What is the role of computed tomographic coronary angiography in diabetic patients?

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Diabetes & Metabolism 34 (2008) 26–32

Mini review

What is the role of computed tomographic coronary angiography in diabetic patients? L. Bordier a , C. Garcia a , P. Goasdoué b , H. Mayaudon a , O. Dupuy a , O. Guiraudet c , B. Bauduceau a,∗ b

a Service d’endocrinologie, hôpital d’Instruction-des-Armées–Bégin, 69, avenue de Paris, 94160 Saint-Mandé, France Service de radiologie, hôpital d’Instruction-des-Armées–Val-de-Grâce, 74, boulevard de Port-Royal, 75005 Paris, France c Service de cardiologie, hôpital d’Instruction-des-Armées–Bégin, 69, avenue de Paris, 94160 Saint-Mandé, France

Received 18 July 2007; received in revised form 26 July 2007; accepted 16 August 2007 Available online 14 January 2008

Abstract All diabetes specialists are aware of the frequency and severity of coronary disease in diabetics. Non-invasive diagnostic tests perform well, but they could be better. Aim. – To assess the role of computed tomographic coronary angiography in diabetics. New cardiac imaging techniques such as CT coronary angiography are promising tools for the selection of patients for conventional X-ray coronary angiography, which remains the key for diagnosis and angioplasty. The limitations of CT coronary angiography, even using the most advanced machines with a 64-slice capacity, are its resolution, the need for an iodine contrast agent and the cumulative radiation from repeated examinations. Conclusion. – CT coronary angiography appears to have great potential for patients at risk where non-invasive tests cannot absolutely exclude coronary disease and for the follow-up of coronary bypass surgery. © 2007 Elsevier Masson SAS. All rights reserved. Résumé Place de l’angioscanner coronaire chez le diabétique ?. Tous les diabétologues connaissent la fréquence et la gravité de la maladie coronaire chez les diabétiques. Les examens non invasifs de dépistage possèdent de bonnes performances mais qui ne sont pas parfaites. Objectif. – Évaluer l’intérêt de l’angioscanner coronaire chez le patient diabétique. Les nouvelles techniques d’imagerie cardiaque, notamment l’angioscanner coronaire, constituent en effet des outils prometteurs pour mieux sélectionner les patients devant bénéficier d’une coronarographie qui reste l’examen clef du diagnostic et qui offre l’avantage de pouvoir réaliser une angioplastie. Les limites de l’angioscanner, même avec les appareils les plus perfectionnés comportant 64 barrettes, sont représentées par des résolutions encore limitées, la nécessité d’une injection de produit de contraste iodé et l’irradiation cumulée en cas de répétition des examens. Conclusion. – L’angioscanner paraît particulièrement intéressant chez les patients à risque lorsque les examens non invasifs n’ont pas permis d’affirmer ou d’écarter formellement une maladie coronaire ou pour le suivi après pontage aortocoronaire. © 2007 Elsevier Masson SAS. All rights reserved. Keywords: Coronary disease; Silent myocardial ischaemia; Computed tomographic coronary angiography; Calcium score; Diabetes Mots clés : Maladie coronaire ; Ischémie myocardique silencieuse ; Angioscanner coronaire ; Score calcique ; Diabète

Coronary disease is particularly frequent and severe in diabetics [1]. Around 20–30% of type 2 diabetics, about 500,000 people are estimated to suffer from myocardial ischaemia. Coro-

∗

Corresponding author. E-mail address: [email protected] (B. Bauduceau).

1262-3636/$ – see front matter © 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.diabet.2007.08.005

nary disease is the main cause of death in these patients. The Multiple Risk Factor Intervention Trial (MRFIT) study [2] showed that men with type 2 diabetes were three times more likely to die of coronary disease than were non-diabetics. These data indicate the need to anticipate, detect and treat as well as possible this difficult complication. While conventional methods of detection can sometimes be misleading, modern imaging techniques, par-

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ticularly computed tomographic (CT) coronary angiography are simple and promising methods for the diagnosis and monitoring of all our patients. 1. Present strategies for diagnosing coronary disease Coronary disease is presently detected by stress tests and/or myocardial scintigraphy. Conventional X-ray coronary angiography must be performed if these tests are positive. The examination is the standard reference for the assessment of coronary artery disease and can be used to guide treatment and to perform an angioplasty in 30% of cases. But the technique is expensive and requires direct arterial catheterization and the injection of a contrast agent that contains iodine, making it an unacceptable risk for asymptomatic patients [3]. The fact that 20–30% of angiographies performed are normal or show insignificant lesions raises the question of the relevance of the indications for this test. CT coronary angiography could lead to a more accurate selection of those patients who can benefit from conventional X-ray coronary angiography. Also, while X-ray coronary angiography is appropriate for evaluating the coronary lumen, it is less suitable for analyzing soft, unstable plaques that, although they are not occlusive (and are thus ‘insignificant’ on X-ray coronary angiography), are implicated in the onset of acute events. Although the reference examination for evaluating the composition of plaques — endocoronary ultrasound — is a cutting-edge technology, CT coronary angiography may also be useful. Revealing such plaques could lead to more ambitious objectives in the management of cardiovascular risk factors. 2. Coronary disease in diabetics Coronary disease is expressed in a particular way in diabetics. In 15% of cases, — which is two times more frequently than in the general population — it corresponds to silent ischaemia. The silent aspect deprives both the patient and doctor of any symptoms of alarm, delays detection of ischaemia and often makes it difficult to diagnose. Silent ischaemia must be detected according to a structured and coherent diagnostic process in which new imaging techniques certainly play a major role [4]. The disease in diabetics is also characterized by a more serious prognosis, as demonstrated in the MRFIT study, in which the risk of death from coronary disease was three times more frequent in type 2 diabetic male patients than in non-diabetic men [2]. Moreover, after an acute event such as myocardial infarction, mortality is significantly more likely in diabetics, independently of gender [5]. Its silent feature can also make the prognosis worse, as it is sometimes discovered in severe complications such as cardiac insufficiency, myocardial infarction or sudden death. The accumulation of cardiovascular risk factors, which is common for these patients, also plays a deleterious role [4]. In addition, coronary disease in diabetics is typically more diffuse and more distal in location [6], making revascularization more difficult. Finally, in diabetic patients, plaques are more often ulcerated and more unstable because of their composition [7].

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3. Advantages of CT coronary angiography The new-generation of multislice computed tomography (MSCT), introduced in 1999, is a technological breakthrough: each rotation of the X-ray tube produces not just one, but 16, 32 or 64 images, depending on the number of detectors. Data-acquisition is therefore faster: the stator rotates every 330 ms so that less than 10 s of apnoea is enough for a 64-slice MSCT to acquire data on the entire heart volume. It is also more accurate, as the detectors are becoming smaller and smaller. It is currently possible to detect details that are less than 1 mm across (0.4 mm with 64 detectors) [8]. Such a high resolution can minimize the effects of partial volumes that cause apparent thickening of dense structures such as coronary calcifications or stents [9]. 3.1. The coronary calcium score Although the calcium score is not the main objective of our review, it can complete the contribution of CT coronary angiography in the field of coronaropathy. The calcium score is determined by calculation of the Agatston score [10], by means of specific software. Any zone with a density greater than 130 Hounsfield units (HU) has a calcified nature (Fig. 1). A score is established for each coronary artery and the sum of all these results determines the total score. It allows determination of risk levels, using four subgroup gradations, according to the Rumberger classification system [11]. The absence of coronary calcifications makes the presence of plaques, including unstable plaques and the occurrence of severe cardiovascular incidents within the next two to five years highly improbable [12]. The higher the calcium score, the greater the probability of coronaropathy. However, the relationship between these two values is not linear. There is also no correlation between calcification topography and localization of coronary stenoses. A very high calcium score is associated with a moderate-to-high risk of a cardiovascular event within two to five years [12].

Fig. 1. Calcifications in the left anterior descending and circumflex coronary arteries.

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The more than 95% negative predictive value of the calcium score allows fewer explorations to be made, especially in those patients whose diagnosis does not rely on invasive screening tests such as women. Given the cost of the various explorations, the possibility of using the calcium score on a wider scale deserves consideration. This suggestion is particularly appropriate among diabetics, who have a greater prevalence of coronary calcifications compared with the general population. For these patients, this examination is appealing, as it does not require an empty stomach, thus allowing the continuation of oral antidiabetic drugs such as metformin or insulin. Finally, determination of the calcium score does not require the injection of iodinated contrast agents and concomitant antihypertensive or antiangina drugs will not cause underestimation of the results. 3.2. CT coronary angiography CT coronary angiography requires the injection of an iodinated contrast agent. It takes only 10 s and is performed on a fasting patient. Some teams administer sublingual nitroglycerin one minute before image acquisition, as with X-ray coronary angiography and use beta-blockers if the heart rate is above 65 beats per minute (bpm) [8,13]. CT coronary angiography data are recorded at the same time as an ECG to synchronize the images with cardiac activity and to produce initially a retrospective cardiac reconstruction in telediastole, the phase during which the heart is most immobile. In some cases, other reconstructions at different phases of the cardiac cycle are necessary, mostly at the beginning of systole. Image acquisition takes a few seconds, reconstruction takes several minutes and interpretation, about a quarter of an hour. 4. Limitations of CT coronary angiography The technology has limitations due to the nature of the examination itself and of the patient as well. First, the resolution of an angiographic scan is only 400 ␮, while that of an X-ray coronary angiography is 200 ␮. Also, its temporal resolution (165 ms for a 64-slice MSCT increasing to 83 ms, depending on technical issues) cannot remove all movement artefacts (which would require a resolution of 19 ms) [8,14]. These artefacts involve mainly the middle segment of the right coronary artery, where expansion of the vessel may be as much as five or six times its diameter due to twisting and torsion of the heart [14] and are even more of a problem in patients with tachycardia [15]. However, reconstructions of images at different phases of the cardiac cycle and the use of beta-blockers may limit these artefacts. Cumulative X-radiation must also be taken into account, especially if examinations are repeated to monitor coronary disease [14]. The dose of radiation delivered during CT coronary angiography is 10–15 mSv, two and a quarter times greater than that delivered during conventional coronary angiography (2–4 mSv). But with modulation of the dose according to the ECG and reduction of voltage, radiation can be decreased: 6.4 ± 1.9 mSv for the 16-slice; and 11 ± 4.1 mSv for the 64-slice [16]. Also, the radiation dose may be reduced by modifying the

Fig. 2. Blooming effect: the stent appears to be larger than the vessel.

examination of the patient’s morphology and weight, as well as by reducing the radiation during systole when, sometimes, no useful image can be reconstructed. The dose injected can also be reduced by 50% so that it becomes the same as that used for conventional X-ray coronary angiography [9,14,15]. Coronary calcifications can cause false-positive artefacts by obscuring visualization of the coronary lumen if they are numerous and also because of the blooming effect, which overestimates their volume compared with the coronary lumen (Fig. 2). The Raff et al. study [8] found that a high calcification score (over 400 HU) reduced CT coronary angiography performance, so that specificity dropped from 97 to 67% and the negative predictive value, from 95 to 67%. This difference was not statistically significant because of the small number of trials analyzed. However, some have proposed, excluding the highly calcified segments from the scan evaluation, to improve examination performance [15]. This was suggested by Gilard et al. [17] in a study of 63 patients who underwent CT coronary angiography before aortic valve replacement. An Agatston score over 1000 HU seems to be the limit above which coronary scanners cannot be interpreted. Patients must cooperate during scanning by holding their breath. The breath-holding time varies according to an inverse relationship with the number of detectors used. Obesity can reduce CT coronary angiography performance [8]. A BMI of over 30 kg/m2 can reduce the sensitivity, specificity and positive and negative predictive values from 100 to 90, 86, 91 and 86%, respectively. The CT coronary angiography data are recorded at the same time of an ECG, but image synchronization is difficult when the heart rate is irregular or too fast, when quality is lost. The heart rate must then be slowed using a beta-blocker. All studies agree that the optimal heart rate is 50–60 bpm [15,18]. A heart rate of over 70 bpm reduces the sensitivity of a 64-slice scanner from 97 to 88% and the specificity, from 95 to 71%. The negative predictive value is similarly reduced from 95 to 83% [8].

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CT coronary angiography is contraindicated for patients who have an arrhythmia such as atrial fibrillation, as in such cases synchronization is seldom possible. Nevertheless, a scan is possible if the patient has a slow auricular fibrillation arrhythmia. Any reduction in image quality can be partly corrected by appropriate resynchronization. Isolated extrasystoles and implants do not prevent CT coronary angiography. The artefacts that occur close to the metal are generally limited and do not interfere with analysis of the coronary arteries. CT coronary angiography requires the injection of contrast agent at high concentrations (350–400 mg of iodine per millilitre), so precautions must be taken to ensure that there is no renal damage. Renal function should also be checked. If there is a moderate change in renal function, the examination should be carried out after appropriate rehydration and preparation with N-acetylcysteine. The most modern, rapid scanners require proportionally smaller doses of contrast agent (100–140 ml), thereby reducing the risk of renal damage. This type of scan should not be performed on patients who are severely allergic to iodine (Quinke oedema and anaphylactic shock). However, in cases of minor allergy, some teams propose using an antiallergenic preparation to allow the examination to be done. The risk–benefit ratio should be clearly evaluated for patients who are allergic or have moderate renal insufficiency. Finally, for diabetic patients taking metformin, treatment should be stopped before performing the examination because of the risk of acute renal insufficiency due to the iodine-based contrast agent. Treatment should not be restarted before confirming that renal function is satisfactory. 5. Indications for CT coronary angiography in diabetics There are many indications for performing CT coronary angiography. It can be used to explore atypical chest pain or to uncover silent myocardial ischaemia, which is two times more frequent in diabetics than in the general population. The study by Goldstein et al. [19] compared the results of CT coronary angiography and myocardial scintigraphy in an emergency department to investigate chest pain with normal ECGs and no enzyme changes. CT coronary angiography offered a significant saving of time, lower costs and good reliability (97% rate of correct diagnoses) in confirming or excluding a diagnosis of coronary disease. The scan is also promising in the study of atherosclerotic plaques because of the good correlation between the results of scans and those of endocoronary ultrasound, the reference method used in several specialist centres. CT coronary angiography can also be used to monitor coronary arteries that have been treated by revascularization. The problem posed by occluded stents, or stenoses, even when using the most up-to-date stents, is particularly important in diabetics. Unfortunately, MSCT does not always mean that a patient will not require conventional X-ray coronary angiography because, although the technique is suitable for evaluating the permeability of coronary endoprostheses, it does not, at present, allow evaluation of intrastent restenosis (Figs. 3 and 4). MSCT can

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Fig. 3. Left anterior descending coronary artery stent.

however be used to study the permeability of coronary bypass grafts and proximal anastomoses [20] (Fig. 5). These images can also be used by the surgeon before performing bypass surgery, as they can reveal calcifications in the left anterior descending coronary artery and the relationship with the internal mammary artery. Coronary angiography using MSCT appears to be promising and improvements in both hardware and software should lead to its wider use for exploring coronary arteries, particularly in diabetic patients. In addition, the three-dimensional nature of coronary scanning data may enable it to be used in the search for abnormal

Fig. 4. Left anterior descending coronary artery stent.

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6. Results of various types of angioscanning

Fig. 5. Triple coronary bypass grafts.

coronary artery distributions, especially in cases of congenital cardiopathy and to detect intramyocardial muscle bypasses. For these, it is more suitable than conventional X-ray coronary angiography. Thus, CT coronary angiography can complete and improve the contribution of the calcium score. These examinations could become integral to different stages of the decision-making process for the detection and evaluation of diabetic coronaropathy. Determination of the calcium score could identify those patients who are at very low risk because of its excellent negative predictive value and CT coronary angiography could constitute the first morphological examination in high-risk subjects (Fig. 6).

The performance of a coronary scanner depends on the number of segments it can visualize. The proximal and medial segments of the three main arteries are accessible to scanners with four detectors. Yet, around 20–30% of the proximal and medial arterial segments are not accessible because of a lack of temporal and spatial resolution [21–23]. Performance is limited in the right coronary, collateral branches, distal arterial segments and vessels with a diameter less than 2 mm. Also, the poor temporal resolution obtained in patients with a heart rate over 70 bpm results in movement artefacts, especially in the circumflex and right coronary arteries [15]. Dirksen et al. [21] found that sensitivity varied from 89 to 95%, specificity from 87 to 91%, positive predictive value from 79 to 85% and negative predictive value from 94 to 97%, depending on the operator. But performance is also dependent on the arterial segment studied; sensitivity was 100% for the left and right and left anterior descending coronary arteries, but only 79% for the circumflex artery. Scanners with 16 detectors [9] can visualize 96% of the main coronary artery segments, compared with only 73% with a 4slice scanner. Yet, if only interpretable segments are taken into account, the 16-slice scanner is only a slight improvement over the 4-slice scanner, although the specificity of the 16-slice scanner is much greater because of the larger number of segments that can be interpreted: the 16-slice scanner allows interpretation of 90% of the coronary vessels whereas the 4-slice scanner is good for only 30%; in addition, the 16-slice scanner has a specificity of 86% to 99% [9]. All scanners appear to perform less well on the circumflex artery [24], perhaps because this vessel is relatively small, its anatomy varies considerably, it frequently changes direction and it is subject to artefacts produced by contraction of the left auricle

Fig. 6. What role could CT coronary angiography and the calcium score play in the screening of diabetic coronaropathy?

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at the end of diastole [9]. The main limitations are the result of movement artefacts and calcifications [18,24]. Bypass imaging is less sensitive to heart movement than are normal coronary arteries except for distal anastomoses. Also, the 16-slice scanner can analyze coronary arteries as small as 1.5–2 mm in diameter. Lesions in smaller arteries are not taken into account as they are frequently seen in diabetics and can have a clinical effect but they cannot be treated by revascularization. 7. Experimental results Mollet et al. [25] evaluated the performance of a 16-slice MSCT in a study of 51 patients who had atypical chest pain or stable coronary disease. Excluded were patients with acute coronary syndrome and those with a coronary bypass or angioplasty. Scanner sensitivity was 96% and specificity was 98%, while the positive predictive value was 87% and the negative predictive value, 99%. All patients whose coronary angiography were normal or showed insignificant lesions — 19/51 patients — were correctly identified by CT coronary angiography. The excellent negative predictive value ensured that the scanner data were included when deciding which patients should benefit from conventional X-ray coronary angiography. The false negatives produced by CT coronary angiography involved the circumflex and right coronary arteries, whereas no significant lesions in the left or left anterior descending coronary arteries escaped detection. Most of the false positives produced by CT coronary angiography were due to coronary calcifications. Kuettner et al. [26] studied the quality of the images obtained from 936 artery segments in 72 patients (13 per patient). The quality was excellent for 35.3% of the patients, good for 34% and mediocre for 16.9%. Major calcifications that obscured the lumen of the vessel were found in 6.7%, while 6.6% of the vessels were not accessible for analysis. Here again, the undetected lesions were in the distal segments and lateral branches. Performance was improved if the analysis excluded segments of the diagonal and marginal arteries and patients who had a high calcification score or a heart rate greater than 70 bpm. This improvement was similar in men and women: diagnoses were correct for 90.5% of men and 90% of women. The main cause of poor image quality from the 64-slice scanner was coronary calcification, resulting in eight false negatives and 24 false positives. Motion artefacts also occurred, but these were rare: only 47 of the 51 segments affected by motion artefacts resulted in moderate reductions in image quality. These artefacts were more likely if the heart rate was rapid, leading to false negatives particularly with the right coronary and circumflex arteries. ECG-pulsing was not used in this study as it prevents the prediastolic examination that is often needed to analyze the right coronary artery. The results were remarkable, with a sensitivity of 94%, specificity of 97%, a positive predictive value of 87% and a negative predictive value of 99%. All vessels with a diameter over 1.5 mm were analyzed and none was excluded. The 4-slice scanner detected stenoses with a sensitivity of 58 to 86%, but up to 32% of arterial segments could not be

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analyzed. The sensitivity of the 16-detector scanners was 73 to 95%, depending on the size of the artery and criteria used to select the patients. But, sometimes, only vessels over 2 mm in diameter could be analyzed [27]. The Raff et al. [8] study analyzed the performance of a 64slice scanner on 70 patients with suspected coronary disease. Of the 1065 segments examined, 935 (88%) could be analyzed. Of these, 83% were analyzed quantitatively and 17% qualitatively. Thus, 279 of the 280 arteries (99%) were assessable. Scanner performance decreased as the calcification score, BMI and heart rate increased. 8. Cost Cost is a major factor in the detection of coronary disease and CT coronary angiography, costing 140 euros, is well-placed [28]. A stress test costs 80 euros, a stress ultrasound test (generally the same as a transthoracic ultrasound) costs 100 euros, while myocardial scintigraphy costs 300–700 euros if a second injection is required after a positive result. Conventional X-ray coronary angiography costs 300 euros. 9. The place of CT coronary angiography today Recently published recommendations [14] emphasize the negative predictive value of CT coronary angiography — it is most reliable for excluding coronary disease. The authors suggest that it be used for patients who are at intermediate cardiovascular risk and for whom non-invasive tests would not conclusively exclude coronary disease. The new scanners also appear to be suitable for the follow-up of coronary bypass patients. However, it is not recommended as a first-line technique for detecting atherosclerotic disorders in asymptomatic patients or for monitoring stents. 10. Conclusion Coronary disease is frequent and severe in diabetic patients, even young ones. Yet, in practice, it is still difficult to diagnose this serious complication, in part because of the limitations of the tests that are currently available. New techniques such as angiographic scanning can simplify exploration and avoid unnecessary diagnostic angiocardiography. However, conventional X-ray coronary angiography remains the key technique for diagnosing lesions and is essential for angioplasty, useful for treating diabetics and other patients with new stent devices. The main limitations of present-day coronary angioscanners are their spatial resolution, artefacts due to movement or calcifications and the build-up of radiation following repeated examinations. However, advances in techniques and materials will undoubtedly improve scanner performance and the potential of MRI should also be considered. While this technology is unsuitable for visualizing coronary arteries at this time, it will undoubtedly evolve.

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11. Conflicts of Interest The authors declare no conflicts of interest.

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