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A double-blind clinical study comparing the safety, tolerance and efficacy of ioversol and iohexol in intravenous urography
Clinical Radiology (1990) 42, 174-176
A Double-Blind Clinical Study Comparing the Safety, Tolerance and Efficacy of Ioversol and Iohexol in Intravenous Urography J. R. C O L T H U R S T , O. CHAN, M. C R E A G H , P. G O R D O N , R. GUY, F. M U N C E Y and A. B. AYERS
Department of Radiology, St Thomas' Hospital, London A double-blind trial in 80 patients showed no significant difference in the efficacy, tolerance and safety for intravenous urography between the new contrast medium Ioversol (Optiray Mallinckrodt Inc.) and the well established medium Iohexol (Omnipaque, Nycomed [UK] Ltd). Minor transient rises in AST/ALT were noted in approximately 10% of each group which were regarded as clinically insignificant. Both media were well tolerated with no significant sideeffects. Colthurst, J.R., Chan, O., Creagh, M., Gordon, P., Guy, R., Muncey, F. & Ayers A.B. (1990). Clinical Radiology 42, 174-176. A Double-Blind Clinical Study Comparing the Safety, Tolerance and Efficacy of loversol and Iohexol in Intravenous Urography
Iohexol (Omnipaque, Nycomed [UK] Ltd) is an established safe non-ionic contrast medium which has been shown to be well tolerated by patients and to have a significant reduction in side-effects in comparison to ionic media (Dawson et al., 1983) when used for intravenous urography (Levorstad et al., 1982; Foord et al., 1985; Kaye et al., 1988). Ioversol (Optiray Mallinckrodt Inc.) is a newly developed non-ionic low-osmolar contrast medium whose chemical structure is shown in Fig. 1. This study has been performed to compare the safety, tolerance and efficacy of these two media in patients requiring intravenous urography.
Chemical
Other Names:
N,N',bis(2,3-dlhyd r o x y p r o p y l ) - 5 [N(2-hydroxyethyl)-glycolamido]. 2,4,6-triiodoisophtalamide
MP-328 (code name) Ioversol (U.S.A.N. proposed)
Structure:
CONHCH2 CHOHCH2 OH
1
METHODS The trial was a randomized, double-blind, parallel group study using an active control and had received the approval of the local Ethical Committee. Eighty patients, 40 in each group were studied. All were clinical referrals to the department for intravenous urography and were entered into the trial, provided they were over 18 years of age and displayed none of the exclusion criteria shown in Table 1. There was no statistical difference in the patient parameters. Each patient gave informed consent. A history was taken and physical examination performed. Blood and urine samples were obtained prior to the injection of contrast medium. The volume of contrast medium to be injected was calculated on the basis of 1 ml per kilogram body weight for both Iohexol 300 and Ioversol 320 (Table 2). The contrast was drawn up in a separate room in similar syringes on each occasion to ensure that the injecting radiologist was unaware of which contrast medium was being used. Neither solution has significant colour. Vital signs (blood pressure, pulse rate and respiration rate) were recorded before the procedure and at 5 and 30 min after injection.
name:
1
CONHCH2 CHOHCH2 OH
HOCH2 CO-N
/"
HOCH -CH 2 2
1
Molecular Formula: C 18 H 2413 N3 09 Molecular Weight:
807.13 Fig. 1
Tolerance At the completion of the prpcedure, the patient was asked to evaluate any sensation of heat based on a four point scale as none, mild, moderate or severe. The patient was also asked to evaluate any sensation of pain, on similar scale. Efficacy
Correspondence to: A. B. Ayers, Department of Radiology, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH.
No restriction was imposed on the number of fil~s requested by the investigator nor on the use of tomogra"
175
DOUBLE-BLIND STUDY COMPARING IOVERSOL AND IOHEXOL Table l - Patient exclusion criteria
RESULTS
The following patients were excluded from this study: 1 patients with a history of sensitivity to iodine-containing compounds 2 Females who are pregnant or nursing 3 Women of child bearing potential, unless the possibility of their being pregnant can be ruled out 4 patients with diabetes, severe asthma, phaeochromocytoma, sickle cell disease, multiple myeloma or paraproteinaemia 5 Patients with significant renal disease or serum creatinine 2.5 mg/dl 6 Patients with combined renal and hepatic disease, severe hypertension (diastolic blood pressure 120 mmHg), or congestive heart failure 7 Patients having undergone any other radiographic procedure utilizing X-ray contrast media during the preceding 24 hour period 8 patients having undergone oral cholecystography within the past 7 days
Tolerance
Efficacy Details of the assessment of radiographic quality are shown in Table 3. All procedures using Iohexol were deemed to be of diagnostic quality but two in the Ioversol group were not. No statistical difference in the ability of either medium to visualize the kidneys, ureters or bladder was identified.
Table 2 - Patient and injection details
Average values
Age (year) Weight (kg) Height (cm) Contrast volume (ml) Contrast volume (ml/kg) Iodine dose (mg/kg) Injection time (s)
In the Iohexol group, two patients complained of mild heat during injection and two of mild pain. In the Ioversol group, one patient complained of moderate heat and one of moderate pain. No other subjective side effect was found in the Ioversol group but one patient complained of a 'bad taste' following Iohexol injection. No clinically significant change was identified in the pulse rate, respiratory rate or blood pressure during the procedure in either group. Comparison of the results showed no statistically significant difference.
Ioversol 320 n=40
Iohexol 300 n=40
Haematology
58.8 71.4 169.8 76.2 1.1 353.4 38.9
52.1 72.4 169.0 76.6 I. 1 320.7 35.9
A number of haematological specimens were unsuitable for analysis, or the patients failed to return for further sampling. O f the 54 patients with satisfactory specimens 28 were in the Ioversol group and 26 were in the Iohexol group. None of these patients showed any haematological change which could not be explained on the basis of their underlying disease.
Clinical Chemistry
phy, which was always available. A further injection of contrast medium was not allowed. However, examinations were supplemented where necessary by an ultrasound examination to ensure that no patient suffered any detriment as a result of inclusion in the trial. The radiographs were subsequently assessed by one of two experienced radiologists (B.A. and P.G.), independent of the procedure. Opacification of the parenchyma, collecting systems, bladder and overall visualization were graded as none, poor, adequate or excellent. The examinations were judged as clinically diagnostic or nondiagnostic.
Biochemical Laboratory Studies Haematological and biochemical parameters were examined prior to the procedure at 24 to 48 h and at 72 to 96 h whenever possible. The haematology tests included haematocrit, haemoglobin, white cell count, red cell Count and platelets. Clinical chemistry included AST (SGOT), A L T (SGPT), alkaline phosphatase, total protein, total bilirubin, B U N and creatinine.
Sixty-nine patients had satisfactory pre- and postinjection analysis of biochemical parameters of which 34 were in the Ioversol group and 35 in the Iohexol group. Nine patients showed changes which could not be explained on the basis of the underlying disease or therapy received and therefore may be related to the procedure (Table 4). Two patients showed a rise in creatinine, one in each group, for which no explanation
Table 3 - Assessment of radiographic quality. Column (a) Ioversol 320. Column (b) Iohexol 300
Region of interest
Excellent (a) (b)
Adequate (a) (b)
Poor (a) (b)
None (a) (b)
Total (a) (b)
Parenchyma Calyces Pelvis Ureters Bladder
22 35 50 34 14
42 28 21 32 24
15 16 8 13 2
0 0 0 0 0
79 79 79 79 40
16 45 54 36 18
23 11 4 7 2
0 1 1 1 0
80 80 80 80 40
Table 4 - Changes in clinical chemistry which may be related to the intravenous injection of Ioversol or Iohexol
Ioversol
Iohexol
Transient rise in ALT/AST Rise in serum creatinine
3 1
4 1
Total
4
5
Statistics Statistical analysis was performed using the chi-square and Fisher's exact test (2-tail) and a P value of 0.05 or less Was regarded as significant.
41 23 21 36 20
176
CLINICAL RADIOLOGY
Table 5 - Details of transient rises in AST and ALT following intravenous injection of Ioversol 320 and Iohexol 300 (* same patient)
Ioversol
Iohexol
Pre-injection Post-injection Pre-injection Post-injection
AST Normal range 9 0-18
ALT 8 Normal range 19 0 2O
20
6 14 16 16
22 20 23* 20
20 23
17 17
25* 23
can be found. Seven patients showed transient rises in A S T / A L T or both - t h r e e following Ioversol and four following Iohexol (Table 5). However, these were only marginal increases above the n o r m a l range.
DISCUSSION The main aim o f this study was to evaluate the new contrast medium Ioversol in patients undergoing excretion urography. A control g r o u p o f patients was used using the well-established m e d i u m Iohexol. A l t h o u g h the chemical structure o f Ioversol (Fig. 1) is very similar to that o f I o p a m i d o l ( N i o p a m , E. Merck Ltd), the active control drug chosen in this trial was Iohexol. In clinical practice there is little to choose between Iohexol and Iopamidol. The incidence o f side-effects in both our groups was extremely low. It is well recognized that non-ionic media have a low incidence o f side-effects and the present study compares favourably with previous reports. ( K e n n e d y et al., 1988). In particular, patients experienced virtually no immediate effects previously associated with the injection o f ionic contrast media. In two patients the radiographic quality using Ioversol was deemed to be non-diagnostic and analysis o f these two cases shows well k n o w n causes o f difficulty in intravenous urography. In the first case, the patient was large with p o o r bowel preparation and the second had impaired renal function due to hypertension and diabetes. U n d e r normal circumstances, both these patients would
have received a further injection o f contrast medium for better visualization but this was not allowed in this Study. All the procedures using Iohexol were deemed diagnostic. A l t h o u g h the n u m b e r o f patients in w h o m an excellent n e p h r o g r a m was obtained is greater in the Ioversol group, the differences are not statistically different. Indeed, none o f the differences in radiographic quality were o f statisti. cal significance. The overall impression o f the assessing radiologists was that Ioversol and Iohexol performed equally well. One patient in each g r o u p had a small rise in serum creatinine for which no explanation is forthcoming and no follow-up information is available. Seven patients showed temporary small rises in serum enzymes (ALT/ AST) which m a y be contrast related. Three o f these were in the Ioversol g r o u p and four in the Iohexol group. AST is a cardiac enzyme and A L T m a y be o f cardiac or liver origin. The levels reached are regarded by the authors as clinically insignificant, but further evaluation may be warranted. The overall conclusion o f this study is that Ioversol is a safe intravenous contrast m e d i u m for excretion urog. r a p h y and c o m p a r e d favourably with the established m e d i u m Iohexol both in the low incidence o f side-effects and in the visualization o f the urinary tract. N o serious haematological or biochemical adverse effect was detected. Acknowledgements: We express our thanks to the radiographers at St Thomas' Hospital for their assistance in the study and to Miss Lynn Rawson for her word processing skills and patience.
REFERENCES
Dawson, P, Grainger RG & Pitfield, J (1983). The new low-osmolar contrast media: a simple guide. Clinical Radiology, 34, 221-226. Foord, KD, Kaye, B, Howard, J & Cumberland, DC (1985). Comparison of the side-effectsof low-osmolar contrast media in intravenous urography. Clinical Radiology, 36, 79-380. Kaye, B, Howard, J, Foord KD & Cumberland, DC (1988). Comparison of the image quality of intravenous urograms using low-osmolar contrast media, British Journal of Radiology, 61, 589-591. Kennedy, C, Rickards, D, Lee, S, Buckley Sharp, M & Dawson, P (1988). A double blind study comparing the efficiency,tolerance and renal effects of Iopromide and Iohexol. British Journal of Radiology, 61, 288-293. Levorstad, K~ Kolbenstvedt, A, Sommerfelt, S Chr, Zachrisson, BE, Jagenburgh, R, Egebland, M, Thrane Nielsen, N, Sjoberg, S, Oldbring J & Sveen,K (1982). Tolerability and diagnostic usefulness of Iohexol in urography. Acta Radiologica Diagnosis, 23, 491-496.
A Double-Blind Clinical Study Comparing the Safety, Tolerance and Efficacy of Ioversol and Iohexol in Intravenous Urography J. R. C O L T H U R S T , O. CHAN, M. C R E A G H , P. G O R D O N , R. GUY, F. M U N C E Y and A. B. AYERS
Department of Radiology, St Thomas' Hospital, London A double-blind trial in 80 patients showed no significant difference in the efficacy, tolerance and safety for intravenous urography between the new contrast medium Ioversol (Optiray Mallinckrodt Inc.) and the well established medium Iohexol (Omnipaque, Nycomed [UK] Ltd). Minor transient rises in AST/ALT were noted in approximately 10% of each group which were regarded as clinically insignificant. Both media were well tolerated with no significant sideeffects. Colthurst, J.R., Chan, O., Creagh, M., Gordon, P., Guy, R., Muncey, F. & Ayers A.B. (1990). Clinical Radiology 42, 174-176. A Double-Blind Clinical Study Comparing the Safety, Tolerance and Efficacy of loversol and Iohexol in Intravenous Urography
Iohexol (Omnipaque, Nycomed [UK] Ltd) is an established safe non-ionic contrast medium which has been shown to be well tolerated by patients and to have a significant reduction in side-effects in comparison to ionic media (Dawson et al., 1983) when used for intravenous urography (Levorstad et al., 1982; Foord et al., 1985; Kaye et al., 1988). Ioversol (Optiray Mallinckrodt Inc.) is a newly developed non-ionic low-osmolar contrast medium whose chemical structure is shown in Fig. 1. This study has been performed to compare the safety, tolerance and efficacy of these two media in patients requiring intravenous urography.
Chemical
Other Names:
N,N',bis(2,3-dlhyd r o x y p r o p y l ) - 5 [N(2-hydroxyethyl)-glycolamido]. 2,4,6-triiodoisophtalamide
MP-328 (code name) Ioversol (U.S.A.N. proposed)
Structure:
CONHCH2 CHOHCH2 OH
1
METHODS The trial was a randomized, double-blind, parallel group study using an active control and had received the approval of the local Ethical Committee. Eighty patients, 40 in each group were studied. All were clinical referrals to the department for intravenous urography and were entered into the trial, provided they were over 18 years of age and displayed none of the exclusion criteria shown in Table 1. There was no statistical difference in the patient parameters. Each patient gave informed consent. A history was taken and physical examination performed. Blood and urine samples were obtained prior to the injection of contrast medium. The volume of contrast medium to be injected was calculated on the basis of 1 ml per kilogram body weight for both Iohexol 300 and Ioversol 320 (Table 2). The contrast was drawn up in a separate room in similar syringes on each occasion to ensure that the injecting radiologist was unaware of which contrast medium was being used. Neither solution has significant colour. Vital signs (blood pressure, pulse rate and respiration rate) were recorded before the procedure and at 5 and 30 min after injection.
name:
1
CONHCH2 CHOHCH2 OH
HOCH2 CO-N
/"
HOCH -CH 2 2
1
Molecular Formula: C 18 H 2413 N3 09 Molecular Weight:
807.13 Fig. 1
Tolerance At the completion of the prpcedure, the patient was asked to evaluate any sensation of heat based on a four point scale as none, mild, moderate or severe. The patient was also asked to evaluate any sensation of pain, on similar scale. Efficacy
Correspondence to: A. B. Ayers, Department of Radiology, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH.
No restriction was imposed on the number of fil~s requested by the investigator nor on the use of tomogra"
175
DOUBLE-BLIND STUDY COMPARING IOVERSOL AND IOHEXOL Table l - Patient exclusion criteria
RESULTS
The following patients were excluded from this study: 1 patients with a history of sensitivity to iodine-containing compounds 2 Females who are pregnant or nursing 3 Women of child bearing potential, unless the possibility of their being pregnant can be ruled out 4 patients with diabetes, severe asthma, phaeochromocytoma, sickle cell disease, multiple myeloma or paraproteinaemia 5 Patients with significant renal disease or serum creatinine 2.5 mg/dl 6 Patients with combined renal and hepatic disease, severe hypertension (diastolic blood pressure 120 mmHg), or congestive heart failure 7 Patients having undergone any other radiographic procedure utilizing X-ray contrast media during the preceding 24 hour period 8 patients having undergone oral cholecystography within the past 7 days
Tolerance
Efficacy Details of the assessment of radiographic quality are shown in Table 3. All procedures using Iohexol were deemed to be of diagnostic quality but two in the Ioversol group were not. No statistical difference in the ability of either medium to visualize the kidneys, ureters or bladder was identified.
Table 2 - Patient and injection details
Average values
Age (year) Weight (kg) Height (cm) Contrast volume (ml) Contrast volume (ml/kg) Iodine dose (mg/kg) Injection time (s)
In the Iohexol group, two patients complained of mild heat during injection and two of mild pain. In the Ioversol group, one patient complained of moderate heat and one of moderate pain. No other subjective side effect was found in the Ioversol group but one patient complained of a 'bad taste' following Iohexol injection. No clinically significant change was identified in the pulse rate, respiratory rate or blood pressure during the procedure in either group. Comparison of the results showed no statistically significant difference.
Ioversol 320 n=40
Iohexol 300 n=40
Haematology
58.8 71.4 169.8 76.2 1.1 353.4 38.9
52.1 72.4 169.0 76.6 I. 1 320.7 35.9
A number of haematological specimens were unsuitable for analysis, or the patients failed to return for further sampling. O f the 54 patients with satisfactory specimens 28 were in the Ioversol group and 26 were in the Iohexol group. None of these patients showed any haematological change which could not be explained on the basis of their underlying disease.
Clinical Chemistry
phy, which was always available. A further injection of contrast medium was not allowed. However, examinations were supplemented where necessary by an ultrasound examination to ensure that no patient suffered any detriment as a result of inclusion in the trial. The radiographs were subsequently assessed by one of two experienced radiologists (B.A. and P.G.), independent of the procedure. Opacification of the parenchyma, collecting systems, bladder and overall visualization were graded as none, poor, adequate or excellent. The examinations were judged as clinically diagnostic or nondiagnostic.
Biochemical Laboratory Studies Haematological and biochemical parameters were examined prior to the procedure at 24 to 48 h and at 72 to 96 h whenever possible. The haematology tests included haematocrit, haemoglobin, white cell count, red cell Count and platelets. Clinical chemistry included AST (SGOT), A L T (SGPT), alkaline phosphatase, total protein, total bilirubin, B U N and creatinine.
Sixty-nine patients had satisfactory pre- and postinjection analysis of biochemical parameters of which 34 were in the Ioversol group and 35 in the Iohexol group. Nine patients showed changes which could not be explained on the basis of the underlying disease or therapy received and therefore may be related to the procedure (Table 4). Two patients showed a rise in creatinine, one in each group, for which no explanation
Table 3 - Assessment of radiographic quality. Column (a) Ioversol 320. Column (b) Iohexol 300
Region of interest
Excellent (a) (b)
Adequate (a) (b)
Poor (a) (b)
None (a) (b)
Total (a) (b)
Parenchyma Calyces Pelvis Ureters Bladder
22 35 50 34 14
42 28 21 32 24
15 16 8 13 2
0 0 0 0 0
79 79 79 79 40
16 45 54 36 18
23 11 4 7 2
0 1 1 1 0
80 80 80 80 40
Table 4 - Changes in clinical chemistry which may be related to the intravenous injection of Ioversol or Iohexol
Ioversol
Iohexol
Transient rise in ALT/AST Rise in serum creatinine
3 1
4 1
Total
4
5
Statistics Statistical analysis was performed using the chi-square and Fisher's exact test (2-tail) and a P value of 0.05 or less Was regarded as significant.
41 23 21 36 20
176
CLINICAL RADIOLOGY
Table 5 - Details of transient rises in AST and ALT following intravenous injection of Ioversol 320 and Iohexol 300 (* same patient)
Ioversol
Iohexol
Pre-injection Post-injection Pre-injection Post-injection
AST Normal range 9 0-18
ALT 8 Normal range 19 0 2O
20
6 14 16 16
22 20 23* 20
20 23
17 17
25* 23
can be found. Seven patients showed transient rises in A S T / A L T or both - t h r e e following Ioversol and four following Iohexol (Table 5). However, these were only marginal increases above the n o r m a l range.
DISCUSSION The main aim o f this study was to evaluate the new contrast medium Ioversol in patients undergoing excretion urography. A control g r o u p o f patients was used using the well-established m e d i u m Iohexol. A l t h o u g h the chemical structure o f Ioversol (Fig. 1) is very similar to that o f I o p a m i d o l ( N i o p a m , E. Merck Ltd), the active control drug chosen in this trial was Iohexol. In clinical practice there is little to choose between Iohexol and Iopamidol. The incidence o f side-effects in both our groups was extremely low. It is well recognized that non-ionic media have a low incidence o f side-effects and the present study compares favourably with previous reports. ( K e n n e d y et al., 1988). In particular, patients experienced virtually no immediate effects previously associated with the injection o f ionic contrast media. In two patients the radiographic quality using Ioversol was deemed to be non-diagnostic and analysis o f these two cases shows well k n o w n causes o f difficulty in intravenous urography. In the first case, the patient was large with p o o r bowel preparation and the second had impaired renal function due to hypertension and diabetes. U n d e r normal circumstances, both these patients would
have received a further injection o f contrast medium for better visualization but this was not allowed in this Study. All the procedures using Iohexol were deemed diagnostic. A l t h o u g h the n u m b e r o f patients in w h o m an excellent n e p h r o g r a m was obtained is greater in the Ioversol group, the differences are not statistically different. Indeed, none o f the differences in radiographic quality were o f statisti. cal significance. The overall impression o f the assessing radiologists was that Ioversol and Iohexol performed equally well. One patient in each g r o u p had a small rise in serum creatinine for which no explanation is forthcoming and no follow-up information is available. Seven patients showed temporary small rises in serum enzymes (ALT/ AST) which m a y be contrast related. Three o f these were in the Ioversol g r o u p and four in the Iohexol group. AST is a cardiac enzyme and A L T m a y be o f cardiac or liver origin. The levels reached are regarded by the authors as clinically insignificant, but further evaluation may be warranted. The overall conclusion o f this study is that Ioversol is a safe intravenous contrast m e d i u m for excretion urog. r a p h y and c o m p a r e d favourably with the established m e d i u m Iohexol both in the low incidence o f side-effects and in the visualization o f the urinary tract. N o serious haematological or biochemical adverse effect was detected. Acknowledgements: We express our thanks to the radiographers at St Thomas' Hospital for their assistance in the study and to Miss Lynn Rawson for her word processing skills and patience.
REFERENCES
Dawson, P, Grainger RG & Pitfield, J (1983). The new low-osmolar contrast media: a simple guide. Clinical Radiology, 34, 221-226. Foord, KD, Kaye, B, Howard, J & Cumberland, DC (1985). Comparison of the side-effectsof low-osmolar contrast media in intravenous urography. Clinical Radiology, 36, 79-380. Kaye, B, Howard, J, Foord KD & Cumberland, DC (1988). Comparison of the image quality of intravenous urograms using low-osmolar contrast media, British Journal of Radiology, 61, 589-591. Kennedy, C, Rickards, D, Lee, S, Buckley Sharp, M & Dawson, P (1988). A double blind study comparing the efficiency,tolerance and renal effects of Iopromide and Iohexol. British Journal of Radiology, 61, 288-293. Levorstad, K~ Kolbenstvedt, A, Sommerfelt, S Chr, Zachrisson, BE, Jagenburgh, R, Egebland, M, Thrane Nielsen, N, Sjoberg, S, Oldbring J & Sveen,K (1982). Tolerability and diagnostic usefulness of Iohexol in urography. Acta Radiologica Diagnosis, 23, 491-496.