Randomized, Double-Blind Study Comparing Patient Comfort and Safety Between Iodixanol 320 mg I/mL and Iopamidol 370 mg I/mL in Patients Undergoing Peripheral Arteriography – The COMFORT II Trial

Abstract: Background. Numerous clinical trials conducted 10-20 years ago evaluated contrast-induced discomfort. It is unknown whether those data are applicable to current-day clinical practice. This study was performed to provide contemporary contrast-induced patient discomfort data obtained during peripheral arteriography procedures using iso-osmolar iodixanol 320 mg I/mL, compared to low-osmolar iopamidol 370 mg I/mL. Methods and Results. Patients receiving iodixanol or iopamidol reported discomfort (heat, coldness, or pain) using a 10-point scale, which was converted to intensity categories: 0 = none; 1–3 = mild; 4–7 = moderate; and 8–10 = severe. Image diagnostic quality was assessed. Patients receiving iodixanol (n = 127; 61% male; mean age, 64 years) had less moderate/severe discomfort (67.7% vs 84.0%; P=.01) than those receiving iopamidol (n = 126; 64% male; mean age, 62 years), with pain contributing predominantly (7.3% vs 44.0%; P<.001) for all injection scores. Patients receiving iodixanol experienced less severe discomfort (16.9% vs 46.4%; P<.001), heat (15.3% vs 36.8%; P<.001), and pain (2.4% vs 23.2%; P<.001) for all injections, compared with patients receiving iopamidol. Image quality was rated as excellent in most patients (iodixanol 86.5% vs iopamidol 82.4%; P=.57). Treatment-emergent adverse events were similar between groups (iodixanol 18.9% vs iopamidol 11.9%; P=.16). Conclusions. Iodixanol injections induced significantly less moderate/severe and severe patient discomfort, heat, or pain than iopamidol, with pain contributing the most. Discomfort did not affect image quality.

J INVASIVE CARDIOL 2017;29(1):9-15

Key words: imaging, contrast media, intraarterial

Peripheral arteriography has been widely used for diagnostic and interventional vascular procedures for decades. When patients are administered iodinated contrast media (CM), they experience discomfort – mainly pain, heat, and/or coldness. It is believed that contrast-induced discomfort may cause patients to move, leading to image artifacts and compromised quality of the arteriograms. Contrast osmolality is thought to be responsible for injection-associated discomfort,^1-4 with patient tolerance inversely related to osmolality.⁵ These discomforts should therefore be considered when selecting the appropriate CM for the patient. Numerous clinical trials conducted 10-20 years ago evaluated contrast-induced discomfort and demonstrated that when patients received iso-osmolar contrast media, they experienced significantly lower incidence and intensity of discomfort compared with patients who received low osmolar contrast media.^6-26 It is unknown whether these results from 10-20 years ago are still applicable to current-day clinical practice. In the past, an average volume of contrast media of 182 mL (range, 155-265 mL) was reported for cardioangiography procedures.¹⁴ Improved technology has resulted in less contrast volume usage, and patients are receiving hydration, which is well accepted as a measure to reduce contrast-induced adverse events. We therefore conducted the present study to provide contemporary contrast-induced patient discomfort data obtained during peripheral arteriography procedures using iodixanol 320 mg I/mL, an iso-osmolar contrast media (osmolality, 290 mOsm/kg H₂O), compared with iopamidol 370 mg I/mL, a low osmolar contrast media (osmolality, 796 mOsm/kg H₂O).

Methods

Financial support and contrast media for the study were provided by GE Healthcare. Non-GE consultant authors had control of the data and all information submitted for publication. The study was conducted in accordance with the Declaration of Helsinki; the Good Clinical Practice Consolidated Guideline, approved by the International Conference on Harmonization; and applicable national and local laws and regulations. Local institutional review boards or ethics committees approved the study protocol before initiation. Informed consent was obtained from all individual participants included in the study. 

This was a phase 4, prospective, multicenter, randomized (1:1), double-blind, parallel group, comparative study of iodixanol 320 mg I/mL (Visipaque; GE Healthcare) and iopamidol 370 mg I/mL (Isovue; Bracco Diagnostics) in patients undergoing upper-extremity, lower-extremity, or carotid peripheral arteriography. Patients were randomly assigned to CM treatment according to a randomization scheme predetermined by the study sponsor, sealed in individual envelopes. Randomization was performed in blocks of four (two iodixanol and two iopamidol). Procedures were performed in accordance with the country-specific CM package insert instructions, and followed each study site’s routine procedural protocols. Study personnel and patients were blinded to the CM administered.

Eligible patients were over 18 years old, were referred to undergo a peripheral arteriography as part of their routine clinical care, and consented to participate. The following patients were excluded: those with known allergies to iodine or history of adverse reaction to iodinated CM; pregnant or lactating patients; those taking metformin; patients who had received CM 24 hours prior to baseline, or were scheduled to receive CM within 24 hours after completion of the study; those with thyrotoxicosis or on dialysis; or patients with unstable clinical conditions, which may have compromised participation.

The primary endpoint was the comparison of patients with moderate/severe maximum-intensity composite score of patient discomfort between the two CMs, as rated verbally by the patient within 10 minutes of contrast administration. Following each injection, the patient was asked to separately rate the sensations of cold, heat, and pain associated with the injection on a scale of 0 to 10, using a pain assessment tool.²⁷Discomfort was defined as the maximum score in any of the three types (cold, heat, or pain). The numerical score was converted to one of four intensity categories: 0 = none; 1-3 = mild; 4-7 = moderate; and 8-10 = severe. Multiple injections were possible during each procedure; all included a diagnostic phase, and some included an intervention phase. For each phase, discomfort scores were reported in three classifications: average discomfort score of all injections, discomfort score for the initial injection only, and the composite score for all but the initial injection.

Subgroup analyses were performed to assess impact on maximum patient discomfort scores: gender, age (<65 or ≥65 years), history of contrast administration, renal insufficiency, diabetes mellitus, congestive heart failure, severe cardiovascular disease, use of non-steroidal antiinflammatory drugs, previous allergic reactions to iodinated contrast, history of atherosclerotic peripheral vascular disease, history of connective tissue disease, and use of sedation medication. A logistic regression analysis was performed post hoc to evaluate these risk factors as independent variables.

Additional objectives of the study included comparing the frequency and severity of patients’ motion affecting the diagnostic quality of the images. Images were assessed for diagnostic quality on-site immediately after completion of the angiogram by experienced (5-28 years), independent investigators or radiologists blinded to the CM administered. Overall image quality was graded on a 3-point scale, based solely on the presence or absence of motion artifacts; excellent (no motion), adequate (mild motion, but image was of diagnostic quality), or poor (severe motion artifacts that degraded diagnostic confidence sufficiently to recommend repeating the procedure). Incidence of adverse events and serious adverse events within 24 hours of CM administration were compared. 

Statistical analysis. Statistical analyses were performed using Statistical Analysis Software SAS version 9.2 (SAS Institute). Continuous parameters were summarized using descriptive statistics (number, mean, median, standard deviation, minimum and maximum value, and 95% confidence interval [95% CI]), whereas categorical parameters were summarized with counts and percentages. The results of the logistic regression analysis reported odds ratio (OR), 95% CI, and P-value. Sample size determination was based on six previous trials comparing iodixanol with another CM.^6-11 With moderate and severe discomfort categories combined, the weighted mean across these studies was 30% for iodixanol and 56% for the comparators. Assuming 80% power, a .05 significance level, and a 2-sided test, 140 evaluable patients were required to detect a significant difference. A maximum sample size of 250 was selected to ensure the study was not underpowered. An interim analysis was planned once 150 patients had been enrolled, to determine whether an adjustment to the sample size was required. When the analysis results were available, 205 patients had been enrolled. Although the results indicated that the study had met its endpoint, the data monitoring committee supported proceeding to the full enrollment target, stating that doing so would add credibility to the study, and would allow greater power for evaluating the secondary endpoints. Populations analyzed included: (1) the safety analysis set (patients enrolled in the study who received either CM); (2) the full analysis set (patients in the safety analysis set who had images available and on-site image quality assessment was recorded); and (3) the per-protocol population (patients in the full analysis set who had an evaluable discomfort score for the first CM injection during the diagnostic phase, and had no major protocol violations). 

Results

The study was conducted in 13 hospitals and outpatient centers in the United States, United Kingdom, Germany, and Spain between November 1, 2011 and February 6, 2013. Patient disposition is shown in Figure 1. Baseline patient demographics are shown in Table 1. The patients were predominantly male (63%), and most had been administered CM previously. One individual reentered the study under a new subject number. This patient’s discomfort rating data were excluded from the analysis.

Details of contrast administration are summarized in Table 2. The volume administered varied widely, because multiple injections were possible. Because approximately one-third of patients had intervention comfort scores available, results reporting will focus on the diagnostic phase. 

The vast majority of patients (98.4%) did not report cold sensations, and therefore, this discomfort variable is not included in tables and figures. 

The percentage of patients who experienced moderate/severe discomfort, heat, or pain during the diagnostic phase is shown in Figure 2. Patients who received iodixanol had significantly less moderate/severe discomfort (67.7% vs 84.0%; P=.01) than those who received iopamidol, with pain contributing predominantly (7.3% vs 44.0%; P<.001) for all CM injection scores. For initial injections, patients receiving iodixanol had significantly less moderate/severe discomfort (42.7% vs 73.6%; P<.001), heat (38.7 vs 65.6%; P<.001), and pain (4.0% vs 16.8%; P=.01) than patients receiving iopamidol. 

The percentage of patients who experienced severe discomfort, heat, or pain during the diagnostic phase is shown in Figure 3. Patients receiving iodixanol experienced significantly less severe discomfort (16.9% vs 46.4%; P<.001), heat (15.3% vs 36.8%; P<.001), and pain (2.4% vs 23.2%; P<.001) for all CM injections, compared with patients who received iopamidol. Differences in severe discomfort were not observed for the initial injection. For both the moderate/severe and severe discomfort analyses, findings for the per-protocol population were similar to those for the safety population (data not shown).

When discomfort scores were averaged, iodixanol patients had significantly lower scores than iopamidol patients in the diagnostic phase for the initial injection (2.8 vs 5.1; P<.001) and the composite score (3.4 vs 7.1; P<.001). 

The exploratory multivariate logistic regression analysis of moderate/severe patient discomfort showed contrast administration was a significant independent predictor; the iodixanol group showed less discomfort than the iopamidol group for all CM injections (67.7% vs 84.0%; OR, 0.29; 95% CI, 0.14-0.59; P<.001), the initial injection (42.7% vs 73.6%; OR, 0.22; 95% CI, 0.12-0.39; P<.001), and composite score excluding the initial injection (61.7% vs 78.0%; OR, 0.37; 95% CI, 0.20-0.70; P=.01) during the diagnostic phase. Male gender and use of sedative medication were also independent predictors, contributing to less moderate/severe discomfort for all three injection scores; presence of diabetes mellitus only contributed to less moderate/severe discomfort for all CM injections and initial injection.

The overall image quality analysis is tabulated in Table 3. Image quality was rated as excellent in the majority of patients, with a slightly higher percentage observed for the iodixanol group (86.5% vs 82.4%; P=.57). A generalized linear model analysis of independent variables demonstrated that total iodine load significantly predicted image quality between contrast groups (P<.001); the other variables did not. No arteriograms had to be repeated in either CM group. Discomfort impacted image quality in very few subjects (3.2% of iodixanol procedures vs 5.6% of iopamidol procedures (P=.34).

Treatment-emergent adverse events excluding discomfort adverse events are summarized in Table 4. A slightly higher but not statistically significant incidence of treatment-emergent adverse events was observed in the iodixanol group (18.9% vs 11.9%; P=.16). When treatment-emergent adverse events were broken out by preferred Medical Dictionary for Regulatory Activities term, there was no difference in incidence between CM groups. Four patients (2 in each group) reported serious adverse events, including 1 death in the iopamidol group; none were considered to be related to CM. One related, but not serious adverse event (severe heat and severe pain), led to discontinuation in the iopamidol group.

Discussion

Despite the changes in clinical practice around the usage of iodinated CM from 10-20 years ago,^6-26 this study provides present-day results showing that contrast-induced patient discomfort, especially pain, was significantly less severe for patients receiving the iso-osmolar contrast media iodixanol 320 mg I/mL compared with patients receiving the low-osmolar contrast media iopamidol 370 mg I/mL during peripheral arteriography. The differences in discomfort scores did not lead to statistical differences in image quality. There is a perception that lower iodine load should compromise image quality, but our results did not support this. The introduction of image reconstruction software and improved technology have enabled reductions in both CM dose and radiation dose without compromising image quality.

Our results are consistent with previously published intraarterial studies.^6-26,28 Manke and colleagues assessed patient discomfort in femoral arteriography and found that patients receiving iodixanol reported less injection-associated pain after the first injection than those receiving iomeprol (7.4% vs 17.6%, respectively; P=.01).⁶ Similar results were obtained by Justesen et al comparing iodixanol and iopromide (0.9% vs 9.5%, respectively; P<.001).⁸ Discomfort scores in these older studies were similar to our study, despite differences in mean CM volumes administered; in the older studies, mean volumes administered ranged between 132 mL and 163 mL,^6,8 whereas in our study, the mean volume was 108 mL. The statistical differences in patient discomfort observed in this trial were primarily driven by pain, which is consistent with other results for intraarterial administration. Interestingly, the results differ from those for intravenous administration.^29,30 Patients receiving iodixanol intravenously using power injectors experienced less moderate/severe heat than those receiving iopamidol (29.8% vs 63.9%, respectively; P<.001); however, differences in pain were not statistically significant.³⁰ The difference between the type of discomfort experienced in intraarterial vs intravenous procedures may be due to immediate exposure of peripheral parenchymal tissues to CM administered intraarterially, whereas the CM may be diluted traveling through the venous system, reaching the parenchymal tissues in lower concentrations following intravenous administration.

Study limitations. Our study had some limitations. Adverse event follow-up of only 24 hours may have limited the observance of delayed reactions, such as skin reactions. Image quality assessments may have had less variability had they been read at a centralized facility rather than on-site. Despite the significant differences in incidence and severity of pain between CM, no differences in image quality were observed. If a more rigorous quality assessment method (more than 3-point scale) had been used, better discrimination may have been possible. The observed lack of differences in image quality is likely due to the low incidence of motion artifacts overall, and the study was not powered to test the statistical significance of this difference. It is not feasible to perform a prospective clinical trial powered to measure the effect of CM on image quality, because the low occurrence of motion artifacts would necessitate an extremely large sample size. However, it is reasonable to assume that pain may lead to movement and motion artifacts and, therefore, to poor image quality. Hence, it is prudent to minimize the need to repeat procedures by selecting the CM that is least likely to cause injection-associated pain. 

When injection-associated discomfort was excluded from the safety analysis, no significant differences in adverse events were observed. The safety profile observed in this study is consistent with that seen in routine clinical use.

Conclusion

Iso-osmolar iodixanol injections induced significantly less moderate/severe and severe patient discomfort, heat, or pain than iopamidol in patients undergoing peripheral arteriography procedures, and provided good to excellent image quality. The discomfort experienced was primarily due to pain. The total average discomfort score was lower for patients receiving iodixanol compared with patients receiving iopamidol. These results support the concept that osmolality is a key determinant in CM discomfort, and suggest that iodixanol is a preferable contrast agent to minimize pain and discomfort in patients undergoing peripheral arteriography.

Acknowledgments. The authors wish to thank Debra Mansfield, Clinical Project Manager, employee of GE Healthcare, for her contributions to this study. We also express appreciation to Stacy Simpson Logan, CMPP, funded by GE Healthcare, for her assistance in drafting the manuscript.

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From the ¹University Medicine Greifswald, Department of Radiology, Ernst Moritz Arndt University, Greifswald, Germany; ²Servicio de Radiología, Hospital Universitario y Politécnico La Fe, Valencia, Spain; ³Section Chief of Interventional Radiology, Hospital Universitario Dr. Peset, Valencia, Spain; ⁴Angioradiology Department, Hospital Clinic de Barcelona, Barcelona, Spain; ⁵Medical Affairs, GE Healthcare Life Sciences, Marlborough, Massachusetts; ⁶Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina.

Funding: This study was funded by GE Healthcare, Marlborough, Massachusetts. GE Healthcare participated in the design and conduct of the study, interpretation of the data; and preparation, review, and approval of the manuscript. H2O, funded by GE, contributed biostatical and data management services. The authors had full editorial control of the manuscript and the decision to publish.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rosenberg was principal investigator in his facility. Dr Martínez-Rodrigo reports grants from GE Healthcare during the conduct of the study; grants from Terumo Europe and St. Jude Medical, outside the submitted work. Dr Lim is employed by GE Healthcare. Dr Todoran reports personal fees from GE Healthcare, outside the submitted work. 

Manuscript submitted August 3, 2016, provisional acceptance given August 22, 2016, final version accepted September 19, 2016.

Address for correspondence: Christian Rosenberg, MD, Klinik für Bildgebende Diagnostik und Interventionsradiologie, Evangelisches Waldkrankenhaus Spandau, StadtrandstraBe 555, 13589 Berlin, Germany. Email: Christian.Rosenberg@pgdiakonie.de