Dual-Source CT Angiography for Detection and Quantification of In-Stent Restenosis in the Left Main Coronary Artery: Comparison with Intracoronary Ultrasound and Coronary Angiography

Abstract: Objectives. The aim of this study was to evaluate the diagnostic accuracy of dual-source computed tomography coronary angiography (CTCA) compared to coronary angiography (CAG) and intravascular ultrasound (IVUS) for detection and quantification of in-stent restenosis after left main (LM) coronary artery stenting. Materials and Methods. Fifty-one patients with percutaneous coronary intervention of the LM were prospectively evaluated. Thirty-four of them underwent 56 complete follow-up examinations (CTCA, CAG, and IVUS as gold standard examination) that focused on detection and quantification of restenosis. Results. Sensitivity, specificity, and positive and negative predictive values were 100%, 94%, 50%, and 100% for CAG, respectively, and 100%, 74%, 18%, and 100% for CTCA, respectively. There was a correlation between the minimal luminal areas (MLA) measured by CTCA and IVUS (r = 0.63; P<.01). A Bland-Altman analysis showed that the MLA measured by CTCA was underestimated (mean difference, 2.14 ± 2.24 mm²). Conclusion. Dual-source CTCA has a high negative predictive value and might be considered a less invasive alternative to CAG for exclusion of LM in-stent restenosis. However, there was only a moderate correlation between the MLA measurements by IVUS and CTCA in the stented LMs. Moreover, the present results suggest a systematic underestimation of MLAs measured by CTCA. Therefore, finding of any restenosis according to CTCA should be re-evaluated by CAG or, better, by subsequent IVUS.

J INVASIVE CARDIOL 2011;23(11):460-464

Key words: computed tomography coronary angiography, coronary angiography, intravascular ultrasound

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Percutaneous coronary intervention (PCI) is an alternative to surgical revascularization in a certain subset of patients who have significant stenosis of the left main (LM) coronary artery.^1,2 Although several investigators have reported the safety and feasibility of this procedure, there is still ongoing debate about the most appropriate follow-up strategy in these patients.^3-6 Several investigations have analyzed the diagnostic performance of computed tomography (CT) in assessing stent patency or the presence and severity of in-stent restenosis.^3,5 Therefore, it has been recommended that the majority of them should be scheduled for routine control CT or invasive angiography within 3 to 12 months.¹

Recently, dual-source computed tomography angiography (CTCA) with an improved temporal resolution has provided a new, non-invasive tool for detecting in-stent restenosis. However, the detection and quantification of in-stent restenosis is still difficult and the diagnostic performance of CTCA is still not known. Therefore, in this pilot study, we determined diagnostic accuracy of CTCA for the detection and quantification of in-LM restenosis in a population of consecutive patients treated by LM stenting. Results of CTCA were compared with CAG and IVUS, which was considered the gold standard.

Methods

From January 2008 to November 2010, a total of 51 consecutive patients with stable or unstable angina pectoris and >50% stenosis of the LM were treated by LM PCI. Exclusion criteria included acute myocardial infarction and patients with LM stenosis. Repeat examinations (CTCA, CAG, and IVUS) for all patients were recommended at 3 to 6 months and subsequently 9 to 12 months after the procedure. However, asymptomatic and/or high-risk patients for procedural complications, as well as patients who refused control check-up, did not undergo repeat examinations. Therefore, fifty-six completed follow-up examinations were performed in 34 patients. Written informed consent was obtained from each patient and the local ethics committee approved all study protocols.

All 34 patients included in the study and treated percutaneously received aspirin (100 mg) and clopidogrel (300 mg) before the procedure and 50 to 80 IU/kg intra-arterial bolus of unfractionated heparin at the start of PCI. The ostium of the LM was treated in 7 patients (21%), the body of the LM in 2 patients (6%), and the distal part of the LM in 25 patients (74%). Direct coronary stenting with implantation of only one stent covering the LM and proximal part of the left anterior descending artery (if needed) was the primary technique used in this study.^6,7 Stents with a nominal diameter of 3.5 to 4.5 mm were used (Figures 1 and 2). High-pressure balloon postdilation or kissing-balloon postdilation were used at the operator’s discretion. The following drug-eluting and bare-metal stents were used: Xience Prime Coronary Stent System (Abbott Vascular), BioMatrix (Biosensors International), FlexMaster F1 coronary stent (Abbott Vascular), and Coroflex Blue (B. Braun). Three bare-metal stents and 31 drug-eluting stents were used. After PCI, aspirin, statins, and other optimal medical treatments were prescribed to all patients. Clopidogrel 75 mg/day was prescribed for 1 month after the implantation of bare-metal stents and for 6 to 12 months after the implantation of drug-eluting stents.

Follow-up CT examinations were performed on a 64-slice dual-source Somatom Definition CT scanner (Siemens Medical Solutions) with 70 to 100 mL of iodixanol (Iomeron, 400 mg/mL; Altana-Bracco) followed by 40 ml saline solution. Two doses of sublingual isosorbide dinitrate spray were used at the start of the examination. For LM evaluation, images were reconstructed with a slice thickness of 0.6 mm and reconstruction increment of 0.3 mm, using a sharp convolution kernel (B46f). AqNET version 1.8.4.5 software (TeraRecon) was used for evaluation and measurements. Identification of minimal lumen was made from longitudinal images of curved planar reconstructions and measurements of minimal luminal area were done manually from images perpendicular to the arterial axis (Figures 3 and 4). Data sets were analyzed by a single, experienced radiologist blinded to the angiographical and clinical data.

CAG was performed one day after CTCA using a 6 Fr guiding catheter. Several angiograms of the left coronary artery were acquired after intracoronary injection of 0.5 mg isosorbide dinitrate. Subsequently, an IVUS catheter was positioned beyond the stent to the left anterior descending artery and slowly withdrawn (0.5 mm/s).⁸ Images were recorded continuously throughout the stent. Area measurements were performed at the minimal luminal area of the LM. Quantitative coronary angiography (Allura Xper; Philips Healthcare) and IVUS (Eagle Eye^® Platinum; Volcano Corporation) measurements were analyzed by an experienced cardiologist blinded to the CTCA results and clinical data. Quantitative analysis was based on the findings showing the most severe narrowing. The CAG reference diameter was calculated by averaging the proximal and distal minimal lumen diameters. The diameter stenosis percentage was calculated by subtracting the reference diameter from the minimal lumen diameter, which was divided by the reference diameter. Binary restenosis was defined as a diameter stenosis ≥50%. Binary restenosis for both IVUS and CTCA was defined as a minimal luminal area (MLA) <6 mm². IVUS examination was considered the gold standard for the LM evaluation.

Continuous variables were expressed as mean ± standard deviation, and categorical variables as counts and percentages. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and the likelihood ratio of CTCA and CAG for the detection of LM restenosis were assessed against IVUS (MLA <6 mm²) as the gold standard. The MLAs of the LM measured by CTCA and IVUS were correlated by means of Bland-Altman analysis and the Pearson correlation coefficient. Receiver-operating-characteristic (ROC) analysis was used to determine the optimal cutoff value for detecting anatomically significant LM restenosis. The area under the ROC curve (AUC) provided a measure of the overall accuracy that was independent of the decision criteria, by plotting true-positive rates against false-positive rates as the cutoff level of the model varies. The optimal cutoff value was defined as the point with the highest sum of sensitivity and specificity. A P-value of <.05 was considered statistically significant. The statistical software Stata 9.2 (StataCorp LP) was used.

Results

A total of 34 patients safely underwent PCI and 56 subsequent complete examinations. Twelve patients underwent only one follow-up examination (3 to 6 months after PCI) while 22 patients had both examinations (3 to 6 and subsequently 9 to 12 months after PCI). The median length between PCI and the follow-up examination was 6 months (mean, 6.9 ± 3 months). Baseline clinical variables of these patients are summarized in Table 1.

All follow-up examinations occurred safely without any complications. All stents were classified as evaluable. Four examinations (7%) were performed in patients with atrial fibrillation. Significant LM restenosis according to IVUS examination was detected in 3 patients (9%) (Table 2); only 1 patient among them suffered from mild angina pectoris, while the other 2 patients with restenosis were asymptomatic. All 3 of these patients were treated by re-PCI. The sensitivity, specificity, predictive values, accuracy, and likelihood ratios of CTCA and CAG for detecting significant restenosis are summarized in Table 3. There was a moderate correlation between the MLAs of stented  LM measured by IVUS and CTCA (r = 0.63; P<.01) (Figure 5). A Bland-Altman analysis showed that the MLA measured by CTCA was underestimated (mean difference, 2.14 ± 2.24 mm²) (Figure 6). There were no differences in the evaluation of the different stents used in this study.

ROC analysis of the MLA derived by CTCA for detecting anatomically significant stenosis (<6 mm²) according to IVUS was performed. The AUC was 0.72 (95% CI, 0.63-0.82) and the best cutoff value was 6.68 mm², with a sensitivity of 50% and a specificity of 87% (Figure 7).

Discussion

The results of the present study have demonstrated that all used methods (CAG, CTCA, IVUS) for follow-up examination in patients with LM stenting are safe and feasible. CAG and CTCA have high negative predictive values and low positive predictive values for the detection of significant LM in-stent restenosis. Therefore, these results suggest that CTCA might be considered a less invasive alternative to CAG for exclusion of LM in-stent restenosis. However, there is only a moderate correlation between the measurements of MLA by IVUS and CTCA. Moreover, the present results have demonstrated a systematic underestimation of the MLA measured by CTCA. Thus, the promising diagnostic performance of CTCA in the detection of significant restenosis was established. However, the potential role of CTCA in the detection of LM bifurcation restenosis after more complex LM interventions is still unclear.

While quantification of in-stent restenosis with 4- to 16-slice CT scanners has had very limited clinical relevance, the recently used 64- to 320-slice single or dual-source scanners allow more accurate stent visualization and restenosis quantification due to increased spatial and temporal resolution.⁹ As these scanners have become widely available in clinical practice, it seems necessary to know whether CTCA has reached the diagnostic accuracy of CAG for detecting and, mainly, accurately quantifying in-stent restenosis.¹⁰ The most common factor that affects assessment of in-stent restenosis is the stent (coronary artery) diameter and it has previously been shown that a better diagnostic performance of CTCA is achieved for stents with diameters ≥3 mm.⁹ Pugliese et al demonstrated 100% sensitivity, specificity, and predictive values with dual-source CTCA for stents with diameters ≥3.5 mm. Furthermore, the rate of unevaluable stents was only 5%.¹¹ Therefore, it seems likely that dual-source CTCA might be a reliable method in the assessment of stents implanted in the LM, because all stents used in this study had diameters ≥3.5 mm and were assessable for CTCA. On the other hand, there are still several patient-related (heart rate and coronary calcification) and stent-related (strut thickness and stent implantation technique) factors influencing visualization of the stent lumen and neointimal hyperplasia,¹² especially the blooming artifacts associated with metal stent components that cause a lowering of the measured luminal area during CTCA. Therefore, the results of this study suggest only a moderate correlation (r = 0.63) between measurements of the MLA measured by IVUS and CTCA and that CTCA systematically underestimates the MLA (mean difference, 2.1 mm²). The systematic underestimation of MLA by CTCA in patients after PCI should be taken into account in clinical practice, because it leads to the lower positive predictive value of CTCA in the evaluation of borderline in-stent lesions.

Although this pilot study was not designed to assess the clinical impact of routine CTCA and invasive follow-up, it seems probable that the incidence of LM in-stent restenosis in the drug-eluting stent era is relatively low. Moreover, recent data published by Biondi-Zoccai et al suggested that routine angiographic follow-up does not provide major clinical benefit and post-LM PCI management can safely be related to the patient’s symptoms as long as a low threshold for control examination is maintained.⁴ Similarly, authors of the French Left Main Taxus Registry recently suggested that a strategy of systematic clinical follow-up with non-invasive testing at 6 to 8 months after PCI and then annually for the first 2 years might replace conventional systematic angiographic controls.⁶ In this pilot study, only 3 patients had significant LM in-stent restenosis; 2 patients were asymptomatic and 1 suffered only from mild angina. Nevertheless, long-term data derived from multicenter and sufficiently powered studies are needed to better appraise optimal post-PCI management in patients with a stent implanted in the LM. 

In spite of promising results of CTCA in the detection and diagnosis of coronary artery disease, this method has the disadvantage of requiring a high radiation dose. Invasive coronary angiography is associated with a mean effective radiation dose ranging from 3 to 9 mSv, while conventional CTCA delivers a dose 2-3 times higher.¹² However, there are a number of strategies that have been taken to reduce the radiation dose and therefore the most modern generation of scanners allow us to perform CTCA acquisition with reduced radiation dose (1-5 mSv) at maintained image quality.¹³

The present study had several limitations. First, all examinations were assessed by only one cardiologist or radiologist. Therefore, inter-observer variability of all measurements was not available. However, it has been documented that inter-observer variability of in-stent quantification with CTCA is very low among experienced cardiologists (radiologists).¹⁴ Second, this study was focused only on detection and quantification of LM in-stent restenosis and possible restenosis in neither the proximal segment of the left anterior descending artery nor the left circumflex artery was assessed. Third, only a moderate inverse correlation between LM minimal luminal area and its hemodynamic or clinical significance was demonstrated in the past.^15-18 However, Jasti et al described a high agreement between LM minimal luminal area ≤5.9 mm² and fractional flow reserve ≤0.75 (IVUS sensitivity and specificity, 93% and 98%, respectively).¹⁷ Therefore, MLA of LM stenosis <6 mm² and diameter of stenosis >50% seem to be a widely accepted threshold for hemodynamically significant stenosis that should be revascularized. Moreover, the MLA derived by CTCA seemed to be simpler and superior to the percentage area stenosis of the lesion for identifying inducible perfusion defects.¹⁹

Conclusion

These results suggested that dual-source CTCA has a high negative predictive value and may provide a valuable tool for follow-up of patients after LM stenting. However, there was only a moderate correlation between the measurements of MLAs by IVUS and CTCA in the stented LMs. Moreover, the present results suggest a systematic underestimation of MLAs measured by CTCA. Therefore, the finding of any restenosis according to CTCA should be re-evaluated by CAG or, better, by subsequent IVUS. Results of this pilot study need to be confirmed by more prospective, multi-center, and long-term data.

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From the Department of Cardiology, CardioVascular Center, University Hospital Motol, 2nd Medical School, Charles University, Prague, Czech Republic.
This study was supported by a grant from the Ministry of Health of the CZ No. 00064203.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted July 6, 2011, provisional acceptance given August 15, 2011, final version accepted September 7, 2011.
Address for correspondence: Prof. Josef Veselka, University Hospital Motol, Dept. of Cardiology, V úvalu 84, Prague 5, 15000, Czech Republic. Email: veselka.josef@seznam.cz