Iomeprol vs Iopamidol in Intraarterial Peripheral Digital Subtraction Angiography D. Dacoronias, M.D.* P. Minguzzi, M.D. * U. Ugolotti, M.D.t and A.G. Dettori, M.D., Ph.D.‡
MILAN and PARMA, ITALY
Abstract The aim of this research was to compare the efficacy and tolerability of iomeprol, 150 mg iodine/mL, a new nonionic contrast medium, and iopamidol, 150 mg iodine/mg in intraarterial (IA) peripheral digital subtraction angiography (DSA) in 100 patients; a group of 40 patients were also submitted to a complete coagulation screening to check the influence of contrast media on blood clotting. The study was a comparative, double-blind clinical trial. The compound was assigned to each patient according to a randomization list. Small size (4-5 French) catheters were used in all patients to minimize arterial trauma and bedding time and to assess the quality of x-ray pictures in this condition. Vital signs, EKG tracings and laboratory parameters were monitored before and after the angiographic procedure; the coagulation screening included: thrombin time, prothrombin time, partial thromboplastin time, euglobulin lysis time, plasma thromboplastin antecedent, and plasminogen activator inhibitor (PAI). Both contrast media did not produce any adverse reaction or clinically significant alteration of studied parameters; in the 40-patient group subjected to massive coagulative screening, no important alteration after contrast media administration was reported. The score for contrastographic efficacy was very good with both media with a prevalence of better results in the iomeprol group.
II Radiology Department and the ‡ V Medicine From the *Medical Department, Bracco Industria Chimica SpA, Milan, and the † Department, Parma Hospital, Parma, Italy Presented to the 37th Annual Meeting, American College of Angiology, Atlanta, Georgia, October, 1990
734 Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
735
Introduction
(CM), synthesized in the Research Laboratories of Bracco Industria Chimica SpA of Milan, Italy. Chemically, the product is N,N’-bis-(2,3-dihydroxy-propyl)-5-[(hydroxyacetyl)-methylamino]-2,4,6-triiodo-1,3-benzendicarboxamide. Contrasting power is supplied by the iodine-trisubstitute benzene ring, water solubility, by the presence of three side chains containing highly hydrophilic groups (Figure 1). Iomeprol is
a new
nonionic, water-soluble
contrast medium
FIG. 1. Chemical structure of
iomeprol.
Because of its physicochemical characteristics the product can be made into aqueous solutions of higher concentration, lower viscosity, and lower osmolality than is the case with nonionic contrast media in current use. Preclinical studies have demonstrated the excellent systemic and local tissue tolerability of the iomeprol molecule and a pattern of pharmacokinetic behavior compatible with a two-compartment model characterized by an apparent volume of distribution matching the extracellular space. Elimination is rapid and is almost exclusively through the renal tract. Iomeprol is not bound to plasma proteins and does not undergo metabolic transformation. Human studies of iomeprol have been conducted in healthy volunteers and in patients. In the phase I study in healthy volunteers iomeprol (aqueous solution, iodine content 400 mg/mL) was administered intravenously in bolus injections of 50, 100, and 200mL vs identical volumes of placebo (physiological saline). The results of comparative measurements in the two treatment groups revealed no difference in terms of hemodynamic or humoral test parameters (liver and kidney function, chemotoxicity markers), indicating very good tolerance. Pharmacokinetic data elicited in the course of that study confirmed the earlier results from preclinical experiments. A pilot clinical study, conducted in patients undergoing urographic examinations, confirmed the excellent tolerability of iomeprol solutions (iodine content 300 mg/mL) in bolus intravenous doses up to 100 mL. It was rapidly eliminated by the renal route and showed excellent contrasting qualities. Five multicenter phase II studies of Iomeprol have been conducted in the clinical areas of urography, computerized axial tomography (CAT), angiocardiography, and conven-
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
736
tional cerebral, visceral, and peripheral angiography. The main purpose of these studies was to assess the tolerability and radiographic quality of intravascular iomeprol prior to the undertaking of comparative studies versus established contrast media. The results of these five multicenter studies, involving a total of 300 patients, showed that iomeprol was well tolerated and effective in intravascular applications. There were no severe or unexpected reactions attributable to iomeprol in any of the contemplated applications. In the proposed phase III clinical trial program the following indications will be studied:
digital arteriography, urography, CAT, phlebography, arthrography, endoscopic retrograde cholengiopancreatography (ERCP), and cardioangiography. The purposes of this study were to compare the tolerability and contrasting effectiveness of iomeprol (iodine content 150 mg/mL) and iopamidol (iodine content 150 mg/mL) in patients needing intraarterial digital subtraction angiography (DSA) of a lower extremity for diagnostic purposes or preoperative assessment. The two contrast agents were assessed in terms of the following parameters: 1. effects of the two compounds on vital signs and laboratory parameters (biochemical and hematologic) 2. subjective tolerability of the two contrast media
conventional and
3. incidence of side effects with the two contrast media 4. radiographic quality.
Patients and Methods The study was conducted on 100 inpatients at the General Parma Hospital needing intraarterial DSA of the lower extremities, for diagnostic purposes and/or preoperative assessment. The study was approved by the Parma Hospital institutional committee. The following patients were excluded from this study by the exclusion criteria: patients scheduled for examinations in emergency conditions, those needing general anesthesia or in clinical conditions likely to preclude cooperation, patients with a history of allergy or hypersensitivity to CM or iodine, pregnant women, patients with multiple myeloma or pheochromocytoma, and patients treated with oral or intravascular CM in the last twenty-four hours before the trial. Each patient had given his/her content to the procedure by filling the form supplied with clinical record forms. Patients received the CM according to a computer-generated random list balanced in blocks of 10, in order to obtain two homogeneous groups of patients : group A iomeprol, group B = iopamidol. Within the three days before the prescribed procedure and for twenty-four hours after its vital signs, EKG tracings, and laboratory parameters were monitored. Patients 21 to 40 and 81 to 100 received a complete coagulation screening including: thrombin time, =
prothrombin time, partial thromboplastin time, blood fibrinogen, euglobulin lysis time, plasma thromboplastin antecedent, and plasminogen activator inhibitor,(PAI) performed on venous blood samples obtained one minute before and at the end of the fast CM injection. During the examination any such symptom as pain or heat sensation was graded for severity by a visual analogue scale as described by Joyce.’ In addition the investigator
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
737
assigned the score for objective evidence of distress as follows: 0 = no evidence of distress ; 1= slight movement and/or vocal complaint; 2 moderate movement and/or com=
plaint ;
3 = forcible movement and/or loud cries.
pictures were examined for technical adequacy by the same two independent radiologists unaware of the contrast medium used. The x-ray pictures graded as technically adequate were graded according to the following scale: 0 = insufficient opacification; 1= sufficient opacification; 2 = good opacification; 3 = excellent opacification. A complete statistical analysis was performed by Braccos’s Biometric Department: patients’ characteristics were evaluated by descriptive statistics. The unpaired t test was used to determine whether there were differences between the baseline values of vital signs and laboratory parameters in the two patient groups; the paired t test was used to compare preprocedure and postprocedure values; nonparametric variables were analyzed with a Mann-Whitney test. All
FIG. 2. Patient characteristics in the two treatment groups.
Results
Figure 2 shows patient characteristics. No significant differences between the two study groups were detected, but a higher mean age was reported in the iomeprol group. In all the procedures pig-tail catheters 4-5 French were used except one in the iopamidol group (Head Hunter 5 French). No significant differences between iomeprol and iomeprol and iopamidol groups were detected in regard to access artery, mean amount of CM used, and total number of injections (Figure 3). Local anesthesia with xylocaine was used in all patients, and premedications with atropine was used in 20 patients in each group. No clinically relevant differences in vital parameters (blood pressure, heart rate) and laboratory findings were shown between the two groups of patients. Two patients (1 iomeprol, 1 iopamidol) reported ventricular extrasystoles after the procedure. The 40 patients submitted to the coagulated screening did not show alterations of studied parameters. Patients’ compliance was very good: subjects referred no pain sensation but a very mild heat sensation at the contrast medium injection. A trend in favor of iomeprol was reported for the warm feeling. No adverse reactions were observed in either group of patients.
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
738
FIG. 3. Clinical data for the two treatment groups.
The contrastographic efficacies of iomeprol and iopamidol are shown in Figure 4. In of disagreement between the two independent radiol-ogists, the lower score was considered. No injection with iomeprol and 8 with iopamidol group were considered insufficient. The x-ray pictures with iopamidol were scored sufficient, good, and excellent, case
FIG. 4. Contrast effectiveness of the two contrast media.
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
739
respectively, in 57, 113, and 68 cases. The iomeprol efficacy was graded cases, good in 151, and excellent in 61.
sufficient in 36
Discussion
The nonionic monomer contrast agents can actually be considered as the gold standard for safety reasons and contrast effectiveness. Their very low incidence of adverse reactions of pain and heat sensation have led most of the world’s radiologists to use and
appreciate them.’-’ of small-size catheters (4-5 French) is appreciated by radiologists because this reduces local complications, patient discomfort, bedding time, and, of course, the total cost of the radiological procedure. (Iopamidol is marketed in the United States; 50 mL of iopamidol costs about $23. Iomeprol is a pre-NDA phase, and hence the commercial price is not available.) Iomeprol showed less patient discomfort and better effectiveness in comparison with iopamidol. As for vital parameters, EKG tracings, laboratory parameters, and side effects, no difference was detected between the two groups of treatment. Data from the coagulation study are in contrast with previous papers,b-8 which have reported a thrombogenic effect due to nonionic CMs. No clinically significant changes in coagulation parameters were reported in our 40 patients. The
use
Conclusions We conclude that both contrast media tested in the present study showed good safety and effectiveness with the small-size catheters (4-5 French). In both group of patients we observed no side effects and obtained good patient compliance and good contrastographic efficacy. A trend in favor of iomeprol could be detected. Neither contrast agent produced any clinically significant alteration in the coagulation study. On this basis we anticipate that the use of small-size catheters and nonionic low-viscosity contrast agents will produce good radiological results with less patient discomfort. Dimitri Dacoronias, M.D. Bracco Industria Chimica Via Folli, 50
20134 Milan, Italy
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
S.p.A.
740
References 1.
Joyce CRB, Zutshi SW, Hoube V, et al: Comparison of fixed Internal and Visual Analogue scales for rating chronic pain. Eur J Pharmacol 8:414-420, 1975. 2. Palmer FJ, et al: The RACR Survey of Intravenous Contrast media Reactions final report. Aust Radiol 32:1988. 3. Katayama H, Yamaguchi K. Kozukat, et al: Adverse reactions to ionic and non-ionic contrast media. Radiology 175, No.3:621-628, June, 1990. 4. Murphy G, Campbell DR, Fraser DB, et al: Pain in peripheral arteriography: An assessment of conventional versus ionic and non-ionic low osmolar contrast agents. J Can Ass Radiol 39:103-106, 1988.
5. Widrich WC, et al: Iopamidol and meglumine diatrizoate : Comparison of effects on patient discomfort during aorto-femoral arteriography Radiology 148:61-64, 1983. 6. Engelhart JA, et al: Aspirated blood and low os-
molarity contrast agents: an embolic hazard? Radiology 165:152-153, 1988. 7. Gasparetti CM, et al: Non-ionic contrast material is associated with thrombus formation during PTCA. Circulation 80:375. Presented at 62nd Scientific Session of The American Heart Association, New Orleans, November 13-16, 1989. 8. Davidson CJ, et al: Thrombotic complications of diagnostic cardiac catherizations with non-ionic contrast. analysis of 7230 patients. Circulation 80 No. 4 11-375, October, 1989. Presented at 62nd Scientific Session of The American Heart Association, New Orleans, November 13-16, 1989.
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
MILAN and PARMA, ITALY
Abstract The aim of this research was to compare the efficacy and tolerability of iomeprol, 150 mg iodine/mL, a new nonionic contrast medium, and iopamidol, 150 mg iodine/mg in intraarterial (IA) peripheral digital subtraction angiography (DSA) in 100 patients; a group of 40 patients were also submitted to a complete coagulation screening to check the influence of contrast media on blood clotting. The study was a comparative, double-blind clinical trial. The compound was assigned to each patient according to a randomization list. Small size (4-5 French) catheters were used in all patients to minimize arterial trauma and bedding time and to assess the quality of x-ray pictures in this condition. Vital signs, EKG tracings and laboratory parameters were monitored before and after the angiographic procedure; the coagulation screening included: thrombin time, prothrombin time, partial thromboplastin time, euglobulin lysis time, plasma thromboplastin antecedent, and plasminogen activator inhibitor (PAI). Both contrast media did not produce any adverse reaction or clinically significant alteration of studied parameters; in the 40-patient group subjected to massive coagulative screening, no important alteration after contrast media administration was reported. The score for contrastographic efficacy was very good with both media with a prevalence of better results in the iomeprol group.
II Radiology Department and the ‡ V Medicine From the *Medical Department, Bracco Industria Chimica SpA, Milan, and the † Department, Parma Hospital, Parma, Italy Presented to the 37th Annual Meeting, American College of Angiology, Atlanta, Georgia, October, 1990
734 Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
735
Introduction
(CM), synthesized in the Research Laboratories of Bracco Industria Chimica SpA of Milan, Italy. Chemically, the product is N,N’-bis-(2,3-dihydroxy-propyl)-5-[(hydroxyacetyl)-methylamino]-2,4,6-triiodo-1,3-benzendicarboxamide. Contrasting power is supplied by the iodine-trisubstitute benzene ring, water solubility, by the presence of three side chains containing highly hydrophilic groups (Figure 1). Iomeprol is
a new
nonionic, water-soluble
contrast medium
FIG. 1. Chemical structure of
iomeprol.
Because of its physicochemical characteristics the product can be made into aqueous solutions of higher concentration, lower viscosity, and lower osmolality than is the case with nonionic contrast media in current use. Preclinical studies have demonstrated the excellent systemic and local tissue tolerability of the iomeprol molecule and a pattern of pharmacokinetic behavior compatible with a two-compartment model characterized by an apparent volume of distribution matching the extracellular space. Elimination is rapid and is almost exclusively through the renal tract. Iomeprol is not bound to plasma proteins and does not undergo metabolic transformation. Human studies of iomeprol have been conducted in healthy volunteers and in patients. In the phase I study in healthy volunteers iomeprol (aqueous solution, iodine content 400 mg/mL) was administered intravenously in bolus injections of 50, 100, and 200mL vs identical volumes of placebo (physiological saline). The results of comparative measurements in the two treatment groups revealed no difference in terms of hemodynamic or humoral test parameters (liver and kidney function, chemotoxicity markers), indicating very good tolerance. Pharmacokinetic data elicited in the course of that study confirmed the earlier results from preclinical experiments. A pilot clinical study, conducted in patients undergoing urographic examinations, confirmed the excellent tolerability of iomeprol solutions (iodine content 300 mg/mL) in bolus intravenous doses up to 100 mL. It was rapidly eliminated by the renal route and showed excellent contrasting qualities. Five multicenter phase II studies of Iomeprol have been conducted in the clinical areas of urography, computerized axial tomography (CAT), angiocardiography, and conven-
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
736
tional cerebral, visceral, and peripheral angiography. The main purpose of these studies was to assess the tolerability and radiographic quality of intravascular iomeprol prior to the undertaking of comparative studies versus established contrast media. The results of these five multicenter studies, involving a total of 300 patients, showed that iomeprol was well tolerated and effective in intravascular applications. There were no severe or unexpected reactions attributable to iomeprol in any of the contemplated applications. In the proposed phase III clinical trial program the following indications will be studied:
digital arteriography, urography, CAT, phlebography, arthrography, endoscopic retrograde cholengiopancreatography (ERCP), and cardioangiography. The purposes of this study were to compare the tolerability and contrasting effectiveness of iomeprol (iodine content 150 mg/mL) and iopamidol (iodine content 150 mg/mL) in patients needing intraarterial digital subtraction angiography (DSA) of a lower extremity for diagnostic purposes or preoperative assessment. The two contrast agents were assessed in terms of the following parameters: 1. effects of the two compounds on vital signs and laboratory parameters (biochemical and hematologic) 2. subjective tolerability of the two contrast media
conventional and
3. incidence of side effects with the two contrast media 4. radiographic quality.
Patients and Methods The study was conducted on 100 inpatients at the General Parma Hospital needing intraarterial DSA of the lower extremities, for diagnostic purposes and/or preoperative assessment. The study was approved by the Parma Hospital institutional committee. The following patients were excluded from this study by the exclusion criteria: patients scheduled for examinations in emergency conditions, those needing general anesthesia or in clinical conditions likely to preclude cooperation, patients with a history of allergy or hypersensitivity to CM or iodine, pregnant women, patients with multiple myeloma or pheochromocytoma, and patients treated with oral or intravascular CM in the last twenty-four hours before the trial. Each patient had given his/her content to the procedure by filling the form supplied with clinical record forms. Patients received the CM according to a computer-generated random list balanced in blocks of 10, in order to obtain two homogeneous groups of patients : group A iomeprol, group B = iopamidol. Within the three days before the prescribed procedure and for twenty-four hours after its vital signs, EKG tracings, and laboratory parameters were monitored. Patients 21 to 40 and 81 to 100 received a complete coagulation screening including: thrombin time, =
prothrombin time, partial thromboplastin time, blood fibrinogen, euglobulin lysis time, plasma thromboplastin antecedent, and plasminogen activator inhibitor,(PAI) performed on venous blood samples obtained one minute before and at the end of the fast CM injection. During the examination any such symptom as pain or heat sensation was graded for severity by a visual analogue scale as described by Joyce.’ In addition the investigator
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
737
assigned the score for objective evidence of distress as follows: 0 = no evidence of distress ; 1= slight movement and/or vocal complaint; 2 moderate movement and/or com=
plaint ;
3 = forcible movement and/or loud cries.
pictures were examined for technical adequacy by the same two independent radiologists unaware of the contrast medium used. The x-ray pictures graded as technically adequate were graded according to the following scale: 0 = insufficient opacification; 1= sufficient opacification; 2 = good opacification; 3 = excellent opacification. A complete statistical analysis was performed by Braccos’s Biometric Department: patients’ characteristics were evaluated by descriptive statistics. The unpaired t test was used to determine whether there were differences between the baseline values of vital signs and laboratory parameters in the two patient groups; the paired t test was used to compare preprocedure and postprocedure values; nonparametric variables were analyzed with a Mann-Whitney test. All
FIG. 2. Patient characteristics in the two treatment groups.
Results
Figure 2 shows patient characteristics. No significant differences between the two study groups were detected, but a higher mean age was reported in the iomeprol group. In all the procedures pig-tail catheters 4-5 French were used except one in the iopamidol group (Head Hunter 5 French). No significant differences between iomeprol and iomeprol and iopamidol groups were detected in regard to access artery, mean amount of CM used, and total number of injections (Figure 3). Local anesthesia with xylocaine was used in all patients, and premedications with atropine was used in 20 patients in each group. No clinically relevant differences in vital parameters (blood pressure, heart rate) and laboratory findings were shown between the two groups of patients. Two patients (1 iomeprol, 1 iopamidol) reported ventricular extrasystoles after the procedure. The 40 patients submitted to the coagulated screening did not show alterations of studied parameters. Patients’ compliance was very good: subjects referred no pain sensation but a very mild heat sensation at the contrast medium injection. A trend in favor of iomeprol was reported for the warm feeling. No adverse reactions were observed in either group of patients.
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
738
FIG. 3. Clinical data for the two treatment groups.
The contrastographic efficacies of iomeprol and iopamidol are shown in Figure 4. In of disagreement between the two independent radiol-ogists, the lower score was considered. No injection with iomeprol and 8 with iopamidol group were considered insufficient. The x-ray pictures with iopamidol were scored sufficient, good, and excellent, case
FIG. 4. Contrast effectiveness of the two contrast media.
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
739
respectively, in 57, 113, and 68 cases. The iomeprol efficacy was graded cases, good in 151, and excellent in 61.
sufficient in 36
Discussion
The nonionic monomer contrast agents can actually be considered as the gold standard for safety reasons and contrast effectiveness. Their very low incidence of adverse reactions of pain and heat sensation have led most of the world’s radiologists to use and
appreciate them.’-’ of small-size catheters (4-5 French) is appreciated by radiologists because this reduces local complications, patient discomfort, bedding time, and, of course, the total cost of the radiological procedure. (Iopamidol is marketed in the United States; 50 mL of iopamidol costs about $23. Iomeprol is a pre-NDA phase, and hence the commercial price is not available.) Iomeprol showed less patient discomfort and better effectiveness in comparison with iopamidol. As for vital parameters, EKG tracings, laboratory parameters, and side effects, no difference was detected between the two groups of treatment. Data from the coagulation study are in contrast with previous papers,b-8 which have reported a thrombogenic effect due to nonionic CMs. No clinically significant changes in coagulation parameters were reported in our 40 patients. The
use
Conclusions We conclude that both contrast media tested in the present study showed good safety and effectiveness with the small-size catheters (4-5 French). In both group of patients we observed no side effects and obtained good patient compliance and good contrastographic efficacy. A trend in favor of iomeprol could be detected. Neither contrast agent produced any clinically significant alteration in the coagulation study. On this basis we anticipate that the use of small-size catheters and nonionic low-viscosity contrast agents will produce good radiological results with less patient discomfort. Dimitri Dacoronias, M.D. Bracco Industria Chimica Via Folli, 50
20134 Milan, Italy
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
S.p.A.
740
References 1.
Joyce CRB, Zutshi SW, Hoube V, et al: Comparison of fixed Internal and Visual Analogue scales for rating chronic pain. Eur J Pharmacol 8:414-420, 1975. 2. Palmer FJ, et al: The RACR Survey of Intravenous Contrast media Reactions final report. Aust Radiol 32:1988. 3. Katayama H, Yamaguchi K. Kozukat, et al: Adverse reactions to ionic and non-ionic contrast media. Radiology 175, No.3:621-628, June, 1990. 4. Murphy G, Campbell DR, Fraser DB, et al: Pain in peripheral arteriography: An assessment of conventional versus ionic and non-ionic low osmolar contrast agents. J Can Ass Radiol 39:103-106, 1988.
5. Widrich WC, et al: Iopamidol and meglumine diatrizoate : Comparison of effects on patient discomfort during aorto-femoral arteriography Radiology 148:61-64, 1983. 6. Engelhart JA, et al: Aspirated blood and low os-
molarity contrast agents: an embolic hazard? Radiology 165:152-153, 1988. 7. Gasparetti CM, et al: Non-ionic contrast material is associated with thrombus formation during PTCA. Circulation 80:375. Presented at 62nd Scientific Session of The American Heart Association, New Orleans, November 13-16, 1989. 8. Davidson CJ, et al: Thrombotic complications of diagnostic cardiac catherizations with non-ionic contrast. analysis of 7230 patients. Circulation 80 No. 4 11-375, October, 1989. Presented at 62nd Scientific Session of The American Heart Association, New Orleans, November 13-16, 1989.
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on April 12, 2015
