coronary angiography is justified.
IV. Management of NSTEMI
There are 4 lines of therapy for NSTEMI:
Initial invasive strategy
Antiplatelet therapy:AspirinPlatelet ADP- receptor antagonists (clopidogrel, prasugrel, ticagrelor)Glycoprotein IIb/IIIa antagonists
Anticoagulants
Anti-ischemic and other therapies
No thrombolytics. Thrombolytics are only useful for STEMI. In NSTE-ACS, the thrombus is nonocclusive and thrombolytics may promote distal embolization, overall worsening myocardial perfusion.58 Also, thrombolytics expose clot-bound thrombin, leading to platelet activation and potentially more thrombus formation in NSTE-ACS.
A. Initial invasive strategy
An initial invasive strategy implies that diagnostic coronary angiography and possible revascularization are performed within 72 hours of presentation, and within 24 hours in the highest risk subgroup. An initial or early invasive strategy does not equate with early PCI. It rather equates with early coronary angiography for risk stratification and subsequent management by PCI, CABG, or medical therapy according to the angiographic findings. It is an early intent to revascularize. In various clinical trials that managed ACS invasively, ~55–60% received PCI, ~15% received CABG, and 25% received medical therapy only.59-61 The initial invasive strategy is contrasted with the initial conservative/selective invasive strategy, in which the patient is treated medically and risk-stratified with stress testing, then invasively managed in case of recurrent true angina or high-risk stress test result.
Three major trials (FRISC II, TACTICS-TIMI 18, RITA 3) established the benefit of an initial invasive strategy and showed that in high-risk ACS patients this strategy reduces the combined endpoint of death and MI in comparison to an initial conservative strategy, particularly in patients with positive troponin, ST-segment changes, or TIMI risk score ≥ 3 (50% reduction in death/MI in those subgroups in all three trials, with an absolute risk reduction of ~5% at 30 days and 1 year).62–64 The mortality was reduced at 1-year follow-up in the overall FRISC II trial (by ~40%, more so in the highest risk groups), and at 5-year follow-up in the overall RITA 3 trial. Those beneficial results were seen despite the narrow difference in revascularization rates between the initial invasive and initial conservative strategy. For example, in TACTICS, 60% of patients in the initial invasive strategy vs. 35% of patients in the initial conservative strategy received revascularization at 30 days, this difference becoming narrower over the course of 6–12 months. These trials did not address revascularization vs. no revascularization in high-risk ACS patients who angiographically qualify for revascularization, in which case revascularization is expected to show more striking benefits. These trials rather addressed the early intent to revascularize vs. the early intent to not revascularize. In trials where the difference in revascularization between groups was narrower, such as the ICTUS trial, the early invasive strategy could not show a benefit over the early conservative strategy (at 1 year, the revascularization rates were 79% vs. 54%).65 The results of the ICTUS trial do not imply a lack a benefit from revascularization, but rather that an initial conservative strategy with a later invasive strategy if needed, sometimes weeks later, may be appropriate in initially stabilized patients who are free of angina, particularly if they have multiple comorbidities and are not ideal candidates for revascularization (class IIb in ACC guidelines; not recommended in ESC guidelines).
Timing of initial invasive strategy in NSTEMI: early invasive strategy <24 hours - The exact timing of the initial invasive strategy has been addressed in the TIMACS trial, where an “early” invasive strategy at < 24 hours was compared to a “delayed early” invasive strategy at 36 hours to 5 days (mainly 48–72 hours).61 The early invasive strategy did not reduce the rate of death/MI in the overall group but reduced it in the highest-risk group, with GRACE risk score >140. VERDICT trial reproduced similar findings.66 Thus, an “early” invasive strategy < 24 hours is reasonable in patients with a GRACE risk score > 140, but also in all patients with elevated troponin or dynamic ST changes, per ACC and ESC guidelines (class I recommendation ESC).4
Immediate invasive strategy <2 hours - Coronary angiography becomes “urgent” in the following, very-high risk cases:
ST elevation develops, or ST depression is recurrent or extensive with ST elevation in V1 or aVR (suggestive of left main disease). This indicates the importance of repeating the ECG during each pain recurrence or during persistent pain.
Angina at rest or minimal exertion that is refractory or recurrent despite the initial anti-thrombotic and anti-ischemic therapies. In patients with negative ECG and troponin, the persistent chest pain is usually not angina, especially when troponin has been negative >3 hours after pain onset.
Hemodynamic instability or sustained VT attributed to ischemia.
Large scale application of urgent coronary angiography (<2 hours) in all comers with NSTEMI did not improve death or MI (ABOARD and EARLY trials).67,68
Delayed initial invasive strategy <72 hours -This delay is acceptable in patients with negative troponin who nonetheless have typical exertional angina with unstable features (intermediate-risk ACS, paragraph III.C).36
Timing of invasive strategy in acute HF- In patients with ischemic ST abnormality, new Q waves, or severe troponin rise (>1 ng/ml), MI is presumed the cause of acute HF (type 1 MI) rather the result of it (type 2 MI). An invasive strategy is indicated and multivessel CAD is expected. Except in acute ST elevation, angiography and PCI are not warranted urgently, as supine positioning and contrast loading during angiography increase preload and aggravate HF, LVEDP and myocardial ischemia. Furthermore, procedural sedation blunts the compensatory vasoconstriction and tachycardia of pre-shock patients. These 3 factors may precipitate a downhill course of shock and massive pulmonary edema requiring urgent intubation in patients who were initially stable. Thus, in somewhat stable patients, coronary angiography is usually performed 1-3 days later, once proper diuresis has been achieved. Only unstable HF patients, such as those with shock or massive pulmonary edema already requiring mechanical ventilation, who also have ongoing deep ST depression, are treated with an immediate invasive strategy within 2 hours (per ESC and ACC).4,36
B. Antiplatelet therapy (Figure 1.4) (see Appendix 4 for a detailed discussion)
Typically, aspirin +/- one ADP-receptor antagonist (ticagrelor, clopidogrel) is started upon admission, upstream of catheterization.36 In the current era of potent ADP-receptor antagonists and quick catheterization <24 hours, upstream therapy with those agents does not seem necessary, and initiation during catheterization appears sufficient (ACCOAST, ISAR-REACT-5 trials).69,70 In fact, ESC guidelines recommend against routine pre-treatment with an ADP receptor antagonist (class III). Upstream IIb/IIIa inhibitor therapy is not beneficial.60,71,72
Figure 1.4 Platelet receptors and antiplatelet mechanisms of action.
Cyclooxygenase 1 (COX-1) allows the synthesis of thromboxane A2 (TXA2), which acts on its platelet receptor, eventually activating the IIb/IIIa receptor. Aspirin irreversibly acetylates COX-1. While the pharmacokinetic half-life of aspirin is only ~20 min – 2 h, the pharmacodynamic effect of aspirin lasts the lifespan of the platelet (5–7 days).