CTA seeks niche triage role in unstable angina patients

Coronary CT angiography has been found to be a powerful tool to evaluate patients suspected of coronary artery disease who are at low to intermediate risk. The task now for many researchers is to further refine specific patient populations for whom coronary CTA can be beneficial. One such patient niche being explored is the group with unstable angina and/or non-ST-segment elevation myocardial infarction.

Persistent ST-segment elevation generally reflects transmural ischemia by total coronary occlusion and characterizes evolving myocardial infarction (STEMI). This occurs in a relatively small population of patients with acute coronary syndrome. In these settings, the therapeutic objective is either primary angioplasty or fibrinolytic treatment to achieve rapid and complete recanalization (Figure 1).1

Patients with non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina present with chest pain associated with ST-depression, T-wave inversion, flat T waves, or nonspecific ECG changes; a normal ECG at presentation can also be the case.

NSTEMI is distinguished from unstable angina by an elevation in serum biochemical markers of myocardial necrosis (troponin T or I). However, the elevation of troponin levels may also be caused by either transient occlusion or microembolization secondary to spontaneous thrombolysis (small infarcts), and hence in the absence of an epicardial coronary artery occlusion, it may be amenable to percutaneous revascularization.

DIAGNOSIS AND RISK STRATIFICATION

Patients with unstable acute coronary syndrome are at risk for myocardial infarction, MI recurrence, or death. Diagnosis and risk stratification are pursued together: During the process of establishing the acute coronary syndrome diagnosis, risk is repeatedly assessed and used as guidance for choosing the best therapeutic strategy. According to the European Guidelines,2 risk stratification of patients with unstable angina/NSTEMI involves integrating relevant information from their histories; e.g., chest pain pattern, physical examination, ECG, and biochemical cardiac markers.

Several clinical decision rules are available for risk stratification.3-6 According to these algorithms, patients can be assigned to low-, intermediate-, or high-risk categories. The presence of thrombus and extent of underlying coronary artery disease (CAD), in particular troponin elevation and signs and symptoms of ongoing myocardial ischemia, can modify a patient's risk category.

Optimal early management of patients with non-ST-elevation acute coronary syndrome is still being debated. Several large randomized trials7-9 and a meta-analysis compared a routine invasive strategy (i.e., early angiography possibly followed by revascularization) with a more conservative strategy (i.e., angiography and revascularization only if medical therapy failed or residual ischemia was documented).10 The early invasive strategy was found to be superior to the conservative strategy in reducing major cardiovascular events as well as severe angina and rehospitalization. RITA-3 (randomized intervention trial of unstable angina)9 was the first study reporting improved survival after early invasive intervention.

Another study11 of 1200 patients with non-ST-elevation acute coronary syndrome demonstrated that if patients were optimally treated before, during, and after revascularization, early cardiac catheterization was not better than a more selective invasive strategy in terms of mortality and recurrence of acute myocardial infarction.

These investigators reported that the restricted use of conventional angiography only in patients experiencing refractory angina or clinically significant ischemia on predischarge exercise tests saved 47% of catheterization procedures without any detrimental effect on long-term follow-up.11 Indeed, a large number of these procedures were merely diagnostic and not followed by revascularization. Results were confirmed at four-year follow-up,12 suggesting that only very high risk patients should undergo early invasive management. Medical therapy might also be tailored to the patient's risk profile.3,6,13,14

Meijboom et al15 compared MSCT coronary angiography and conventional angiography for the detection of > 50% coronary obstructions in 104 patients with NSTEMI. At a patient level, both sensitivity and negative predictive value of MSCT were 100%, with no difference between low-risk and high-risk patients. Another study, by Dorgelo et al,16 showed that MSCT could effectively be substituted for diagnostic conventional angiography in approximately one-third of patients with unstable CAD.

It could be argued that a major limitation of MSCT is its inability to provide information on the hemodynamic significance of moderate (50% to 70%) lesions, which might lead to unnecessary catheterizations. However, these data showed that MSCT can rule out the diagnosis of acute coronary syndrome and has the potential to reduce hospital admissions.

MSCT IN LOW-RISK PATIENTS

Although only a minority of patients classified as low risk actually suffer from myocardial ischemia,17 it has been reported that up to 8% of patients who actually have acute coronary syndrome are inappropriately discharged home.18,19 These patients have increased morbidity and mortality. Because the consequences of missing the diagnosis are so severe, it has been standard practice to evaluate all patients with suspected acute coronary syndrome (including low-risk patients) with serial ECG and cardiac enzymes, followed by a rest and/or stress-imaging study. Such an approach is time-consuming and costly.

Goldstein et al20 randomized 197 low-risk chest pain patients to either ECG-gated MSCT coronary angiography or standard diagnostic evaluation. In the MSCT group, 67% of patients had minimal CAD and were discharged immediately; 8% had at least one stenosis > 70% and were referred for catheterization.

The MSCT scan alone could immediately identify or exclude coronary disease as the cause of chest pain in 75% of patients. The remaining patients had intermediate lesions on MSCT or nondiagnostic scans and thus underwent stress testing. Stress testing was negative in 20% of patients, who were discharged directly from the emergency department during the index visit; importantly, none of these patients suffered from major acute cardiac events over the six-month follow-up period. In patients who required further testing, the MSCT strategy ultimately arrived at a correct diagnosis in 95% of cases.

Rubinshtein et al21 prospectively studied 58 patients with chest pain of uncertain origin. These authors reported 100% sensitivity, 92% specificity, and 100% negative predictive value for MSCT compared with standard diagnostic tests (i.e., new biomarker elevation, abnormal myocardial perfusion scintigraphy, and/or invasive angiography) in the diagnosis of acute coronary syndrome. At 15-month follow-up, sensitivity of MSCT for predicting major cardiovascular events was 92%, specificity 76%, and negative predictive value 97%.21

CORONARY PLAQUE ANALYSIS

The potential to visualize the coronary artery wall and several characteristics of atherosclerotic plaques noninvasively, rather than with such invasive techniques as intravascular ultrasound, has raised interest in plaque imaging to define patient risk.

Noninvasive identification of the vulnerable plaque; (i.e., plaque that will rupture and cause an acute event) is probably an elusive goal with current imaging technology. Nevertheless, MSCT can detect obstructive/nonobstructive lesions, evaluate location/distribution of CAD, and estimate left ventricular function. For instance, MSCT might allow a patient to be reclassified from the low-risk category to a higher risk category when three-vessel disease, involvement of the left main stem, or impaired LV function is seen.

It was recently shown22 that mixed plaques were independent predictors of acute events in patients with CAD. Mixed plaques may contain a necrotic component (necrotic core) and be associated with higher risk of rupture than densely calcified plaques. The detection and differentiation of noncalcified plaque components from calcified plaque components is feasible with MSCT; the distinction between necrotic areas and fibrous areas, conversely, is more challenging. Nevertheless, some studies have explored the ability of MSCT coronary angiography to differentiate large necrotic cores from fibrous lesions by measuring the CT attenuation values within the plaques.23-25 Although these studies report significant variation of attenuation values within plaques of the same type, plaques with a necrotic core demonstrated by IVUS consistently showed lower CT attenuation values than fibrous plaques (Figure 2).

NONOBSTRUCTIVE CAD

Bugiardini et al26 evaluated a large cohort of non-ST-elevation acute coronary syndrome patients drawn from international multicenter trials.27-33 This study showed that most of the patients classified as low-risk had nonobstructive CAD or normal coronary arteries. The presence of nonobstructive CAD detected by conventional angiography was associated with a higher risk of events (one-year follow-up) than that associated with normal coronary angiograms.

Hoffmann et al34 performed MSCT in 103 chest pain patients presenting at the emergency department with no ischemic ECG changes and negative initial biomarkers. This study found that the absence of coronary artery plaque or obstructions at MSCT had a high negative predictive value for the subsequent diagnosis of acute coronary syndrome. Moreover, the presence of any plaque or coronary obstruction provided information incremental to conventional risk factors in predicting the risk of acute coronary syndrome.

Pundziute et al22 reported on the prognostic value of MSCT coronary angiography in symptomatic patients with known or suspected CAD and a high prevalence of conventional risk factors. At 16 months, a 100% event-free survival was noted in patients with normal MSCT coronary angiography. Patients with coronary atherosclerosis identified on MSCT had a worse prognosis. In keeping with the previous studies, although the risk of events was the highest in patients with obstructive CAD, the risk associated with nonobstructive CAD (Figure 3) was higher than that associated with a normal MSCT study.

The study by Bugiardini et al shows that low-risk patients might be a heterogeneous group and that risk stratification should be improved in these patients. All three of these studies support the concept that detecting the presence of CAD, whether associated with obstructive lesions or not, may be used for improving risk definition within the low-risk patient category.

CLINICAL EVIDENCE

More hard data are needed to define the clinical and prognostic value of specific MSCT findings in patients with acute coronary syndrome. Large trials will have to prove the clinical meaning of mixed/noncalcified plaques, plaque location, and plaque distribution in both the short and the long-term.

In spite of tremendous technical developments, the resolution of multislice CT is still far from what is needed to visualize individual structures of the atheroma such as the fibrous cap, which is regarded as the pathological marker of vulnerable plaques. The reproducibility and inter-reader agreement in MSCT coronary plaque imaging will also have to be tested in the real world beyond the academic context.

Nevertheless, the available data consistently support the excellent negative predictive value of a normal multislice CT in patients with suspected acute coronary syndrome. Using these data may consistently reduce the number of unnecessary hospital admissions. The finding that not only obstructive lesions but also nonobstructive CAD and mixed plaques are associated with a worse prognosis22,26 is in keeping with the notion that many patients are entirely asymptomatic up to their first acute event, and that plaque composition, in addition to stenosis severity, contributes to the occurrence of events.

Although the routine use of multislice CT in patients with suspected acute coronary syndrome is not supported yet by practice guidelines, the concepts discussed here lay the foundation for use of MSCT in these patients. In the near future, MSCT might find a role in the diagnostic algorithm of low-risk patients with non-ST-elevation acute coronary syndromes to rule out obstructive CAD, reducing times and costs of care and improving risk stratification.

Dr. Pugliese is a radiologist and Dr. Krestin is the radiology chair, both at Erasmus MC University Medical Centre Rotterdam in the Netherlands.

References

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