46 Non-ST-segment elevation acute coronary syndromes

Non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are life-threatening disorders, usually caused by acute coronary thrombosis and subsequent myocardial ischaemia, presenting without persistent ST-segment elevation in the initial electrocardiogram. According to the occurrence of myocardial necrosis, NSTE-ACS are divided into non-ST-segment myocardial infarction (NSTEMI) or unstable angina (UA). The management of NSTE-ACS requires an early diagnosis and risk stratification, urgent hospitalization, monitoring, and medical treatment, including antithrombotic therapy with dual antiplatelet therapy (aspirin plus one P2Y12 inhibitor) and parenteral anticoagulation, anti-ischaemic treatment, and preventative therapies. After the initial medical therapy is established, an invasive strategy, consisting of coronary angiography with coronary revascularization (either percutaneous coronary intervention or coronary bypass graft surgery), as appropriate, should be decided. The timing of the invasive strategy should be adjusted according to the patient’s risk. Given the high event rate of patients with NSTE-ACS after hospital discharge, an aggressive long-term preventative therapy should be put in place to improve prognosis.

ACS is an operational term used to refer to any constellation of clinical symptoms that are compatible with acute myocardial ischaemia. These are life-threatening disorders and a major cause of emergent medical care and hospitalization. It encompasses two different diagnoses: myocardial infarction (MI) and unstable angina (UA). NSTE-ACSs comprise NSTEMI and UA. While the first is defined by the presence of myocardial injury (usually detected by an elevation of biomarkers of necrosis such as troponin), the diagnosis of UA relies on the presence of compatible symptoms and ST-segment depression or prominent T wave inversion, without myocardial necrosis. NSTE-ACSs are usually caused by atherosclerotic coronary artery disease (CAD) and acute coronary thrombosis. Early diagnosis and treatment are needed to reduce the increased risk of short- and long-term cardiac death and subsequent MI associated with this syndrome. ST-elevation myocardial infarction (STEMI) and other potentially severe diseases causing the symptoms, such as aortic dissection or pulmonary embolism (PE), should be ruled out as soon as possible, and a risk stratification of the NSTE-ACS is then required.

The incidence of NSTE-ACS in developed countries is three times as high as that of STEMI [1, 2]. Moreover, while STEMI incidence is declining (see Figure 46.1), probably in relation to a better control of coronary risk factors in the general population, the incidence of NSTE-ACS remains stable and is even expected to increase, mainly because of the progressive ageing of the population, the increase in the number of patients that survive an acute event and are thus exposed to recurrent events, and the increasing number of diabetic people [2]. In addition, the incorporation of high-sensitivity biochemical assays to the standards for the diagnosis of acute myocardial infarction (AMI) [3, 4] will result in the reclassification of CAD patients who would not have previously qualified for NSTE-ACS. The rates of in-hospital mortality and complications are lower for NSTE-ACS than for STEMI patients [1, 5]; however, long-term outcomes are poorer.

Most ACS are the result of a thrombotic complication of coronary atherosclerosis [6–8] (see Chapter 40). Thrombosis usually occurs in response to plaque rupture or, less frequently, erosion [9, 10]. After plaque rupture, the exposure of TF and other components of the lipid core triggers platelet adhesion, activation, and aggregation and initiates the extrinsic pathway of coagulation, leading to fibrin generation [6–8, 11–13].

Rupture-prone plaques are characterized, among other factors, by a large lipid-rich core and by a thin and inflamed fibrous cap (see Figure 46.2), whereas factors predisposing to plaque erosion are largely unknown [9,10]. A prospective study, using multimodality intracoronary imaging, in ACS patients showed that most non-culprit lesions that caused new coronary events were angiographically mild and identified a thin-capped fibroatheroma, a larger plaque burden, and a smaller minimal luminal area as predictors of plaque complication [14]. Vulnerability to coronary thrombosis not only depends on plaque-related factors, but also on systemic factors enhancing thrombosis or inflammation, as suggested by the observation in autopsy studies of ruptured plaques without thrombosis [15, 16] or by the finding of multiple complicated lesions in some ACS patients [17, 18]. Much less frequently, ACS occurs in the absence of atherosclerosis and may be caused by coronary spasm, embolization, spontaneous dissection, or arteritis [10].

In contrast to STEMI, where a totally occlusive intracoronary thrombosis is the paradigm at early angiography, patients with NSTE-ACS have a relatively low prevalence of occlusive thrombosis [19]. Angiographically visible collaterals are not uncommon and might be protective in these patients [20]. Transient coronary occlusion, increased vasoreactivity, microembolization, and platelet-mediated damage, alone or in combination, may have a particularly significant contribution to myocardial injury in NSTE-ACS patients [9, 21–23].

Correct identification of patients with NSTE-ACS is critical, not only to start management as soon as possible, but also to identify patients with other potentially life-threatening illnesses and to safely discharge those with trivial causes for their symptoms. Patient misclassification may have serious consequences if an ACS is not detected or conversely may lead to unnecessary admissions and use of resources [24].

Given the heterogeneous presentation of NSTE-ACS, this diagnosis may be challenging. It is based on clinical data, the ECG, and cardiac biomarkers, with additional tests being needed in selected patients. Since these items are also the pillars of early risk stratification, diagnosis and risk assessment can usually be made in parallel.

Most patients present with chest pain (CP), in the form of prolonged, new-onset, or crescendo angina. Angina is often reported as intermittent or persistent substernal or precordial pressure, or heaviness radiating, or not, to the shoulders, arms, neck, or jaw, that may worsen during exercise, can be accompanied by sweating, nausea, or vomiting, and usually alleviates with nitroglycerin [25]. Other presentations that may be associated with chest discomfort or appear in isolation include epigastric pain, dyspnoea, fatigue, syncope, or even cardiac arrest. Atypical presentations without CP or with atypical pain are more frequent among the elderly, in women, or in patients with diabetes mellitus or renal failure [26, 27].

History and physical examination can detect the precipitating causes of ACS such as arrhythmias, anaemia, infection, or thyrotoxicosis. The existence of previous CAD, vascular disease in other territories, or risk factors of CAD—especially diabetes or a strong family history—increases the probability that the symptoms are due to NSTE-ACS [28, 29]. Ongoing cardiovascular medications, major comorbidities, and potential contraindications to therapy should be recorded.

Physical examination is often normal. Heart rate, blood pressure, and Killip class are strongly associated with prognosis and must be assessed on admission. A fourth heart sound is common. Auscultation of a third heart sound or a systolic murmur of MR during CP episodes usually reflects extensive ischaemia and a worse prognosis. History and physical examination may help differentiate between NSTE-ACS and other diagnoses (see Table 46.1).

An ECG should be recorded within 10 min from the first medical contact (FMC) and repeated during the first hours, after 24 hours, and during recurrence of symptoms. It is useful to compare tracings obtained with and without CP and also to assess changes with respect to previous tracings, if available, particularly in the presence of intraventricular conduction disturbances or signs of left ventricular (LV) hypertrophy or myocardial necrosis [30].

The ECG in NSTE-ACS can show ST-segment depression, transient ST-segment elevation, or T wave inversion, or can be completely normal, especially if obtained when the patient is asymptomatic (see Figure 46.3). Ongoing ischaemia frequently causes ST deviation, whereas negative T waves typically appear once ischaemia has resolved.

ECG may help to identify patients with an acute coronary occlusion, despite lacking a significant ST-segment elevation, which could benefit from an immediate reperfusion therapy. Persistent ST-segment depression in leads V1–V4 must point to the diagnosis of an acute posterior (inferobasal) MI [31, 32], due to occlusion of the left circumflex artery or one of its branches, and is often considered a STEMI equivalent. More rarely, posterior transmural ischaemia does not cause ST deviation in the 12-lead ECG and might be detected by the non-standard V7–V9 leads. An upsloping ST depression, with tall, positive T waves in the precordial leads, is a rare feature of an acute proximal occlusion of the LAD coronary artery [33]. Finally, a minor ST elevation in any territory has been related to a high frequency of acute, complete coronary occlusion [34]. An immediate coronary angiography should be strongly considered in a patient with persistent angina and any of these ECG features.

Blood troponin levels are essential for diagnosis and risk stratification and should be measured in all patients. Abnormal troponins reflect myocardial damage and, in the setting of myocardial ischaemia, allow differentiating between MI and UA. Troponins are more sensitive and specific than other markers of cardiac damage such as CK or its MB fraction (CK-MB) or myoglobin. Troponin I and T have similar kinetics and can be used indistinctly. Troponins become abnormal approximately 4–6 hours after symptom onset and peak at 24–48 hours. Serial sampling is recommended, with a second determination at 3 hours after symptom onset [30]. Troponin measurement by high-sensitivity assays allows an earlier detection of an AMI, with higher sensitivity and NPV, although with somewhat less specificity than by conventional assays [35–39]. If these tests are used and the first determination is normal, a second determination after 3 hours allows to rule out MI, with a sensitivity approaching 100% (see Figure 46.3) [37, 38]. It has recently been shown that 1-hour algorithms [40, 41] or even a single determination of very low or undetectable levels of high sensitive troponins [42, 43] maintain an excellent sensitivity with a reasonable specificity for NSTEMI diagnosis (see Figure 46.4). However, this excellent sensitivity has not been reproduced by other studies [44] and these algorithms probably should be avoided in patients presenting very early after the onset of symptoms [44, 45].

Given that troponin levels may remain elevated for up to 2 weeks after infarction, their usefulness to detect reinfarction or periprocedural MI is a matter of controversy, and CK-MB might be better for these purposes [39, 46].

Troponin elevation, by itself, does not diagnose an AMI. Troponins can be elevated in multiple cardiac and extracardiac conditions, different from ACS—some of them associated with CP such as PE, aortic dissection, stroke, myocarditis, apical ballooning syndrome, heart failure, arrhythmias, or hypertensive crisis, or in cardiac damage of any cause, as well as in renal failure [30]. With the newer high-sensitivity assays, troponin elevations above the 99th percentile of the URL have been detected in patients with stable CAD or even in apparently healthy individuals. (See also Chapter 36.)

The presence of dynamic ST–T changes or a significant elevation of cardiac biomarkers in a patient with symptoms compatible with myocardial ischaemia allows establishing a working diagnosis of NSTE-ACS—that should be confirmed by early coronary angiography—and starting medical management. There are patients, however, that present with symptoms suggestive of, or compatible with, angina, in whom the ECG is normal or shows non-specific changes and troponins are negative. To detect those with a true NSTE-ACS—that may represent about 10–20% of these patients [47]—further non-invasive tests are often needed. Performing an exercise ECG reasonably allows ruling out an ACS in most cases [48] and has become standard practice in this subgroup in many Chest Pain Units (CPUs). Stress imaging with echocardiography (see Chapter 20), nuclear myocardial perfusion imaging (MPI), or cardiac magnetic resonance (CMR) imaging (see Chapter 23) may be of help, especially in the presence of a non-interpretable ECG or in patients unable to exercise [49–51]. Finally, a multidetector CT may accurately detect coronary lesions and has proven useful for the non-invasive evaluation of CP patients in the emergency room [52].

A rest echocardiogram allows a rapid assessment of ventricular function and helps identifying other causes of CP and should be available in the emergency room [30].

Risk assessment is important, because there is evidence that an aggressive treatment, including a more potent antithrombotic treatment and a rapid invasive strategy, can improve the prognosis in high-risk NSTE-ACS patients [30, 53]. The risk of ACS relates to the severity of ischaemia, the burden of CAD, the myocardial mass at risk, the baseline function of the LV, and the patient’s clinical profile (age, comorbidities, etc.). Risk changes over time, depending on the evolution of the causal factors (evolution of coronary thrombosis), the development of complications, and the response to treatment, so the risk assessment is a dynamic process that starts at the time of FMC and must be updated to register clinical changes and response to therapy.

Simple risk stratifications have been proposed, according to the presence or absence of some key prognostic factors such as older age, markers of ischaemia (positive troponins, dynamic ST-segment changes, ischaemic recurrences on adequate treatment), signs of haemodynamic or electrical instability, signs of myocardial dysfunction (heart failure, LV dysfunction), comorbidities (diabetes, renal dysfunction, anaemia), and others (see Table 46.2). The ECG contains important prognostic information on NSTE-ACS patients. A new ST-segment depression –even as low as 0.5 mV–is strongly associated with a higher mortality, a more severe coronary disease, and a greater benefit of an early invasive strategy [54–56]. The magnitude and extent of ST depression provide additional prognostic information [57]. ST depression in the lateral leads, with elevation in aVR, predicts extensive subendocardial ischaemia, often due to left main or multivessel disease, and a particularly poor prognosis [58, 59] The prognostic implications of negative T waves are less important [54, 55], although evolving deep, symmetrical, negative T waves in the anterolateral leads usually indicate a proximal LAD involvement. Troponin elevation has been associated with an increased thrombotic burden, as well as with higher short- and long-term mortality and reinfarction rates in these patients [60–62]. This increased risk is independent of that predicted by clinical evaluation and the ECG. Other biomarkers (see Chapter 36), such as brain natriuretic peptide (BNP), NT-proBNP [63, 64], and high-sensitivity CRP, are also associated with long-term prognosis [63, 65–67], but not used in routine practice, due to the marginal incremental value in predicting short-term outcomes and help in selecting the initial management over standard evaluation. Other haematological or biochemical determinations, such as white blood cell count or glycaemia on admission or in the first fasting sample, provide prognostic information as well [30]. Finally, it is essential to assess the renal function—preferably by calculating the creatinine clearance or the eGFR—not only because it is related to long-term mortality, but also to help select the pharmacological treatment and adjust the doses, if necessary [30].

Qualitative risk stratification is simple and helps select patients with an elevated risk of adverse cardiovascular events but does not allow estimating their individual absolute risk, precluding from weighing the individual patient’s risk with the potential benefits and risks associated with the use of available interventions. Therefore, quantitative risk estimations are more helpful than qualitative risk stratifications in guiding therapy for ACS patients. The TIMI risk score for UA/NSTEMI is a simple semi-quantitative score that includes seven variables to predict the 14-day risk of the composite endpoint of death, MI, or urgent revascularization. These seven variables are classified into variables taken from the clinical history: (1) age (<65 or >65 years), (2) ≥3 risk factors for CAD, (3) known CAD (stenosis ≥50%), (4) aspirin use in the past 7 days; and variables related to the presentation, (5) recent (≤24 hours) severe angina, (6) ST-segment deviation of ≥0.5 mm, and (7) positive cardiac markers. One point is given for the presence of each predictor, so the score ranges from 0 (lowest risk) to 7 (highest risk), which correlate well (c-statistic 0.65) with the selected outcome (14-day incidence of all-cause mortality, MI, and severe recurrent ischaemia prompting urgent revascularization) and mortality. The TIMI risk score has been proven useful for clinical decision-making, as it showed increased benefits of enoxaparin [68] or GPIs in high-risk patients [69] or proved the efficacy of clopidogrel in high-risk patients with NSTE-ACS [70].

The original GRACE risk score used eight independent predictors of death or a combined outcome of death and MI, both in hospital and at 6 months: (1) age, (2) heart rate on admission, (3) systolic blood pressure on admission, (4) the Killip class, (5) the initial serum creatinine concentration, (7) cardiac arrest at admission, (8) ST-segment deviation, and (9) elevated cardiac markers, which are incorporated into a continuous model. This risk score has been recently updated (GRACE 2.0), and 1-year and 3-year outcomes can be estimated now. However, as the risk calculation is complex, a specific calculator is needed (available at: <http://www.gracescore.org/WebSite/WebVersion.aspx>. The clinical utility of this score in selecting patients for a specific therapy has been proven in clinical trials, such as for the identification of patients with greater benefit with fondaparinux, compared with enoxaparin [71], or the benefit of an early invasive strategy restricted to higher-risk patients (GRACE risk score >140), as shown in the TIMACS trial [72].

Antithrombotic therapies and invasive strategies are key steps in the management of NSTE-ACS but increase the bleeding risk. As haemorrhages are associated with higher mortality when they are not mild, the assessment of the bleeding risk in ACS patients is important for the calculation of trade-offs between an ischaemic risk reduction and spontaneous and treatment-related bleeding hazards [30, 73–76]. For these reasons, the estimation of the bleeding risk has become important in the management of ACS. Two risk scores are available. The CRUSADE bleeding score [77] identified eight independent baseline predictors (baseline haematocrit <36%, creatinine clearance, heart rate, female sex, signs of chronic heart failure at presentation, systolic blood pressure ≤110 mmHg, systolic blood pressure ≥180 mmHg, prior vascular disease, and diabetes mellitus) of major bleeding during hospitalization. The rate of major bleeding increased by bleeding risk score quintiles: from 3.1% for those at very low risk (score ≤20) to 19.5% for those at very high risk (score ≥50). One other risk score uses seven independent predictors, six baseline factors (female sex, advanced age, elevated serum creatinine, white blood cell count, anaemia, type of MI), and one treatment-related variable (the use of heparin plus a GPI, rather than bivalirudin alone) to discriminate patients with different 30-day rates of non-CABG-related TIMI major bleeding [76].

The treatment of ACS is integrated in the clinical management of patients with chest pain, as shown in Figure 46.5. As soon as ACS is suspected, an ECG must be performed immediately to rule out ST-segment elevation or STEMI-equivalent (see Figure 46.3). If no ST-segment elevation or ECG with non-interpretable repolarization is present, the diagnosis of NSTE-ACS should be confirmed and, at the same time, early risk stratification performed. When NSTE-ACS is confirmed, treatment with anti-ischaemic and antithrombotic drugs should be started and coordinated with the planned strategy of coronary angiography and revascularization (see Figure 46.5).

Ongoing CP should be treated with sublingual or IV nitroglycerin to relieve ischaemia and discomfort. Morphine may be used in refractory cases but should not be routinely used given the risk of reducing the gastric absorption of oral antithrombotic drugs [78, 79]. If morphine is needed, a large coronary artery occlusion with low ECG expression (i.e. posterior or posterolateral infarcts due to circumflex occlusion) should be suspected. O₂ should only be used in patients with dyspnoea and/or SpO₂ of <90% [80, 81].

Given the pathophysiology of NSTE-ACS, most frequently based on an intracoronary thrombosis triggered by platelet aggregation, antiplatelet therapy plays an essential role in the treatment of this disease. Anticoagulation is also required to stabilize the process.

Platelet activation and subsequent aggregation play a key role in the pathophysiology of ACS. Therefore, antiplatelet therapy should be instituted as early as possible when the diagnosis of ACS is made, in order to reduce the risk of progression or recurrence of ischaemic complications. Platelets can be inhibited by three classes of drugs, with distinct mechanisms of action (see Chapter 44): aspirin (acetylsalicylic acid), P2Y12 platelet receptor inhibitors (oral, such as ticlopidine, clopidogrel, prasugrel, and ticagrelor, or intravenous such as cangrelor), and GPI (tirofiban, eptifibatide, and abciximab).

In general, patients with NSTE-ACS should be treated with DAPT, i.e. the combination of two oral antiplatelets, aspirin plus one P2Y12 inhibitor. Specific recommendations for the use of DAPT have been recently published [82]. Occasionally, patients may need triple therapy, adding one GPI during PCI. In the absence of contraindications, all patients with ACS should be treated with aspirin, beginning with a loading dose of between 150 and 300 mg of chewed plain aspirin [83], followed by a daily maintenance dose of 75–150 mg [84]. Gastric and duodenal erosions or ulcers, the most frequent side effects of aspirin, can be prevented by the concomitant use of gastric protectors, particularly PPIs. For patients with an aspirin allergy, rapid desensitization protocols have been shown effective.

Clopidogrel, with a 300 mg oral loading dose, followed by a 75 mg dose once daily for 9–12 months, on top of aspirin, reduces ischaemic events, mainly MIs, without an effect on mortality [85]. This benefit was seen in most patients [86], including those who underwent CABG, despite the increased perioperative bleeding risk [87], but more markedly in those who underwent PCI [88]. The benefits of the treatment with clopidogrel are limited by a number of factors such as a slow beginning of its antiplatelet effect, a reduced and hardly predictable maximal level of platelet inhibition, and a wide variability in the pharmacodynamic response to clopidogrel, influenced by genotype polymorphisms of enzymes needed for its intestinal absorption or its conversion to its active metabolite, and the interactions produced by drugs that activate or inhibit cytochrome P450. All interventions directed to overcome these limitations, such as the use of higher loading and maintenance doses of clopidogrel [84], the use of genetic testing or ex vivo platelet function to guide changes in DAPT, failed to improve outcomes. Although a warning was released, regarding the concomitant use of clopidogrel and omeprazole, the real clinical significance of this association was never defined.

Prasugrel has a more rapid, powerful, and consistent platelet inhibitory effect than clopidogrel [89], not influenced by CYP inhibitors, PPIs, or CYP2C19 gene variants [90]. Prasugrel is superior to clopidogrel for DAPT in patients with moderate to high risk NSTE-ACS who are not receiving clopidogrel, have already undergone coronary angiography, and in whom treatment with PCI has been decided, because it reduces the incidence of ischaemic events (cardiovascular death, non-fatal MI, or stroke) mostly by decreasing the risk of MI without changing the risk of death or non-fatal stroke [91]. Prasugrel is particularly useful in reducing stent thrombosis [91] and recurrent ischaemic clinical events [92], with an increased clinical benefit in diabetic patients [93]. Prasugrel increases the risk of TIMI major bleeding and life-threatening and fatal bleeds, particularly in patients with prior cerebrovascular events, in whom this drug is contraindicated [91]. In addition, prasugrel at standard doses provides no net clinical benefit in patients >75 years of age and in patients with a body weight of <60 kg [91]. In patients with NSTE-ACS, the use of prasugrel should be restricted to the catheterization laboratory (see Figure 46.6), because the routine use of prasugrel before coronary angiography in patients with NSTE-ACS is associated with a significant increase in major bleeding, with no clinical benefit [94], and because the treatment with prasugrel does not provide any clinical benefit and increases the bleeding risk in patients with NSTE-ACS who are medically managed [95].

Ticagrelor is an oral platelet inhibitor with faster, stronger, and more consistent platelet inhibitory effects than clopidogrel. Although it belongs to a different chemical class, it shows similar pharmacodynamic properties to prasugrel, with the exception of a shorter plasma half-life of approximately 12 hours. Ticagrelor (180 mg loading dose, followed by 90 mg twice daily for up to 12 months) is superior to clopidogrel for DAPT in patients with moderate- to high-risk NSTE-ACS, not only in reducing ischaemic events (death from vascular causes, MI, or stroke) and stent thrombosis, but also—and this is different from clopidogrel and prasugrel—vascular and all-cause mortality [96], clinical benefits that increase over time during 12 months and are independent of the management strategy, as seen in patients undergoing PCI [97], CABG [98], and those medically managed [99]. Ticagrelor did not increase PLATO-defined major bleeding but caused an increase in minor bleeds and major bleeding unrelated to CABG surgery [96]. Ticagrelor also causes dyspnoea and ventricular pauses, most frequently within the first week of treatment, which only infrequently causes treatment discontinuation [96, 100–102].

Two strategies for DAPT can be used in patients with NSTE-ACS (see Figure 46.7). An early or non-selective strategy is defined by the routine initiation of DAPT with aspirin plus one P2Y₁₂ inhibitor, early after the NSTE-ACS diagnosis. This was the approach used when ticagrelor or clopidogrel were tested for the management of ACS, in which it was shown that early treatment with these drugs showed clinical benefits outweighing the bleeding risk in all patients, regardless of their management strategy, including those medically managed or treated with CABG. Although clopidogrel or ticagrelor are associated with higher rates of blood transfusion and reoperation after CABG, these are associated with better outcomes than with aspirin alone or aspirin plus clopidogrel, respectively, particularly before surgery (see Chapter 48) [98, 103]. For that reason, the decision to interrupt DAPT before CABG to prevent perioperative bleeding needs to be carefully balanced with the risk of the patient. The delayed or selective strategy of DAPT consists of the initiation of DAPT when the coronary anatomy is known, i.e. after coronary angiography, and PCI decided as the mode of coronary revascularization. It is specifically recommended for DAPT with prasugrel and has the advantage to reduce the bleeding risk in patients treated with CABG, and to avoid the treatment of patients with no significant CAD. Unfortunately, no trials have tested the efficacy or safety of early versus delayed use of ticagrelor or clopidogrel in patients with ACS, so the 2015 ESC NSTE-ACS Guidelines do not give recommendation for this strategy.

Glycoprotein IIb/IIIa receptor inhibitors (GPI)—tirofiban, eptifibatide, and abciximab—are potent IV antiplatelets that may be used in the treatment of NSTE-ACS, on top of DAPT, in the setting of PCI with a high risk of procedural MI due to the presence of a large thrombus burden by coronary angiography, and without a high bleeding risk. On the contrary, the early use of these drugs does not improve clinical outcomes but increases major bleedings [104, 105] and, therefore, is not recommended in general. GPIs may be exceptionally started before coronary angiography, in high-risk patients who have not been treated with a P2Y12 inhibitor, or those on DAPT with refractory ischaemia, provided they are at low bleeding risk.

Cangrelor—Cangrelor is an intravenous reversible P2Y₁₂ receptor inhibitor. It produces a fast and potent inhibition of ADP-induced platelet aggregation after intravenous bolus administration, with restoration of platelet function within 2 hours of infusion discontinuation, as its plasma half-life is quite short (<10 min). Cangrelor has been tested as a co-adjuvant therapy for PCI (30 mg/kg bolus at procedure initiation, and 4 mg/kg/min infusion) in patients treated with clopidogrel given at different doses and timings in a series of the three Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) trials [106–108]. A meta-analysis of these studies showed a 19% relative risk reduction in MACE among patients who underwent PCI for ACS, with a 38% increase in TIMI major and minor bleeds [109].

Anticoagulation, in addition to platelet inhibition, reduces ischaemic events in patients with NSTE-ACS (see Chapter 44). In general, anticoagulation should be initiated after the diagnosis has been established and stopped after completion of coronary revascularization, unless another indication for anticoagulation is present. Several anticoagulants have shown to be able to reduce the risk of ischaemic events, increasing the bleeding risk. UFH is used as a weight-adjusted dose, with an initial IV bolus of 60–70 IU/kg, with a maximum of 5000 IU, followed by an infusion of 12–15 IU/kg/hour, to a maximum of 1000 IU/hour [110], with frequent monitoring to adjust the maintenance dose, guided by aPTT levels, with an optimal target level between 1.5 and 2.5 times the upper limit of normal (50–75 s). Compared with UFH, LMWH shows an almost complete absorption after an SC administration, a more predictable dose–effect relationship, less platelet activation, and a lower risk of HIT [110]. Enoxaparin, the best studied of these drugs, is better than UFH in reducing death or MI at 30 days, with no clear increase in major bleeding [111]. It is used at a SC dose of 1 mg/kg twice a day, that should be reduced to 0.75 mg/kg/12 hours in patients >75 years of age or to 1 mg/kg once daily in patients with a creatinine clearance of <30 mL/min, due to the severe increase in bleeding risk [112]. Fondaparinux—at a 2.5 mg fixed daily SC dose, is the preferred anticoagulation regime in patients with NSTE-ACS not requiring full anticoagulation for another reason (i.e. AF), in whom an urgent invasive strategy is not planned. This dose is equally effective in preventing ischaemic events as enoxaparin but halves major bleeds and reduces the 30-day mortality [113]. However, catheter thrombus formation occurs more frequently if anticoagulation with fondaparinux only is used for coronary angiography [113]. Therefore, extra anticoagulation during the procedure is recommended with a standard dose of UFH (IV bolus of 85 IU/kg, reduced to 60 U/kg if GPIs are used) in patients undergoing PCI on fondaparinux [114]. Anticoagulation with bivalirudin alone was initially shown to reduce by half the incidence of major bleeding, being non-inferior with respect to a composite ischaemic endpoint compared with the combination of either UFH or LMWH plus a GPI, in patients with NSTE-ACS with coronary angiography planned [115, 116]. Thus, bivalirudin may be considered as an option for anticoagulation in patients with NSTE-ACS at high bleeding risk, in whom an early invasive strategy with the use of GPI is planned. However, latter studies did not show such benefit compared with UFH [117].

Anti-ischaemic drugs decrease the myocardial O₂ demand and/or increase the O₂ supply and, in NSTE-ACS, are mainly aimed at providing symptomatic relief.

Nitrates induce venodilation—that, in turn, decreases the cardiac preload—and dilate the coronary arteries, thus decreasing the O₂ demand and increasing the O₂ supply. Sublingual or IV nitroglycerin can abrogate an anginal crisis. Despite the lack of evidence that nitrates reduce major adverse events (AEs), these drugs are commonly prescribed on admission in NSTE-ACS patients, and, in most cases, they can be safely discontinued after revascularization. Nitrates are especially useful in patients with associated LV failure, or in those with vasospastic angina, and should be avoided in hypotensive patients and in those on phosphodiesterase-5 inhibitors.

These drugs reduce the myocardial O₂ consumption, by lowering the heart rate, blood pressure, and contractility, and may reduce the rates of recurrent ischaemia or reinfarction and improve prognosis in NSTE-ACS patients [118]. Oral β-blockers are often initiated in NSTE-ACS patients and are mandatory in those with LV dysfunction, in the absence of contraindications (bradycardia or AV conduction disturbances, decompensated heart failure, or a history of asthma). IV β-blockers are rarely needed but can be useful in patients with severe hypertension or tachycardia, provided that they do not have significant heart failure. Recent studies suggest that the use of β-blockers in patients without heart failure of LV dysfunction may produce no long-term benefit [119].

CCBs are vasodilators with varying effects on the cardiac contractility, heart rate, and AV conduction. Short-acting nifedipine may induce tachycardia and uncontrolled hypotension and should be avoided. In contrast, verapamil or diltiazem have an anti-ischaemic effect, similar to that of β-blockers, and might reduce the risk of AEs. CCBs are usually indicated in patients with contraindications to β-blockers or, in combination with other anti-ischaemic drugs, in those with refractory angina, and they are the preferred therapy in the subset of patients with vasospastic angina.

Ivabradine, an inhibitor of the I(f) current, and nicorandil, a K⁺ channel opener, improve symptoms and may reduce AEs in patients with stable angina, but there is very little information on their effects in the acute setting. In a large RCT in patients with NSTE-ACS, ranolazine, an inhibitor of the late Na⁺ current, had no effect on the rates of major AEs, compared with placebo, but reduced recurrent ischaemia [120].

Hyperglycaemia (see Chapter 69) is strongly associated with a worse prognosis in NSTE-ACS, both in diabetic patients and in those without known diabetes. SC or IV insulin should be administered to these patients to avoid severe hyperglycaemia (>180 mg/dL or 10 mmol/L), with care not to induce hypoglycaemia, which has been proven to be dangerous, especially in critically ill patients [121].

Haemoglobin levels should be measured on admission (see Chapter 71). In patients with anaemia, the cause should be investigated, and interventions carrying a high risk of bleeding avoided, if possible. Blood transfusions may be harmful and should be restricted to patients with haemodynamic compromise or severe anaemia (haematocrit value <25% or haemoglobin level <7 g/dL). Iron supplements are indicated if an iron deficiency is detected, but erythropoietin or its derivatives must be avoided in the acute setting, because their use has been associated with an increased rate of thrombotic events. PPIs are recommended in patients with a previous indication or in those at increased risk of GI haemorrhage. The presence of anaemia should be taken into account for the revascularization strategy.

Secondary prevention therapy should be initiated during admission. Statins are always indicated with late LDL cholesterol target levels of <70 mg/dL (<1.8 mmol/L). As mentioned earlier, β-blockers are recommended in patients with LV dysfunction and/or heart failure. ACE-inhibitors or, if not tolerated, ARBs are recommended for patients with an LVEF of ≤40% and in those with heart failure, diabetes, hypertension, or chronic renal failure, in the absence of contraindication, and could protect also against vascular events in all other patients. Finally, patients must receive counselling and support regarding smoking cessation, and their inclusion in a formal post-discharge rehabilitation programme is highly advisable [30].

The performance of coronary angiography (see Chapter 43) during the acute phase, with the objective to attempt coronary revascularization whenever feasible, defines an invasive strategy. As coronary revascularization improves prognosis, relieves symptoms, and shortens hospital stay in patients with NSTE-ACS, deciding a strategy for coronary angiography and revascularization is one of the key steps in their management (see Figure 46.4) and is recommended in the majority of patients. Only low-risk patients or those who are not candidates for coronary revascularization for any given reason are not candidates for an invasive strategy. Thus, a risk stratification should be performed early to identify intermediate- to high-risk patients who are candidates for an invasive approach, to select the timing, and to decide on the antithrombotic strategy accordingly. The management of NSTE-ACS patients without coronary angiography and revascularization is called a conservative, non-invasive, or selective invasive strategy, and the patients not undergoing coronary revascularization are often defined as medically managed. These, tend to have a worse prognosis [122].

Several RCTs have compared the clinical efficacy of a routine invasive vs a conservative or selective invasive approach, with contradictory results in the individual trials [123–128], as well as in the results of a number of meta-analyses evaluating the effect on short-term and long-term outcomes [129–133]. This inconsistency may be explained by the differences in the routine pharmacological therapy that the patients received, the changes in the use of technical advances for coronary revascularization, including coronary stents, and the variable definitions of what is a true conservative strategy. The latter is particularly important, because the rate of coronary revascularization ranged from 9% to 40% in the conservative arms of the different trials, being positive in the trials with a greater difference in revascularization rates between the invasive and conservative arms and neutral in those with higher revascularization rates in the conservative arm [134]. In general, a routine invasive strategy is recommended for patients at intermediate to high risk, particularly those with troponin elevation [30]. This is also true for older patients [135]. On the contrary, it is not recommended for low-risk patients. In fact, it has been suggested that an early invasive strategy may increase the event rates in troponin-negative women [130]. It is important that, whenever possible, the radial access is used to reduce bleedings and mortality [136].

Based on the very high short-term risk, but with no clinical evidence, it is recommended that patients with clinical or haemodynamic instability (refractory angina, severe heart failure, CS, severe MR) or presenting with life-threatening ventricular arrhythmias should undergo an emergent invasive approach (within 2 hours), regardless of the ECG or biomarker findings [30]. The optimal timing for a routine invasive strategy is not well established [137]. Observations from two randomized trials found that high-risk patients, those with a GRACE risk score of >140, or those with a troponin elevation may obtain a long-term mortality benefit if coronary angiography and revascularization are performed in the first 24 hours [138, 139]. However, there is no solid evidence to suggest that an urgent routine invasive strategy (within 24 hours) is appropriate for all patients [140]. The ESC guidelines recommend to consider this strategy for patients with a GRACE risk score value of >140, troponin elevation, or dynamic ECG changes (symptomatic or silent). For patients with GRACE risk score values of <140, but with the presence of diabetes mellitus, renal insufficiency, an LVEF of <40%, early post-infarction angina, recent PCI, and prior CABG, an early routine invasive strategy (between 24 and 72 hours) is recommended. Other patients should undergo further risk stratification with non-invasive testing before hospital discharge, and coronary angiography performed if there is evidence of significant myocardial ischaemia [30].

Coronary angiography reveals the absence of significant CAD in 15–20% of patients, more frequently women [141] who are not candidates for revascularization. In such patients, using a provocation test to detect coronary vasospasm may be advisable. Single vessel disease is found in approximately one-third of patients and multivessel disease in half of them [142, 143], a more frequent finding than in patients with STEMI. Despite the lack of RCTs comparing revascularization vs medical therapy or revascularization with PCI vs CABG specifically in patients with NSTE-ACS, coronary revascularization is recommended, whenever feasible, if significant CAD is present, given the high risk of recurrent events in these patients. In general, PCI is the preferred technique for the majority of patients with NSTE-ACS, while CABG is indicated in 4–10% of cases [125]. Different revascularization strategies can be used in patients with multivessel disease: multivessel PCI (either complete revascularization at one time or PCI of the culprit lesion and scheduled PCI of pending lesions), combined revascularization (i.e. PCI of the culprit lesion and later surgical revascularization of the rest of coronary arteries), or CABG only. The decision to use one or another revascularization mode depends on the coronary anatomy, the patient’s clinical profile, the estimated risk, and preferences. Local availability and results may be considered as additional information. For PCI, the choice between BMS or DES should be individualized [144], although evidences are becoming stronger in favour of DES. The decision in complex patients should be taken by a heart team that includes clinical cardiologists, interventionalists, and cardiac surgeons. The use of the SYNTAX score to quantify the anatomical complexity is useful to help decide between PCI or surgery [145] (see Chapter 12). When CABG is the option, timing depends on the patient’s risk, the clinical or haemodynamic instability, and the coronary anatomy. In high-risk unstable patients, CABG should be performed as soon as possible, regardless of the medical therapy received. In patients in whom the culprit lesion has been treated with PCI, surgery can be delayed. In patients with surgical indication who can be stabilized without PCI and the immediate risk is not very high (i.e. critical thrombotic stenosis), CABG can be delayed for some days [146], but, in general, patients with left main or three-vessel disease, involving the proximal LAD artery, should be submitted for surgery during the initial hospitalization. The risk–benefit of withdrawing P2Y12 inhibitors before CABG to prevent perioperative bleeding has been discussed previously. (See also Chapters 47 and 48.)

The systematic assessment of the quality of care during the management of AMI has been recommended by the ESC [147]. For this, a set of quality indicators covering different dimensions of ACS care have been described, including structural conditions, performance measures, outcomes and patient satisfaction (Table 3). A higher compliance with these quality indicators by treating centres has been shown to be associated with lower mid- and long-term mortality [148, 149].

In general, the long-term prognosis after an NSTE-ACS is not benign. Contrary to the early phase, recurrent events after discharge are more frequent in patients with NSTE-ACS. Thus, there is catch-up in the mortality risk of patients with NSTE-ACS, compared with those with STEMI, after 6–12 months of the initial event [53, 150]. The higher incidence of recurrent events is mostly explained by their older age, a more extensive CAD, and a greater prevalence of comorbidities than in STEMI patients [1, 5, 55, 150]. Identification of higher-risk patients and intensive secondary prevention measures are warranted in this population. For that, risk scores have been developed [151].