Rationale and Objectives
The impact of iso-osmolar versus low-osmolar iodinated contrast on diagnostic accuracy for coronary computed tomography angiography (CCTA), against the reference standard of invasive coronary angiography (ICA), has not been determined. We sought to compare in an international multicenter randomized controlled trial the impact of iso-osmolar iodixanol versus low-osmolar iopamidol on diagnostic accuracy, image quality, patient symptoms, and heart rate variability.
Materials and Methods
Adult patients who were clinically referred for ICA were randomly assigned to receive either iodixanol ( n = 133) or iopamidol ( n = 133) with an investigational CCTA. CCTA stenosis and image quality were scored by consensus of independent blinded core laboratory readers. Degree of stenosis by ICA was evaluated using quantitative coronary angiography and used to calculate diagnostic accuracy. Heart rate variability and patient-reported symptom questionnaires were compared between the two groups.
Results
A total of 266 subjects underwent both CCTA and ICA (57 ± 11 years, 58% male). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for detecting coronary artery disease were 86.8%, 93.7%, 84.6%, 94.7%, and 91.7% for iodixanol and 94.7%, 88.4%, 76.6%, 97.7%, and 90.2% for iopamidol, respectively, on a per-patient level. These values were not significantly different between the two groups. There was no significant difference in image quality and heart rate increase or variability. The majority of patients reported symptoms (59.4%), with no differences in the overall or individual rate of any or moderate to severe symptoms between the two groups. Patients receiving iodixanol reported lower incidence of moderate to severe flushing (3.0% vs. 12.8%, P = .005). Lower rates of moderate to severe symptoms were particularly evident for patients with ≥55 years receiving iodixanol versus iopamidol (8.5% vs. 24.6%, P = .01).
Conclusions
Diagnostic performance and image quality were similar for CCTA performed with iso-osmolar versus low-osmolar iodinated contrast. Indices of patient comfort were improved with iso-osmolar iodinated contrast.
Introduction
Coronary computed tomography angiography (CCTA) is increasingly utilized to examine patients with suspected coronary artery disease (CAD) because of its high diagnostic performance to identify and exclude obstructive stenoses . Nevertheless, the diagnostic performance of CCTA is related to factors such as heart rate , and medications such as beta-blockers which are typically employed to lower the heart rate to minimize motion artifact and optimize image quality . The administration of iodinated contrast agents often evokes adverse symptoms and may cause a transient increase in heart rate in a manner related to the agent osmolality .
Iso-osmolar contrast agents are theoretically advantageous to older low-osmolar contrast agents for computed tomography (CT) scanning because of decreased renal toxicity among susceptible patients . Although prior studies have compared the impact of iodixanol, a nonionic iso-osmolar contrast agent, to iopamidol, a nonionic low-osmolar contrast agent for contrast attenuation, patient discomfort, contrast-induced nephropathy, and heart rate variability, the effect of contrast osmolality on the most clinically relevant aspects of diagnostic accuracy and image quality have not been determined . To date, there is a lack of direct comparative data between these agents with regard to diagnostic performance of CAD detection, symptoms, and heart rate response among patients undergoing CCTA and receiving rate-control medications.
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Materials and Methods
Patients
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CCTA Performance
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CCTA Interpretation
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ICA Interpretation
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Statistical Analyses
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Results
Study Population
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Table 1
Baseline Patient Characteristics
Iodixanol Iopamidol_P_ Value Age (years) 57.2 ± 11.7 56.2 ± 10.9 0.48 Male gender 70 (52.6%) 83 (62.4%) 0.11 BMI (kg/m 2 ) 28.0 ± 5.5 28.5 ± 5.9 0.48 Diabetes 46 (34.6%) 60 (45.1%) 0.08 Hypertension 95 (71.4%) 96 (72.2%) 0.89 Hyperlipidemia 61 (46.6%) 73 (55.7%) 0.14 Current smoking 23 (17.3%) 26 (19.7%) 0.61 Family history 15 (11.4%) 27 (20.8%) 0.04 Race 0.86 South Asian 76 (57.1%) 67 (50.4%) Arab 18 (13.5%) 22 (16.5%) Hispanic 16 (12.0%) 17 (12.8%) Caucasian 11 (8.3%) 14 (10.5%) East Asian 12 (9.0%) 12 (9.0%) Black 0 1 (0.8%) Serum creatinine (mg/dL) 0.95 ± 0.22 0.97 ± 0.23 0.85 Beta-blockers use prior scan 123 (92.5%) 119 (89.5%) 0.39
Percent or mean with standard deviation provided. BMI, body mass index.
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Diagnostic Performance and Image Quality
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Table 2
Diagnostic Performance for Obstructive CAD Detection
Iodixanol Iopamidol_P_ Value Per-patient diagnostic accuracy ( n = 133, 133) Sensitivity (95% CI) 86.8% (71.9–95.6%) 94.7% (82.3–99.4%) 0.23 Specificity (95% CI) 93.7% (86.8–97.6%) 88.4% (80.2–94.1%) 0.20 PPV (95% CI) 84.6% (69.5–94.1%) 76.6% (62.0–87.7%) 0.35 NPV (95% CI) 94.7% (88.0–98.3%) 97.7% (91.9–99.7%) 0.30 Accuracy (95% CI) 91.7% (85.7–95.8%) 90.2% (83.9–94.7%) 0.67 Per-artery combined diagnostic accuracy ( n = 395, 398) Sensitivity (95% CI) 81.3% (67.4–91.1%) 91.8% (80.4–97.7%) 0.13 Specificity (95% CI) 97.1% (94.8–98.6%) 95.7% (93.0–97.6%) 0.32 PPV (95% CI) 79.6% (65.7–89.8%) 75.0% (62.1–85.3%) 0.57 NPV (95% CI) 97.4% (95.1–98.8%) 98.8% (97.0–99.7%) 0.18 Accuracy (95% CI) 95.2% (92.6–97.1%) 95.2% (92.6–97.1%) 1.00 Per-LAD artery diagnostic accuracy ( n = 133, 133) Sensitivity (95% CI) 77.3% (54.6–92.2%) 90.5% (69.6–98.8%) 0.24 Specificity (95% CI) 97.3% (92.3–99.4%) 94.6% (88.7–98.0%) 0.31 PPV (95% CI) 85.0% (62.1–96.8%) 76.0% (54.9–90.6%) 0.45 NPV (95% CI) 95.6% (90.0–98.5%) 98.1% (93.5–99.8%) 0.29 Accuracy (95% CI) 94.0% (88.5–97.4%) 94.0% (88.5–97.4%) 1.00 Per-LCX artery diagnostic accuracy ( n = 133, 133) Sensitivity (95% CI) 77.8% (40.0–97.2%) 83.3% (51.6–97.9%) 0.75 Specificity (95% CI) 96.8% (91.9–99.1%) 95.9% (90.6–98.6%) 0.71 PPV (95% CI) 63.6% (30.8–89.1%) 66.7% (38.4–88.2%) 0.87 NPV (95% CI) 98.4% (94.2–99.8%) 98.3% (94.0–99.8%) 0.95 Accuracy (95% CI) 95.5% (90.4–98.3%) 94.7% (89.5–97.9%) 0.76 Per-RCA artery diagnostic accuracy ( n = 129, 132) Sensitivity (95% CI) 88.2% (63.6–98.5%) 100% (79.4–100%) 0.16 Specificity (95% CI) 97.3% (92.4–99.4%) 96.6% (91.4–99.1%) 0.76 PPV (95% CI) 83.3% (58.6–96.4%) 80.0% (56.3–94.3%) 0.79 NPV (95% CI) 98.2% (93.6–99.8%) 100% (96.8–100%) 0.15 Accuracy (95% CI) 96.1% (91.2–98.7%) 97.0% (92.4–99.2%) 0.69 Per-segment diagnostic accuracy ( n = 1715, 1769) Sensitivity (95% CI) 76.7% (64.0–86.6%) 83.9% (72.3–92.0%) 0.32 Specificity (95% CI) 99.3% (98.8–99.7%) 98.7% (98.1–99.2%) 0.08 PPV (95% CI) 80.7% (68.1–90.0%) 70.3% (58.5–80.3%) 0.17 NPV (95% CI) 99.2% (98.6–99.5%) 99.4% (98.9–99.7%) 0.49 Accuracy (95% CI) 98.5% (97.9–99.1%) 98.2% (97.5–98.8%) 0.49
CI, confidence interval; NPV, negative predictive value; PPV, positive predictive value; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery. P value is two-sample test of proportions. The 95% CI are exact binomial CIs.
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Patient Symptoms
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Table 3
Patient-Reported Symptoms
Iodixanol Iopamidol_P_ Value Overall symptoms Overall score 1.8 ± 2.6 2.3 ± 3.5 0.86 Any 79 (59.4%) 79 (59.4%) 1.00 Moderate or severe 21 (15.8%) 30 (22.6%) 0.16 Flushing Score 0.5 ± 1.5 0.9 ± 1.9 0.16 Any 28 (21.1%) 36 (27.1%) 0.25 Moderate or severe 4 (3.0%) 17 (12.8%) 0.005 Discomfort Score 0.4 ± 1.2 0.6 ± 1.4 0.39 Any 21 (15.8%) 26 (19.6%) 0.42 Moderate or severe 7 (5.3%) 11 (8.3%) 0.33 Chest pain Score 0.4 ± 1.3 0.3 ± 1.1 0.85 Any 19 (14.3%) 18 (13.5%) 0.86 Moderate or severe 5 (3.8%) 5 (3.8%) 1.00 Nausea or vomiting Score 0.3 ± 1.2 0.2 ± 0.7 0.98 Any 11 (8.3%) 11 (8.3%) 1.00 Moderate or severe 3 (2.3%) 2 (1.5%) 1.00 Headache Score 0.2 ± 0.8 0.1 ± 0.5 0.87 Any 11 (8.3%) 12 (9.0%) 0.83 Moderate or severe 2 (1.5%) 0 0.50 Itching Score 0.02 ± 0.26 0.03 ± 0.24 0.57 Any 1 (0.8%) 2 (1.5%) 1.00 Moderate or severe 0 0 – Muscular pain Score 0.01 ± 0.09 0.03 ± 0.35 1.00 Any 1 (0.8%) 1 (0.8%) 1.00 Moderate or severe 0 1 (0.8%) 1.00 Arm pain Score 0.05 ± 0.45 0.06 ± 0.30 0.31 Any 3 (2.3%) 6 (4.5%) 0.50 Moderate or severe 1 (0.8%) 0 1.00 Dyspnea or wheezing Score 0 0 – Any 0 0 – Moderate or severe 0 0 –
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Table 4
Patient-Reported Symptoms by Gender
Male ( n = 153) Iodixanol ( N = 70) Iopamidol ( N = 83)P Value Female ( n = 113) Iodixanol ( N = 63) Iopamidol ( N = 50)P Value Overall symptoms Overall symptoms Symptom score 1.4 ± 2.2 2.3 ± 3.7 0.27 Symptom score 2.4 ± 3.0 2.2 ± 3.0 0.50 Any 32 (45.7%) 45 (54.2%) 0.30 Any 43 (68.3%) 31 (62.0%) 0.49 Moderate or severe 8 (11.4%) 17 (20.5%) 0.13 Moderate or severe 12 (19.1%) 10 (20.0%) 0.90 Flushing Flushing Overall score 0.4 ± 1.4 1.2 ± 2.2 0.02 Overall score 0.7 ± 1.7 0.5 ± 1.3 0.45 Any 13 (18.6%) 27 (32.5%) 0.05 Any 15 (23.8%) 9 (18.0%) 0.45 Moderate or severe 2 (2.9%) 14 (16.9%) 0.006 Moderate or severe 2 (3.2%) 3 (6.0%) 0.65 Discomfort Discomfort Overall score 0.3 ± 1.0 0.6 ± 1.3 0.13 Overall score 0.6 ± 1.3 0.6 ± 1.7 0.80 Any 8(11.4%) 17 (20.5%) 0.13 Any 13 (20.6%) 9 (18.0%) 0.73 Moderate or severe 2 (2.9%) 6 (7.2%) 0.29 Moderate or severe 5 (7.9%) 5 (10.0%) 0.75 Chest pain Chest pain Overall score 0.3 ± 1.0 0.2 ± 0.9 0.90 Overall score 0.5 ± 1.5 0.6 ± 1.4 0.83 Any 7 (10.0%) 8 (9.6%) 0.94 Any 12 (19.1%) 10 (20.0%) 0.90 Moderate or severe 3 (4.3%) 2 (2.4%) 0.66 Moderate or severe 2 (3.2%) 3 (6.0%) 0.65 Nausea or vomiting Nausea or vomiting Overall score 0.2 ± 1.2 0.2 ± 0.6 0.76 Overall score 0.3 ± 1.1 0.2 ± 0.9 0.77 Any 5 (7.1%) 7 (8.4%) 1.00 Any 6 (9.5%) 4 (8.0%) 0.78 Moderate or severe 1 (1.4%) 1 (1.2%) 1.00 Moderate or severe 2 (3.2%) 1 (2.0%) 1.00 Headache Headache Overall score 0.1 ± 0.5 0.1 ± 0.3 0.99 Overall score 0.3 ± 1.0 0.3 ± 0.7 0.66 Any 4 (5.7%) 5 (6.0%) 1.00 Any 7 (11.1%) 7 (14.0%) 0.64 Moderate or severe 0 0 – Moderate or severe 2 (3.2%) 0 (0%) 0.50 Itching Itching Overall score 0.04 ± 0.4 0.02 ± 0.2 0.90 Overall score 0 ± 0 0.04 ± 0.3 0.26 Any 1 (1.4%) 1 (1.2%) 1.00 Any 0 (0%) 1 (2.0%) 0.44 Moderate or severe 0 0 – Moderate or severe 0 0 – Muscular pain Muscular pain Overall score 0 ± 0 0.05 ± 0.4 0.36 Overall score 0.02 ± 0.1 0 ± 0 0.37 Any 0 (0%) 1 (1.2%) 1.00 Any 1 (1.6%) 0 (0%) 1.00 Moderate or severe 0 (0%) 1 (1.2%) 1.00 Moderate or severe 0 0 – Arm pain Arm pain Overall score 0 ± 0 0.1 ± 0.4 0.02 Overall score 0.1 ± 0.7 0 ± 0 0.12 Any 0 6 (7.2%) 0.03 Any 3 (4.8%) 0 (0%) 0.25 Moderate or severe 0 0 – Moderate or severe 1 (1.6%) 0 (0%) 1.00 Dyspnea or wheezing Dyspnea or wheezing Overall score 0 0 – Overall score 0 0 – Any 0 0 – Any 0 0 – Moderate or severe 0 0 – Moderate or severe 0 0 –
Table 5
Patient-Reported Symptoms by Age
Age ≥55 years ( n = 154) Iodixanol ( N = 78) Iopamidol ( N = 76)P Value Age <55 years ( n = 112) Iodixanol ( N = 55) Iopamidol ( N = 57)P Value Overall symptoms Overall symptoms Symptom score 1.3 ± 2.0 2.5 ± 3.8 0.11 Overall symptom score 2.7 ± 3.1 2.0 ± 3.0 0.09 Any 36 (46.2%) 44 (57.9%) 0.15 Any 39 (70.9%) 32 (56.1%) 0.11 Moderate or severe 6 (7.7%) 17 (22.4%) 0.01 Moderate or severe 14 (25.5%) 10 (17.5%) 0.31 Flushing Flushing Overall score 0.4 ± 1.3 1.1 ± 2.2 0.02 Overall score 0.7 ± 1.8 0.6 ± 1.5 0.54 Any 13 (16.7%) 24 (31.6%) 0.03 Any 15 (27.3%) 12 (21.1%) 0.44 Moderate or severe 1 (1.3%) 11 (14.5%) 0.002 Moderate or severe 3 (5.5%) 6 (10.5%) 0.49 Discomfort Discomfort Overall score 0.4 ± 1.0 0.6 ± 1.4 0.43 Overall score 0.5 ± 1.3 0.6 ± 1.4 0.71 Any 12 (15.4%) 15 (19.7%) 0.48 Any 9 (16.4%) 11 (19.3%) 0.69 Moderate or severe 3 (3.9%) 8 (10.5%) 0.13 Moderate or severe 4 (7.3%) 3 (5.3%) 0.71 Chest pain Chest pain Overall score 0.2 ± 0.6 0.3 ± 1.2 0.55 Overall score 0.7 ± 1.8 0.4 ± 1.1 0.39 Any 7 (9.0%) 9 (11.8%) 0.56 Any 12 (21.8%) 9 (15.8%) 0.41 Moderate or severe 1 (1.3%) 3 (4.0%) 0.36 Moderate or severe 4 (7.3%) 2 (3.5%) 0.43 Nausea or vomiting Nausea or vomiting Overall score 0.1 ± 0.4 0.2 ± 0.7 0.08 Overall score 0.6 ± 1.7 0.2 ± 0.8 0.12 Any 2 (2.6%) 7 (9.22%) 0.10 Any 9 (16.4%) 4 (7.0%) 0.15 Moderate or severe 0 (0%) 1 (1.3%) 0.49 Moderate or severe 3 (5.5%) 1 (1.8%) 0.36 Headache Headache Overall score 0.2 ± 0.8 0.1 ± 0.5 0.97 Overall score 0.2 ± 0.8 0.2 ± 0.5 0.87 Any 6 (7.7%) 6 (7.9%) 0.96 Any 5 (9.1%) 6 (10.5%) 1.00 Moderate or severe 1 (1.3%) 0 (0%) 1.00 Moderate or severe 1 (1.8%) 0 (0%) 0.49 Itching Itching Overall score 0.04 ± 0.3 0.05 ± 0.3 0.56 Overall score 0 0 – Any 1 (1.3%) 2 (2.6%) 0.62 Any 0 0 – Moderate or severe 0 0 – Moderate or severe 0 0 – Muscular pain Muscular pain Overall score 0.01 ± 0.1 0.05 ± 0.5 0.98 Overall score 0 0 – Any 1 (1.3%) 1 (1.3%) 1.00 Any 0 0 – Moderate or severe 0 (0%) 1 (1.3%) 0.49 Moderate or severe 0 0 – Arm pain Arm pain Overall score 0.1 ± 0.6 0.04 ± 0.2 0.99 Overall score 0 ± 0 0.1 ± 0.4 0.09 Any 3 (3.9%) 3 (4.0%) 1.00 Any 0 (0%) 3 (5.3%) 0.24 Moderate or severe 1 (1.3%) 0 (0%) 1.00 Moderate 0 0 – Dyspnea or wheezing Dyspnea or wheezing Overall score 0 0 – Overall score 0 0 – Any 0 0 – Any 0 0 – Moderate or severe 0 0 – Moderate or severe 0 0 –
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Heart Rate and Heart Rate Variability
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Discussion
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Conclusion
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Acknowledgments
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