasive management to minimize the risk of contrast-induced nephropathy.
Diabetes mellitus
ACS patients with diabetes mellitus (DM) may more commonly present with non-specific symptoms, which can lead to delays in both diagnosis and access to treatment. Both treatment in the acute phase and risk factor management post-ACS is poorer in patients with DM and these patients tend to have more advanced CAD at diagnosis. These factors likely contribute to the worse long-term prognosis associated with ACS in patients with DM, particularly in patients requiring insulin treatment.649–651
All patients with ACS, regardless of a history of DM, should have their glycaemic status evaluated during hospitalization. Given that the ACS itself may give rise to hyperglycaemia due to catecholamine-induced stress, a diagnosis of DM made during hospitalization should be subsequently confirmed. While several studies have shown the benefits of managing hyperglycaemia (>11.0 mmol/L or 200 mg/dL) in hospitalized ACS patients, the risk of hypoglycaemia-related events when using intensive insulin therapy should not be neglected ,
Glucose lowering is important in order to prevent microvascular complications in patients with DM. However, recent trial evidence has shown that the reduction in the risk of new ACS events, HF, and renal impairment with glucose-lowering medications like sodium–glucose co-transporter 2 (SGLT2) inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1-RA) is independent of baseline glycosylated haemoglobin (HbA1c) levels. This should be taken into consideration when choosing glucose-lowering therapy for patients with DM and concomitant CAD. For further details, please refer to the 2023 ESC Guidelines on diabetes and cardiovascular diseases and the 2021 ESC Guidelines on cardiovascular disease prevention.
. Older adults with frailty and multimorbidity
The older person
Older adults represent an increasing proportion of ACS patients. One of the major predictors of adverse outcomes following ACS is age, but patients aged ≥75 years are often excluded from or under-represented in clinical trials.Older age is associated with frailty, multimorbidity, and a greater risk of both ischaemic and bleeding events in patients with ACS. Hs-cTn assays have an excellent diagnostic performance in the older person, but the specificity of the test is lower than in younger patients, and elevated cTn levels are more commonly associated with conditions other than ACS in older patients ,
There are limited data on the optimal management of older adults with ACS. A small RCT enrolling older patients (≥80 years) with NSTE-ACS reported the superiority of an invasive vs. a conservative strategy in the reduction of the composite of MI, need for urgent revascularization, stroke, and death. No treatment effect was shown for all-cause death and the benefit associated with the invasive strategy was diluted with increasing age. In the absence of robust clinical trial evidence, decisions regarding how to manage older patients should be individualized based on patient characteristics (i.e. ischaemic and bleeding risks, estimated life expectancy, comorbidities, the need for non-cardiac surgery, quality of life, frailty, cognitive and functional impairment, patient values and preferences, and the estimated risks and benefits of an invasive strategy).
In the context of STEMI, PPCI has drastically improved outcomes for all ages. However, data are limited in the ‘very old’ cohort, with lack of formal assessment of frailty or comorbidity. In the context of CS and cardiac arrest, age is an independent predictor of mortality following PCI . In the absence of robust RCT data, PPCI should be considered for all patients with STEMI. When PPCI cannot be performed in a timely manner, fibrinolysis may be a reasonable strategy in these patients.
Frailty and multimorbidity
Geriatric syndromes (i.e. frailty and multimorbidity) are associated with adverse outcomes in older patients with ACS. Frailty is a syndrome characterized by reduced biological reserve, leading to a failure of homeostatic mechanisms following stressor events, including ACS. There is a lack of consensus on which frailty assessment tool is optimal in older patients with CV disease.
Frail patients with NSTE-ACS less frequently receive ACS pharmacotherapies and invasive assessment, have more complex coronary disease, have longer durations of hospital stay, and are at higher risk of death. Specifically, frail patients are reported to have a higher rate of a composite of all-cause mortality, MI, stroke, unplanned revascularization, and major bleeding .Frail older adults with NSTE-ACS have poor health-related quality of life (HRQoL) at baseline. Invasive management appears to be associated with modest improvements in HRQoL through to 1 year follow-up in these patients. This improvement in HRQoL is most marked in frail and pre-frail patients, who receive a proportionally larger benefit than robust patients . In older adults with NSTE-ACS referred for coronary angiography, the presence of multimorbidity is associated with an increased risk of long-term adverse CV events, driven by a higher risk of all-cause mortality.
Undiagnosed cognitive impairment is also common in older patients with NSTE-ACS undergoing ICA, and these patients are more likely to experience MACE at 1 year.
In the absence of robust RCT data to inform healthcare professionals about the management of frail patients presenting with ACS, it is recommended to adapt a holistic approach to individualize interventional and pharmacological treatments after careful evaluation of risks vs. benefits. To aid in decision-making, the routine assessment of frailty (e.g. Rockwood Frailty Score) and comorbidity (e.g. Charlson index) in ACS patients is recommended. Following risk stratification using frailty assessment and evaluation of the comorbidity burden, it may be reasonable to offer optimal medical therapy plus an invasive strategy to frail patients at high risk of future CV events and low risk of complications, and to offer optimal medical therapy alone to those who are deemed to be at low risk of future events with a high risk of developing procedural complications. For those patients for whom any form of treatment might be futile, then a palliative end-of-life care approach should be considered.
Pregnancy
Acute coronary syndrome diagnostic criteria are the same for pregnant and non-pregnant patients. Pregnant women with STEMI should not be managed differently to non-pregnant women. Given the high mortality associated with STEMI in pregnancy, PPCI is the preferred reperfusion therapy. The management plan for pregnant women with ACS should be determined by a multidisciplinary team consisting of cardiologists, obstetricians, anaesthesiologists, and neonatologists, and these patients should be treated in an intensive care unit that can provide maternal monitoring and obstetric care .
ACS treatment should not be delayed for delivery. Delivery should be ideally postponed for at least 2 weeks post-ACS as there is increased risk of maternal mortality during this time.678 It has been demonstrated that SCAD is the most common cause of AMI in pregnancy, and this tends to occur mainly in the late pregnancy or early post-partum periods.
Patients with cancer
The four most common types of cancer in patients with ACS are prostate, breast, colon, and lung. Patients with a history of cancer should be treated like all other ACS patients, but the management of ACS patients with active cancer has some specific issues that need to be taken into consideration. Outcomes vary across types of cancer and the balance between the ischaemic and bleeding risks should be considered on an individual basis.
The percentage of ACS patients with a current diagnosis of cancer is rising, and currently constitutes ∼3% of patients in large observational studies. Patients with active cancer presenting with ACS pose important challenges as there are significant gaps in scientific knowledge. Therefore, recommendations based on solid evidence are scarce. Patients with active cancer presenting with ACS tend to be older, with a larger number of comorbidities and more extensive CAD. These patients often have concomitant haematologic and coagulation abnormalities that may present a challenge with respect to both the use of antithrombotic therapy and the performing of PCI Observational studies have reported that ACS in patients with cancer is associated with increased risk of major CV events, bleeding, and cardiac and non-cardiac mortality. As per the ARC-HBR criteria, patients with active cancer diagnosed in the past 12 months are considered as HBR.
The diagnosis of ACS in patients with cancer should be based on the same principles as in patients without cancer. The management of ACS in patients with cancer can be challenging because of frailty, increased bleeding risk, thrombocytopaenia, and increased thrombotic risk.
Temporary interruption of cancer treatment and an urgent multidisciplinary approach is recommended. Cancer patients with ACS have been reported to less frequently undergo invasive management; however, invasive management (and PCI with DES if needed) is recommended in ACS patients with cancer, as long as the prognosis is >6 months or, irrespective of the prognosis, if the patient is unstable Retrospective data have reported both a lower use of invasive management in cancer patients with STEMI, and better outcomes in patients who do undergo invasive management.
Invasive management in patients with advanced cancer or life expectancy <6 months has been reported to not demonstrate a mortality benefit compared with a conservative approach and therefore a conservative strategy should be considered in these patients
When the coronary anatomy is not amenable for PCI, CABG surgery can be considered after a multidisciplinary team discussion and where the cancer prognosis is >12 months. Given that they are considered to be HBR, the preferred P2Y12 inhibitor for ACS patients with active cancer is clopidogrel. Potential drug–drug interactions with cancer therapies should be checked when using ticagrelor or clopidogrel, since some pharmacokinetic-based drug–drug interactions via CYP450 may occur.
When acute ischaemia is provoked by cancer therapy, alternative cancer therapies should be considered after a multidisciplinary team discussion. Some specific cancer treatments can have cardiotoxic vascular effects that can lead to ACS . Following ACS, a review of the cancer medications is recommended, and any cancer drug associated with thrombosis and MI should be stopped. Cancer therapies that are not associated with MI can be restarted once revascularization (when indicated) has been completed and the patient is stabilized on ACS medical therapy without complications
Long-term treatment
Secondary prevention after ACS is central to increase quality of life and to decrease morbidity and mortality. This should start as early as possible after the index event. The topic is covered in detail in the 2019 CCS Guidelines and the 2021 Prevention Guidelines. Optimal medical therapy and treatment targets are well defined and are summarized in Figure .
Lifestyle management
Lifestyle management is one of the cornerstones of comprehensive CR While most of the evidence regarding the benefits of a healthy lifestyle on prognosis comes from primary prevention, studies in secondary prevention settings indicate similar beneficial effects.
Tobacco
Tobacco abstinence is associated with a reduced risk of re-infarction (30–40%) and death (35–45%) after ACS. Measures to promote cessation of smoking are therefore a priority after ACS. Interventions for smoking cessation should begin during hospitalization using a combination of behavioural interventions, pharmacotherapy, and counselling Many patients continue or resume smoking after ACS, in particular patients with depression and environmental exposures. During encounters with smokers, the ‘very brief advice’ evidence-based intervention should be used to facilitate dialogue between the patient and healthcare worker. Drug interventions, including nicotine-replacement therapy (NRT), bupropion and varenicline, should be considered along with behavioural support. All forms of NRT are effective, and the anti-depressant bupropion aids in long-term smoking cessation with similar efficacy to NRT. Varenicline is the most effective medical treatment to support smoking cessation and is safe to use in ACS patients.
An average weight gain of 5 kg can be expected when a person quits smoking, but it is important to recognize that the CV risk from continued smoking outweighs the CV risk from gaining weight.
E-cigarettes have been used to help smokers quit, but evidence on their impact on successful smoking cessation is insufficient, particularly with regard to whether using e-cigarettes actually helps the person remain tobacco free. While e-cigarettes do contain nicotine, they do not contain as many tobacco chemicals as cigarettes. Caution should be given with respect to the use of e-cigarettes, as current evidence suggests they are harmful to CV health by increasing arterial stiffness, heart rate and blood pressure, and by causing endothelial dysfunction.
Nutrition and alcohol
A healthy diet and eating habits influence CV risk. Adopting a Mediterranean-style diet can help reduce CV risk in all individuals, including persons at high CV risk and patients with ASCV
With regard to alcohol consumption, recent data suggest that alcohol abstainers have the lowest risk of CVD outcomes, that any amount of alcohol uniformly increases blood pressure and body mass index, and that a weekly consumption of >100 g of alcohol is associated with decreased life expectancy. Accordingly, it is recommended to restrict alcohol consumption to a maximum of 100 g per week (same limit for men and women).
Physical activity and exercise
Based on extensive data from the general population, sedentary behaviour, defined as time spent sitting or lying with low energy expenditure, while awake, is an independent risk factor for all-cause mortality.
According to recommendations from the World Health Organization, adults with chronic conditions should limit their amount of sedentary time, replacing it with physical activity of any intensity (including light intensity)
General physical activity recommendations include a combination of regular aerobic physical activity and resistance exercise throughout the week, which also forms the basis of recommendations for patients post-ACS. However, it is important to recognize that daily physical activity does not replace participation in exercise-based CR. With support from multiple randomized trials, exercise training is a pivotal part of comprehensive CR and participation in exercise-based CR should be offered to all patients after ACS.779 Cardiorespiratory fitness is a strong predictor of future prognosis both in the general population and in post-ACS patients.
Psychological considerations
There is a two-fold risk of anxiety and mood disorders in patients with heart disease. Depression, anxiety, and psychological stress are associated with worse outcomes. Psychological and pharmacological interventions can have a beneficial effect and should be considered for ACS patients with depression, anxiety, and stress. It is recommended that all patients have their mental well-being assessed using validated tools before discharge, with consideration of onward psychological referral when appropriate. For further details, please refer to the 2021 ESC Guidelines on cardiovascular disease prevention.
Pharmacological treatment
Antithrombotic therapy
Lipid-lowering therapy
Dyslipidaemia should be managed according to the current dyslipidaemia guidelines, with a combination of lifestyle and pharmacological interventions.Trials have consistently demonstrated that lower low-density lipoprotein-cholesterol (LDL-C) levels after ACS are associated with lower CV event rates. The current treatment goal for secondary prevention is to lower LDL-C to <1.4 mmol/L (<55 mg/dL) and to achieve a ≥50% LDL-C reduction from baseline. For patients who experience a second CV event within 2 years (not necessarily of the same type as the first event), an LDL-C goal of <1.0 mmol/L (<40 mg/dL) appears to confer additional benefit.
After an ACS event, lipid-lowering treatment should be initiated as early as possible, both for prognostic benefit and to increase patient adherence after discharge. It is recommended that a high-intensity statin (e.g. atorvastatin or rosuvastatin) is initiated as early as possible after hospital admission, preferably before planned PCI, and prescribed up to the highest tolerated dose in order to reach the LDL-C goals. The intensity of statin therapy should be increased in patients who were receiving low- or moderate-intensity statin treatment before the ACS even
As such, if patients are on a maximally tolerated statin dose, or have no prior statin treatment, and have LDL-C levels which indicate it is unlikely that targets will be reached with statin therapy alone, initiating ezetimibe in addition to a statin (or statin plus ezetimibe combination treatment) may be considered during the ACS hospitalization. In the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab was initiated as early as 1 month after ACS. Treatment with PCSK9 inhibitors has been shown to be safe and effective in lowering LDL-C in patients hospitalized with ACS Recent data have also shown improvements in plaque phenotype and plaque regression in ACS patients treated with PCSK9 inhibitors. Combined with the data from trials on the long-term benefits of PCSK9 inhibitors and observational data on the importance of lowering LDL-C early after ACS, PCSK9 inhibitor treatment should be initiated during ACS hospitalization in patients who were not at their LDL-C goal despite being on statin and ezetimibe treatment before admission.
In all cases, lipid levels should be re-evaluated 4–6 weeks after each treatment or dose adjustment to determine whether treatment goals have been achieved and to check for any safety issues; the therapeutic regimen can then be adapted accordingly. If the LDL-C goals are not achieved with the maximum tolerated dose of a statin alone after 4–6 weeks following ACS, adding ezetimibe is recommended. Initiation of PCSK9 inhibitor treatment is recommended in patients who do not reach their LDL-C goal despite maximum tolerated statin and ezetimibe therapy. Finally, icosapent ethyl, at a dose of 2 g b.i.d., can be used in combination with a statin in patients with ACS and triglyceride levels of 1.5–5.6 mmol/L (135–499 mg/dL) despite statin treatment.
Beta-blockers
The clinical benefit of beta-blockers after ACS in patients with reduced LVEF is supported by evidence from contemporary trials. However, the evidence for prescribing beta-blockers after uncomplicated ACS in patients with LVEF >40% is less well established. With the exception of the CAPRICORN (CArvedilol Post-infaRct survIval COntRolled evaluatioN) trial, which only recruited patients with LVEF ≤40%, all large RCTs testing the benefits of post-MI beta-blocker maintenance were performed in the pre-reperfusion era. Pooled data demonstrated that post-MI beta-blocker therapy reduced the risk of death by >20%. These trials mostly enrolled patients with STEMI, making the evidence for their benefit in NSTEMI less robust. In addition, since these trials were performed, the clinical scenario has changed dramatically, with improvements in invasive strategies and associated pharmacotherapy resulting in an improved prognosis for patients with ACS Modern observational studies and meta-analyses of these trials have yielded mixed results, with some studies suggesting a benefit of beta-blocker therapy irrespective of LVEF, and others reaching the opposite conclusion.
There is only one small, open-label trial, CAPITAL-RCT (Carvedilol Post-Intervention Long-Term Administration in Large-scale Randomized Controlled Trial), that randomized 801 STEMI patients with successful PPCI and preserved LVEF to carvedilol or control.
. Nitrates and calcium channel blockers
Intravenous nitrates may be useful during the acute phase in STEMI patients with hypertension or HF, provided there is no hypotension or RV infarction. In the ISIS-4 (Fourth International Study of Infarct Survival) trial, oral nitrates had no survival benefit in MI patients. Their use is therefore restricted to the control of residual angina, as recommended in the 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes
Renin–angiotensin–aldosterone system inhibitors
Angiotensin-converting enzyme (ACE) inhibitors have been demonstrated to improve outcomes in post-MI patients with additional conditions, such as clinical HF and/or LVEF ≤40%, diabetes, CKD, and/or hypertension.
A systematic overview of (old) trials of ACE inhibition early in STEMI showed that their use is associated with a small but significant reduction in 30-day mortality, especially in anterior MIs.
In the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial, valsartan was found to be non-inferior to captopril in patients with a recent MI plus HF and/or LVEF ≤40%.
Medications for diabetes
Sodium–glucose co-transporter 2 inhibitors
Pharmacological blockade of SGLT2 induces glycosuria with lowering of plasma glucose levels, improving glycaemic control without hypoglycaemia, and leading to reductions in weight and blood pressure. In patients with type 2 diabetes and established ASCVD, three trials (with empagliflozin, canagliflozin, and dapagliflozin) have demonstrated significant CV benefits. In a meta-analysis of these three trials, MACE were reduced by 11%, with no clear effect on stroke or MI. This benefit was only seen in patients with established ASCVD. The benefits of SGLT2 inhibitors may relate more to cardio-renal haemodynamic effects than to atherosclerosis.
In patients with HF regardless of their LVEF, dapagliflozin and empagliflozin have been shown to significantly reduce the risk of worsening HF or CV death, both in the presence or absence of type 2 diabetes. In the EMMY (EMpagliflozin in patients with acute MYocardial infarction) trial, empagliflozin led to a significant improvement in NT-pro BNP reduction over 26 weeks post-MI, accompanied by a significant improvement in echocardiographic functional and structural parameters. Ongoing outcome trials in ACS populations will be useful to better define the role of these agents in the absence of HF.
Glucagon-like peptide-1 receptor agonists
In a systematic review and meta-analysis of seven trials (56 004 patients with type 2 diabetes) testing different GLP1-RAs, their use was associated with reductions in the incidence of MACE, CV death, all-cause mortality, MI, and stroke.
Proton pump inhibitors
Proton pump inhibitors (PPIs) reduce the risk of upper gastroduodenal bleeding in patients treated with antiplatelet agents. Therapy with a PPI is indicated for patients receiving any antithrombotic regimen who are at high risk of gastrointestinal bleeding
PPIs that inhibit CYP2C19, particularly omeprazole and esomeprazole, may reduce the pharmacodynamic response to clopidogrel, though there is no strong evidence that this results in an increased risk of ischaemic events or stent thrombosis in clinical trials and propensity score-matched studies. Importantly, no interaction between the concomitant use of PPIs and aspirin, prasugrel or ticagrelor has been observed.
Vaccination
An annual influenza vaccination in patients with stable ASCVD appears to be associated with reduced incidence of MI, an improved prognosis in patients with HF, and decreased CV risk in adults aged 65 years and older. In addition, influenza vaccination given early after an MI or in high-risk CAD has been shown to result in a lower risk of all-cause death and CV death at 12 months. Therefore, influenza vaccination is recommended for all ACS patients and should be given preferentially during index hospitalization during influenza season for those not protected by a seasonal influenza vaccination.
Anti-inflammatory drugs
Inflammation plays a central role in the pathogenesis of atherosclerosis and acute coronary events. Several recent trials have tested the role of the anti-inflammatory agent colchicine in acute and chronic coronary syndromes. In the Colchicine Cardiovascular Outcomes Trial (COLCOT), which enrolled 4745 patients with a recent ACS event, low-dose colchicine (0.5 mg daily) was associated with a significant reduction of the primary composite endpoint (CV death, resuscitated cardiac arrest, MI, stroke, or urgent revascularization) in comparison to placebo. Of note, pneumonia was more frequent in the colchicine group. The Low-dose Colchicine trial-2 (LoDoCo2) enrolled 5522 patients with CCS (84% of whom had prior ACS) who were randomized to colchicine (0.5 mg daily) or placebo. The primary endpoint (composite of CV death, MI, stroke, or ischaemia-driven coronary revascularization) rate was significantly lower in the colchicine group; however, the incidence of non-CV death was higher in the colchicine group. The benefits of colchicine in reducing CV events have been shown to be consistent irrespective of history and timing of prior ACS.
Key messages
Epidemiology of ACS
Acute coronary syndromes encompass a spectrum of conditions that include patients with a recent change in clinical symptoms or signs, with or without changes on 12-lead ECG and with or without acute elevations in cardiac troponin concentrations. ACS are commonly classified based on ECG at presentation and the presence or absence of troponin elevation into UA, NSTEMI, or STEMI. The incidence of STEMI is decreasing whereas the incidence of NSTEMI is increasing. While there are some sex differences in the epidemiology of ACS, women and men receive equal benefit from invasive and non-invasive management strategies and, in general, should be managed similarly.
Diagnostic tools (ECG, troponin, and non-invasive imaging)
Chest pain/discomfort is the most common symptom initiating the ACS diagnostic and therapeutic pathway. High-sensitivity troponin measurements and rapid ‘rule-in’ and ‘rule-out’ algorithms should be used in patients with suspected NSTE-ACS. MI is not the only condition resulting in cardiomyocyte injury and cardiac troponin elevation, and other conditions should also be considered in the differential diagnosis. Non-invasive imaging can be useful to increase diagnostic accuracy and optimize risk assessment.
STEMI management networks
Co-ordination between EMS and hospitals with common written protocols is central to the management of STEMI. EMS should transfer patients immediately to 24/7 high-volume PCI centres regardless of the initial treatment strategy (PPCI or pre-hospital fibrinolysis). EMS should always alert the PCI centre immediately after selection of the reperfusion strategy, and patient transfer to the PCI centre should bypass the ED.
Invasive strategy and reperfusion therapy
An invasive strategy is recommended for patients with ACS. Invasive strategies are time sensitive. For STEMI and very high-risk NSTE-ACS, an immediate invasive strategy is recommended. For patients with NSTE-ACS an inpatient invasive strategy is recommended; in NSTE-ACS patients with high-risk characteristics, an early invasive strategy (<24 h) should be considered. If timely (within 120 min from time of diagnosis) PPCI cannot be performed in patients with STEMI, fibrinolytic therapy is indicated within 12 h of symptom onset in patients without contraindications.
Antithrombotic therapy
Antithrombotic therapy is indicated in all ACS patients, regardless of the management strategy. This consists of both antiplatelet and anticoagulant therapy. Aspirin is recommended for all ACS patients at an initial loading dose and a longer-term maintenance dose. In addition to aspirin, a P2Y12 receptor inhibitor is recommended, and should be maintained over 12 months unless there are concerns regarding HBR. Regarding P2Y12 receptor inhibitor choice, prasugrel and ticagrelor are recommended in preference to clopidogrel, and prasugrel should be considered in preference to ticagrelor for ACS patients who undergo PCI. Pre-treatment (i.e. treatment with a P2Y12 receptor inhibitor prior to coronary angiography) in patients with NSTE-ACS is not recommended routinely but may be considered for patients with STEMI undergoing PPCI. Parenteral anticoagulation is recommended for all patients at the time of diagnosis. Discontinuation of parenteral anticoagulation should be considered immediately after the invasive procedure. Some patients with ACS will also have an indication for long-term OAC, most commonly AF. In these patients, TAT for up to 1 week, followed by DAT using a NOAC at the recommended dose for stroke prevention and a single oral antiplatelet agent (preferably clopidogrel), is recommended as the default strategy.
ACS with unstable presentation
A PPCI strategy is recommended in patients with resuscitated cardiac arrest and an ECG with persistent ST elevation (or ST elevation equivalents), whereas routine immediate angiography is not recommended in patients with an ECG without persistent ST elevation (or equivalents). Temperature control (i.e. continuous monitoring of core temperature and active prevention of fever [i.e. >37.7°C]) is recommended in patients with OHCA who remain unresponsive after ROSC. In patients with CS complicating ACS, emergency coronary angiography is recommended, whereas the routine use of IABP in ACS patients with CS and no mechanical complications is not.
Early care
Following reperfusion, it is recommended to admit high-risk ACS patients, including all STEMI patients, to a CCU/ICCU. ECG monitoring for arrhythmias and ST-segment changes is recommended for at least 24 h after symptom onset in all high-risk patients with ACS. It is recommended that all hospitals participating in the care of high-risk ACS patients have an ICCU/CCU equipped to provide all required aspects of care including treatment of ischaemia, severe HF, arrhythmias, and common co-morbidities. It is also recommended that the LVEF is determined before hospital discharge in all patients with ACS. Discharge of high-risk ACS patients within 48–72 h should be considered in selected patients if early rehabilitation and adequate follow-up are arranged.
Technical aspects during PPCI
Routine radial access and use of DES are the standard of care during PCI for ACS. Intravascular imaging should be considered to guide PCI and may be considered in patients with ambiguous culprit lesions. Routine thrombus aspiration is not recommended. CABG should be considered in patients with an occluded IRA when PCI is not feasible or unsuccessful and there is a large area of myocardium in jeopardy. In patients presenting with SCAD, PCI is recommended only for patients with symptoms and signs of ongoing myocardial ischaemia, a large area of myocardium in jeopardy, and reduced antegrade flow.
Management of patients with MVD
For patients with MVD, it is recommended to base the revascularization strategy (IRA PCI, multivessel PCI/CABG) on the patient’s clinical status and comorbidities, as well as their disease complexity, according to the principles of management of myocardial revascularization. For patients with MVD presenting with CS, IRA-only PCI during the index procedure is recommended. For patients with STEMI undergoing PPCI, complete revascularization is recommended either during the index PCI or within 45 days. In patients presenting with NSTE-ACS and MVD, complete revascularization should be considered, preferably during the index procedure. For patients with STEMI, it is recommended that decisions regarding PCI of non-IRA are based on angiographic severity, whereas for patients with NSTE-ACS, functional invasive evaluation of non-IRA severity during the index procedure may be considered.
MINOCA
The term MINOCA refers to the situation where patients present with symptoms suggestive of ACS and demonstrate troponin elevation and non-obstructive coronary arteries at the time of coronary angiography, i.e. coronary artery stenosis <50% in any major epicardial vessel. MINOCA is best considered as a working diagnosis that encompasses a heterogenous group of underlying causes (both cardiac and extra-cardiac) and is found in 1–14% of patients with ACS. In all patients with an initial working diagnosis of MINOCA, it is recommended to follow a diagnostic algorithm to determine the underlying cause. CMR imaging is a key diagnostic tool in patients with a working diagnosis of MINOCA.
Special patient subsets
Chronic kidney disease: moderate to severe CKD is present in >30% of ACS patients. These patients receive less interventional and pharmacological treatment and have a worse prognosis in comparison to patients with normal kidney function. It is recommended to apply the same diagnostic and therapeutic strategies in patients with CKD (dose adjustment may be necessary) as for patients with normal kidney function.
Older adults: in general, older adults should undergo the same diagnostic and treatment strategies, including invasive angiography and revascularization, as younger patients.
Patients with cancer: management of ACS in patients with cancer can be challenging for several reasons, including frailty, increased bleeding risk, thrombocytopaenia, and increased thrombotic risk. An invasive strategy is recommended in cancer patients presenting with high-risk ACS with expected survival ≥6 months. A conservative non-invasive strategy should be considered in ACS patients with poor cancer prognosis (with expected survival <6 months) and/or very high bleeding risk.
Long-term treatment
Secondary prevention after ACS should be offered to every patient and should start as early as possible after the index event. This includes cardiac rehabilitation, lifestyle management, and pharmacological treatment, and has been shown to both increase quality of life and decrease morbidity and mortality.
Patient perspectives
Some of the key first steps in the timely diagnosis and treatment of ACS are reliant on a comprehensive assessment of symptoms. An incomplete history or poorly elicited symptoms can result in delay or misdiagnosis. Patient-centred care is recommended as a critical tenet of routine clinical management and involves consideration of a patient’s physical, emotional, and psychological needs.
The provision of care that is respectful of, and responsive to, individual patient preferences, needs and values, is important in the management of patients with ACS. It is recommended, as much as possible, to include ACS patients in decision-making. Preparing for discharge begins on admission. Educating and informing the patient using the teach back method and educationally appropriate material should be integrated into the patient care pathway.
Quality indicators
Acute coronary syndrome QIs aim to audit practice and improve clinical outcomes in real-life patients by demonstrating the gap between optimal guideline-based treatment and actual care of ACS patients. Subsequent measures to improve QI attainment can be implemented based on the local, regional, and global assessment of QIs.
