CTA seeks niche triage role in unstable angina patients

January 10, 2008

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.

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

1. Bertrand ME, Simoons ML, Fox KA, et al. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2002;23(23):1809-1840.

2. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J 2007;28(13):1598-1660.

3. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA 2000;284(7):835-842.

4. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA 2004;291(22):2727-2733.

5. Lagerqvist B, Diderholm E, Lindahl B, et al. FRISC score for selection of patients for an early invasive treatment strategy in unstable coronary artery disease. Heart 2005;91(8):1047-1052.

6. Boersma E, Pieper KS, Steyerberg EW, et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation 2000;101(22):2557-2567.

7. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Lancet 1999;354(9180):708-715

8. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. NEJM 2001;344(25):1879-1887.

9. Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina. Lancet 2002;360(9335):743-751.

10. Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA 2005;293(23):2908-2917.

11. de Winter RJ, Windhausen F, Cornel JH, et al. Early invasive versus selectively invasive management for acute coronary syndromes. NEJM 2005;353(11):1095-104.

12. Hirsch A, Windhausen F, Tijssen JG, et al. Long-term outcome after an early invasive versus selective invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome and elevated cardiac troponin T (the ICTUS trial): a follow-up study. Lancet 2007;369(9564):827-35.

13. Calvin JE, Klein LW, VandenBerg EJ, et al. Validated risk stratification model accurately predicts low risk in patients with unstable angina. J Am Coll Cardiol 2000;36(6):1803-1808.

14. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. NEJM 1997;337(7):447-452.

15. Meijboom WB, Mollet NR, van Mieghem CA, et al. 64-slice computed tomography coronary angiography in patients with non-ST elevation acute coronary syndrome. Heart 2007 (doi: 10.1136/hrt.2006.112771. Available online at http://heart.bmj.com/cgi/content/abstract/hrt.2006.112771v1).

16. Dorgelo J, Willems TP, Geluk CA, et al. Multidetector computed tomography-guided treatment strategy in patients with non-ST elevation acute coronary syndromes: a pilot study. Eur Radiol 2005;15(4):708-13.

17. Reilly BM, Evans AT, Schaider JJ, et al. Impact of a clinical decision rule on hospital triage of patients with suspected acute cardiac ischemia in the emergency department. JAMA 2002;288(3):342-350.

18. McCarthy BD, Beshansky JR, D'Agostino RB, Selker HP. Missed diagnoses of acute myocardial infarction in the emergency department: results from a multicenter study. Ann Emerg Med 1993;22(3):579-582.

19. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. NEJM 2000;342(16):1163-1170.

20. Goldstein JA, Gallagher MJ, O'Neill WW, et al. A randomized controlled trial of multi-slice coronary computed tomography for evaluation of acute chest pain. J Am Coll Cardiol 2007;49(8):863-871.

21. Rubinshtein R, Halon DA, Gaspar T, et al. Usefulness of 64-slice cardiac computed tomographic angiography for diagnosing acute coronary syndromes and predicting clinical outcome in emergency department patients with chest pain of uncertain origin. Circulation 2007;115(13):1762-1768.

22. Pundziute G, Schuijf JD, Jukema JW, et al. Prognostic value of multislice computed tomography coronary angiography in patients with known or suspected coronary artery disease. J Am Coll Cardiol 2007;49(1):62-70.

23. Schroeder S, Kopp AF, Baumbach A, et al. Noninvasive detection and evaluation of atherosclerotic coronary plaques with multislice computed tomography. J Am Coll Cardiol 2001;37(5):1430-1435.

24. Schroeder S, Kuettner A, Leitritz M, et al. Reliability of differentiating human coronary plaque morphology using contrast-enhanced multislice spiral computed tomography: a comparison with histology. JCAT 2004;28(4):449-454.

25. Leber AW, Knez A, Becker A, et al. Accuracy of multidetector spiral computed tomography in identifying and differentiating the composition of coronary atherosclerotic plaques: a comparative study with intracoronary ultrasound. J Am Coll Cardiol 2004;43(7):1241-1247.

26. Bugiardini R, Manfrini O, De Ferrari GM. Unanswered questions for management of acute coronary syndrome: risk stratification of patients with minimal disease or normal findings on coronary angiography. Arch Intern Med 2006;166(13):1391-1395.

27. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 1999;100(15):1593-1601.

28. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. NEJM 2004;350(15):1495-1504.

29. Cannon CP, McCabe CH, Wilcox RG, et al. Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation 2000;102(2):149-156.

30. Lindahl B, Venge P, Wallentin L. Relation between troponin T and the risk of subsequent cardiac events in unstable coronary artery disease. The FRISC study group. Circulation 1996;93(9):1651-1657.

31. Morrow DA, Cannon CP, Rifai N, et al. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. JAMA 2001;286(19):2405-2412.

32. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285(13):1711-1718.

33. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. NEJM 2001;345(7):494-502.

34. Hoffmann U, Nagurney JT, Moselewski F, et al. Coronary multidetector computed tomography in the assessment of patients with acute chest pain. Circulation 2006;114(21):2251-2260.