Introduction
A non–ST-elevation acute coronary syndrome (NSTE-ACS) is caused by a severe flow-limiting stenosis or acute thrombotic obstruction of a coronary artery (see Chapter 13 ). In the absolute majority of cases,levels of myocardial markers also are elevated, indicating myocardial damage related to thrombotic obstruction at the site of the culprit coronary lesion, as well as to downstream embolization of thrombotic material from the lesion. The thrombotic component of the disease can be influenced by treatment with anticoagulant and antiplatelet agents (see Chapter 18 and Chapter 19 ). Most often, however, one or more severe coronary stenoses remain, with consequent high risk for recurrent events during or after withdrawal of the initially intense antithrombotic treatment. Intervention to improve coronary flow is the rationale for early use of coronary angiography and revascularization.
Elimination or bypass of the flow-limiting lesions by means of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) complements medical therapy for rapid initial as well as long-term stabilization of the patient’s condition. The benefits and risks are related not only to lesion characteristics but also to patient characteristics that affect the progression of atherothrombosis and the risk of complications with these invasive procedures (see Chapter 17 ). Early risk stratification (see Chapter 11 ) is important to identify patients at high immediate- and long-term risk for death and cardiovascular events, in whom an early invasive strategy with adjunctive medical therapy may reduce that risk.
Coronary Angiography
Invasive coronary angiography, followed by coronary revascularization, is performed in a majority of patients hospitalized with NSTE-ACS in geographic regions with well-developed health care systems. The decision for an invasive strategy should carefully weigh the risks of invasive diagnostics and the potential benefits. The decision to proceed with coronary revascularization, once the anatomy is defined by angiography, takes into account the risk in terms of morbidity and mortality associated with the proposed procedure (PCI or CABG) and the benefits in terms of short- and long-term prognosis, symptom relief, quality of life, and duration of hospital stay.
In the vast majority of cases, coronary angiography allows clinicians to achieve the following:
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Confirm the diagnosis of ACS related to obstructive epicardial coronary artery disease (CAD) (or rule out epicardial CAD as the origin of chest pain).
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Guide subsequent antithrombotic treatment or avoid unnecessary exposure to antithrombotic agents.
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Identify the culprit lesion(s).
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Establish an indication for coronary revascularization and assess the suitability of coronary anatomy for PCI and CABG.
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Stratify the patient’s short- and long-term risk.
Angiographic patterns of CAD in patients with NSTE-ACS are diverse, ranging from a normal appearance of epicardial coronary arteries to a severely and diffusely diseased coronary artery tree. In patients with a clinical diagnosis of ACS, approximately 10% will be found to have disease of the left main artery, 25% will have three-vessel disease, 25% will have two-vessel disease, 25% will have one-vessel disease, and 15% will have no significant CAD at coronary angiography. Risk indicators such as age, male gender, diabetes mellitus, previous myocardial infarction (MI), previous severe angina, renal dysfunction, left ventricular dysfunction (manifesting as elevated B-type natriuretic peptide), ST-segment depression, elevated troponins, elevated growth differentiation factor 15 (GDF15), and higher risk response on stress testing are associated with a higher likelihood of multivessel or left main coronary artery disease (see Chapter 11 ). However, the correlations between the extent of CAD and these risk indicators are rather weak.
Identification of the Culprit Lesion
In patients with NSTE-ACS, it is important to try to identify the culprit lesion on angiography. Such lesions typically are seen as intraluminal filling defects, consistent with thrombus, plaque ulceration, plaque irregularity, dissection, or impaired flow. Multiple vulnerable plaques may coexist, mostly as thin-cap fibroatheroma, within the coronary tree of a patient with NSTE-ACS (see Chapter 3 ). Nearly one fourth of patients with NSTE-ACS present with an acute occluded coronary artery, and two thirds of the occlusions are already collateralized at the time of angiographic examination. As a consequence, differentiation between an acute or subacute and chronic occlusion may sometimes be challenging, and identification of the culprit lesion based solely on angiography findings may not be possible.
Routine Invasive Versus Selective Invasive Management
Multiple clinical trials and meta-analyses have compared a routine invasive versus selective invasive management strategy in patients with NSTE-ACS. Compared with a selective invasive strategy, a routine invasive strategy improves clinical outcomes and reduces rates of recurrent ACS, subsequent rehospitalization, and revascularization ( Figure 16-1A-C ). The FRISC-2, TACTICS-TIMI 18, and the RITA-3 trials were the first three trials in which patients received contemporary antithrombotic therapy, and most of the revascularization procedures were either PCI with routine stenting or CABG. All three trials demonstrated a reduction in the composite of death, MI, and recurrent severe angina, with a routine invasive strategy compared with a primarily conservative (selective invasive) treatment. Although an early hazard with more procedure-related MIs during hospitalization was noted for FRISC-2 and TACTICS-TIMI 18, a reduction of death and MI was seen in the intermediate term on follow-up evaluation at 6 months. In long-term follow-up extending to 5 years, other benefits included persistent reduction in the composite of death and MI and a trend toward improved overall survival (see Figure 16-1A-C ).
Somewhat surprisingly, the ICTUS trial, performed in a population of patients with troponin-positive NSTE-ACS, demonstrated no advantage with an early invasive approach over a more selective approach with revascularization only in those with ischemia at rest or exercise (see Figure 16-1D ). However, the differing outcome in this trial compared with that in the other two is likely to be explained by a substantial crossover of 44% of patients receiving the noninvasive management to an invasive intervention.
Across the multiple trials of early invasive versus conservative management, the proportion of patients undergoing revascularization in the different trials varied markedly. In some trials, less than 50% of patients in the invasive arm underwent early revascularization procedures, compared with a 35% to 45% early revascularization rate in the noninvasive arm ( Figure 16-2 ). Consequently, the ability to demonstrate a mortality benefit with routine revascularization may depend on the difference in revascularization rate between randomized arms ( Figure 16-3 ).
Furthermore, the true benefit of a routine invasive treatment shown in trials probably is underestimated—not only because revascularization was allowed when patients deteriorated while on medical therapy (crossover) but also because trials excluded those with very-high-risk features and did not include consecutive patients. When the ICTUS trial began enrolling patients, the availability of results from previous trials might have increased the likelihood of excluding high-risk patients from the trial by sending them directly to invasive treatment.
Meta-Analyses
The first meta-analysis, by Mehta and colleagues, reported an overall benefit of routine invasive treatment, with reductions in the composite of death and MI, and in MI alone ( Table 16-1 ). There was, however, an early (in-hospital) risk of ischemic events in patients in the routine invasive treatment group. During the time span of enrollment in studies included in this meta-analysis (1994 to 2005), several aspects of the management of NSTE-ACS patients changed, including the use of thienopyridines and glycoprotein GPIIb/IIIa inhibitors, as well as the evolution of interventional technology, such as placement of coronary stents. In a stratified analysis, the reduction in ischemic events was more pronounced in studies published after 1999, as compared with those published earlier. In a subanalysis of the three studies with troponin results available, substantial benefit was seen among patients with elevated troponin, with no apparent benefit for a routine invasive management strategy in patients with no elevation in troponin level. An analysis of all included studies using any biomarker of myocardial damage (i.e., creatine kinase, creatine kinase–MB fraction, or troponin) revealed similar results.
| Trial/Study | Year Published | N | Meta-analysis | |||
|---|---|---|---|---|---|---|
| Mehta et al. (2005) | Bavry et al. (2006) | O’Donoghue et al. (2008) | Fox et al. (2010) | |||
| TIMI-IIIB | 1994 | 1473 | x | x | ||
| VANQWISH | 1998 | 920 | x | x | ||
| MATE | 1998 | 201 | x | x | ||
| FRISC-II | 1999 | 2457 | x | x | x | x |
| TRUCS | 2000 | 148 | x | |||
| TACTICS-TIMI 18 | 2001 | 2220 | x | x | x | |
| VINO | 2002 | 131 | x | x | x | |
| RITA-3 | 2002 | 1810 | x | x | x | x |
| ISAR-COOL | 2003 | 410 | x | |||
| ICTUS | 2005 | 1200 | x | x | x | |
| Outcome | ||||||
| Death/MI | OR, 0.82 (0.72-0.93) | Not reported | OR, 0.92 (0.69-1.23) | HR, 0.85 (0.75-0.96) | ||
| Death | OR, 0.92 (0.77-1.09) | RR, 0.75 (0.63-0.90) | OR, 0.97 (0.71-1.32) | HR, 0.90 (0.77-1.05) | ||
| MI | OR, 0.75 (0.65-0.88) | RR, 0.83 (0.72-0.96) | OR, 0.84 (0.64-1.12) | HR, 0.77 (0.65-0.90) | ||
O’Donoghue and colleagues included all studies included in the previous analysis conducted by Mehta and associates, along with one additional study (ICTUS), and also extracted gender-specific information (see Table 16-1 ). After addition of data for the neutral ICTUS trial, no statistically significant difference was evident in the endpoints of death/MI and MI alone; however, routine invasive management reduced the composite endpoint of death, MI, and rehospitalization. This benefit was greatest in patients with elevated risk (as reflected in elevated levels of biomarkers of myocardial damage), for both men and women. Among women with negative biomarker assay results, a routine early invasive strategy provided no apparent benefit. Analogously, in a meta-analysis of data for women included in FRISC-II, RITA-3, ICTUS, and OASIS-5, a routine invasive management strategy offered no benefit over that of a selective invasive approach and appeared to result in higher mortality. In the meta-analysis performed by Bavry and colleagues, one requirement for inclusion was the availability of GPIIb/IIIa inhibitors and thienopyridines. Also, studies that included fibrinolysis were excluded. As a consequence, the earliest trials were not included (see Table 16-1 ). Routine invasive management reduced both mortality and subsequent MI; as well, the early hazard of MI and mortality previously described with this approach was not apparent, with similar reductions in ischemic events at 1 month and later during follow-up.
Long-Term Outcomes
Five-year outcomes (as opposed to up to 1 year in the preceding three meta-analyses) with a routine invasive versus selective invasive strategy were assessed in a patient-level meta-analysis of the FRISC-II, RITA-3, and ICTUS trial data. A routine invasive strategy was consistently associated with lower rates for the composite endpoint of death and MI, and for MI alone, when compared with a selective invasive strategy, and with a hazard ratio (HR) of 0.90 (CI, 0.77 to 1.05) for mortality alone. In a patient-pooled analysis of individual data from the FRISC-II, ICTUS, and RITA-2 trials, the effect of age on long-term outcomes with a routine or selective invasive strategy was assessed. The long-term, 5-year benefit of the routine invasive strategy was attenuated in patients younger than 65 years of age, as well as in women. The more recently published 10-year results of the RITA-3 trial showed that the survival advantage afforded by a routine approach attenuated after 5 years and disappeared at 10 years regardless of patient risk. The rates of all-cause and cardiovascular death were similar for the routine approach and the selective invasive strategy groups (all-cause death: 25.1% versus 25.4%; P = 0.94; and cardiovascular death: 15.1% versus 16.1%; P = 0.65) for routine and selective invasive treatment, respectively). However, an interaction between treatment and time associated with lower all-cause mortality was evident during the first 5 years, but this rate was higher during the second 5 years for routine than for selective invasive treatment.
The significant treatment effect from the initial studies, the widespread clinical uptake of the findings, and guideline recommendations are likely to have caused the shift in clinical practice toward more routine invasive care.
Patient Selection
An early invasive strategy is recommended in a majority of patients with ACS,both to identify all severe coronary lesions and to improve clinical outcomes by early revascularization. Although the vast majority of data support a routine invasive strategy, guidelines also highlight the importance of risk stratification in the decision-making process ( Figure 16-4 ; Table 16-2 ). Both European Society of Cardiology (ESC) and American Heart Association/American College of Cardiology (AHA/ACC) guidelines state that an early invasive strategy is not recommended in patients with extensive comorbidity, in whom the risks associated with revascularization and the comorbid conditions are likely to outweigh the benefits of invasive treatment. Furthermore, patients with acute chest pain and a low likelihood of ACS who are troponin assay–negative are not likely to benefit from routine invasive strategy.
