Evaluation of the contrast density of iomeprol

EUROPEAN JOURNAL OF RADIOLOGY

European Journal of Radiology 18 Suppl. I (1994) S97-SlO3 ELSEVIER SCIENCE

IRELAND

Evaluation of the contrast density of iomeprol

Erhard Schmiedel

Department of Clinical Development, Bracco-Byk Gulden GmbH. Max-Stromeyer Strasse 57, D-78447 Konstanz Germany

(Received I9 October 1993; accepted 31 October 1993)

Abstract

The recently developed monomeric nonionic contrast medium iomeprol was tested in concentrations of 150, 200, 250, 300, 350, and 400 mgI/ml in open multicentre Phase III studies. The clinical testing was performed in a nonselected patient population (n = 4811); a total of 15 850 injections of the contrast medium was used. All the common radiological methods were used in the study, which was performed in over 150 centres. The contrast density was evaluated as good or satisfactory in 99X of the total patient population. Relevant heat and pain sensations occurred rarely; severe heat and pain were reported only 1.25% and 0.3% of the patients, respectively.

Key woruk Contrast media, comparative study; Contrast media, effects; Radiography, contrast media

1. Introduction

The new nonionic contrast medium iomeprol developed by Bracco s.p.a. has several advantages which distinguishes it from the monomeric nonionic contrast media already on the market. Iomeprol has a lower osmolality and viscosity. Because of the favourable physicochemical properties, iomeprol is also available in a concentration of 400 mgI/ml. Iomeprol is the first nonionic contrast medium not to contain any EDTA as an additive [ 1,2].

Animal studies and the Phase I and II clinical testing showed extremely good tolerance (31. The aim of the open Phase III clinical testing in Germany was to evaluate the contrast density and tolerance in all common radiological procedures within a large nonselected patient population.

2. Patients and methods

The open clinical testing was performed in a total of 48 11 patients in over 150 study centres and in 50 indications, grouped into 13 different indication areas (Table 1). A total of 15,850 injections of the contrast medium

were used; mainly due to repeated injections in angiography. The testing was performed between January and December 1990. Iomeprol was administered in concentrations of 150, 200, 250, 300, 350, and 400 mgI/ml. Iomeprol300,350, and 400 were used most often (Table 1). Iomeprol 300/350/400 was tested in intravenous DSA, iomeprol200/250/300 in peripheral phlebography iomeprol 150/200/300 in intra-arterial DSA, iomeprol 300/350/400 in conventional arteriography, and iome- pro1 350/400 in selective coronary angiography/angiocardiography.

The patient population comprises 3116 men (64.8%) and 1685 women (35.0%); the sex of 10 patients (0.2%) was not recorded. The mean age was 57.3 f 14.3 years. The youngest patient was 18 and the oldest was 91 years. The mean body weight was 73.8 f 13.2 kg (Table 2).

Risk factors were found in a large proportion of the case histories: cardiovascular diseases (45.3%), allergic predisposition (22.00/o), and kidney diseases (15.1%). The testing was performed with standardized Case Re- port Forms. The contrast density was classified as follows: good, satisfactory, and unsatisfactory. In addi- tion, it was determined whether radiological diagnosis was possible or not possible. If the latter applied, a note

0720-048X/94607.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved.

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S98 E. SchmiedeI/Eur. J. Rudiol. 18 Suppl. (1994) S97-SIO3

Table I Table 2

Indication, distribution of patients receiving iomeprol Background factors of patients receiving iomeprol

Indication/formulation Number of Number of patients injections

Indication Conventional angiography Intraarterial DSA Selective coronary arterio-

graphy + angiocardio-

graphy Interventional coronary

arteriography Interventional radiology Intravenous DSA Peripheral

phlebography + DSP Computed tomography Urography Retrograde urography Cavemosography Cavity and gland imaging

Total

Formulation’ 150 mgI/ml 200 mgI/ml 250 mgl/ml 300 mgI/ml 350 mgl/ml 400 mgI/ml

765 (15.9%) 2149 708 (14.7%) 3591 576 (I 1.97%) 3942

I21 (2.5%) 988

137 (2.8%) 657 (13.7%)

500 2264

498 (10.4”/“) 342 (7. I?‘“) 449 (9.33%) I30 (2.7%) 146 (3.03%) 282 (5.86%)

4811

1051 342 449 130 146 298

I.5 850

425 (8.8%) 515 (10.7%) I50 (3.1%)

1962 (40.8”/;,) I122 (23.3”/“) 755 (15.7%)

‘Including multiple nominations.

Factor Patients

Sex

Male Female Missing data

Age (years) <20 20-29 30-39 40-49 50-59 60-69 70-79 280 Missing data Mean f SD. (Min-Max)

Body weight (kg) <50 50-59 60-69 70-79 80-89 90-99 100-109 rll0 Missing data Mean f S.D. (Min-Max)

Patients with risk Allergic disposition Cardiovascular disease Renal disease

31 I6 (64.8%) 1685 (35.0%)

IO (0.2%)

26 (0.5%) 237 (4.9%) 308 (6.4”/“) 688 (14.3%)

1262 (26.2”/“) 1342 (27.9%) 736 (15.3%) 201 (4.2%)

I I (0.2%) 57.3 f 14.4 (18-91)

95 (2.0%) 493 (10.2”/“)

II39 (23.7%) 1471 (30.6%) 1064 (22.1%) 386 (8.0%) I IO (2.3%) 43 (0.9%) IO (0.2%) 73.8 f 13.2 (32-190)

1058 (22.0%) 2178 (45.3%)

725 (15.1%)

was made of whether this was due to the contrast medium or to other factors such as the technique or appara- tus used, the method of investigation, or the patient.

The patients were asked about any sensations of heat or pain during and after injection of the contrast medium. The intensity of these sensations was classified as mild, moderate, or severe. The frequency and symptoms of systemic side effects are given elsewhere [3].

The differences between the subgroups reported in this publication are not tested for statistical significance. Test-statistical analyses in large multicentre studies with high variability in the basic factors (over 150 study centres, 50 different indications, six contrast medium concentrations, widely varying injection data, different hospitals, etc.) are not deemed appropriate even if percentage results make calculations of statistical significance seem justified. For example, in Table 7 the symptom ‘Severe heat sensations’ shows a noticeable continuous increase in percentage frequency from iomeprol 150 to iomeprol 400. Heat sensations are un- doubtedly dependent on the osmolality of the contrast medium, but also on factors such as the contrast medium dose and flow and, in particular, on the site of injection of the contrast medium.

3. Results

The total doses of the contrast medium (median, 50% range, minimal and maximal dose) per examination with the tested concentrations are shown for several indications in Fig. 1. High injection volumes were used particularly in DSA and conventional arteriography. This is shown clearly in Fig. 2. Here the total doses of the contrast medium are presented in the form of contrast medium content, i.e. iodine content (g), the values for the tested formulations being added together.

In the total patient population (except excretion, urography, retrograde urograph y, and cavernosography) the contrast density was evaluated as good and satisfactory in 86.3% and 12.7% of cases, respectively. The contrast density was unsatisfactory in 1.0% of the patients; in 0.2% of cases the investigator gave the contrast medium as the cause (Table 3).

The best results were obtained in coronary angiography/angiocardiography conventional peripheral arteriography and interventional radiology. less favourable results are seen in DSA after intra-arterial and intravenous injection with good contrast in 76.1% and

Schmiedel/ Eur. J. Radiol. 18 Suppl. (1994) S97-S103 s99

“Or La. DSA Conventional Coronary I.v. DSA ~-twophY Awloa. 550.

n-57 Phlabogr.

Fig. 1. Dosage (ml) per examination. Median, 50% range, minimum, maximum.

Table 3 Contrast density of iomeprol

P

60

60

40

20

0

Fig. 2. Dosage (81) per examination. Median, 50% range, minimum, maximum.

Indication N Contrast Diagnosis not possible

Good Satisfactory Unsatisfactory Total Due to CM

Conventional angiography 761 137 20 4 8 0

Intraarterial DSA

Selective coronary arteriography/ angiocardiography

Interventional coronary arteriography

Interventional radiology

Intravenous DSA

Peripheral phlebography/DSP

Computed tomography

Intravenous urography

Retrograde urography

Cavernosography

Cavity and gland imaging

708

516

121

136

645

497

341

445

I28

146

23S

96.8% 2.6% 0.5%

539 I68 I

76. I ‘%, 23.1% 0. I ‘%I

553 23 0 96.0% 4.0”!” 0%

I21 0 0 100% 0% 0%

132 4 0

91.1% 2.9% w 471 I48 26

73.0% 22.9% 4.0%

426 67 4

85.7% I 3.5% 0.8%

286 50 5

83.9% 14.7% I .5’%, a I il

b b b

a

205 30 0 87.2”/;, 12.8% W%,

a a

1.1% 8

1.1% I

0.2% I

0 8% 0’ 0% 36 5.6% I I .4’%1 4

I .2X 20 4.5%

1 0.8”/;1

0 0%

6 2.6%

0%

I

0. I’%

0.2% 0 0% 0 0% 3 0.5% 0 0% I 0.3% 3 0.7% 0 0% 0 (Y% 0 0%

Total 4020 3470 510 40 92 9 86.3% 12.7% I .o% 1.9% 0.2%

‘See Table 4. bSeparate evaluation of ureter, bladder, urethra. cExcluding ERCP.

SIOO E. Schmiedel/ Eur. J. Rudiol. 18 Suppl. (1994) S97-S103

Table 4 Contrast enhancement of iomeprol

Indication Contrast


Nephrogram

Pelvicalyceal

Ureter

Cavemosography

Morphology of corpus cavemosum

Dorsal veins of the penis

Ectopic veins

Good

Right

303 67.5%

319 7 1 0%” 285 63.5%

132 90.0% 114 78.1%

73 50.0%

Left

280 62.4%

313 69 7% 281 62.6%

Satisfactory

Right

113 25.2% 70 15.6% 75 16.7%

11 7.5% 13 8.9% 15 10.3%

Left

123 27.4% 70 15.6% 76 16.9%

Unsatisfactory

Right Left

30 36 6.7% 8.0% 22 25 4.9% 5 6% 41 42 9.1% 9.4%

1 0.7% 5 3 4% 6’ 4.1 ‘%I

73.0% of cases, respectively. A possible cause in intraarterial DSA is the testing of iomeprol 300, iomeprol 200, and the low-concentration iomeprol 150; the iodine content of iomeprol 150 was probably insufficient in some cases. The not entirely satisfactory result with intravenous DSA may be attributable to the high proportion of patients with cardiovascular diseases and/or the high proportion of patients over 70 years. Nevertheless, the percentage of patients in whom a radiological diagnosis could not be made because of poor density of contrast medium was relatively low at 0.1% and 0.5% (Table

3).

Table 5 Contrast enhancement of different iomeprol concentrations

In intravenous urography the evaluation of the nephrographic phase (right/left) was good in 67.5%/ 62.4% of cases and satisfactory in 25.20/o/27.5% of cases. The results of the biometrical evaluation were 71.00/o/69.7% and 15.6%/15.6% for the pelvicalyceal sys- tem, and 63.5%/62.6% and 16.7%/l 6.9% for the ureters. In cavernosography the contrast density of the corpora cavemosa was evaluated as good in 90.0% and satisfactory in 7.5% of cases; the results for the dorsal veins of the penis were 68.1% and 8.9% (Table 4).

The choice of the contrast medium concentration has an effect on contrast density; comparison of the high

Concentration

150 mgI/ml

200 mgI/ml

250 mgI/ml

300 mgI/ml

350 mgI/ml

400 mgbml

Total

‘Excluding urography.

N Contrast Diagnosis not possible

Good Statisfactory Unsatisfactory Total Due to CM

231 179 48 4 9 2 77.5% 20.8%~ 1.7% 3.9% 0.9%

412 356 55 1 6 1 86.6% 13.4% 0.2% 1.5% 0.2%)

166 136 29 1 1 0 81.9% 17.5% 0.6% 0.6% 0%

1648 1390 234 24 45 4 84.3% 14.2% I. 5% 2.7% 0.2%

936 832 96 8 24 3 88.9% 10.3% 0.9% 2.6% 0.3%

754 681 68 5 10 2 90.3% 9.0% 0.7% I. 3% 0.3%

4147” 3574 510 43 95 12 86.2% 12.8”% 1 .O”/;# 2.3% 0.3%

E. Schmiedel/ Eur. J. Radio/. 18 Suppl. (1994) S97-S103 SIOI

Table 6 Heat sensation of iomeprol

Indication N Absent Mild Moderate Severe Missing data

Conventional angiography

Intra-arterial DSA

Selective coronary arteriographyj angiocardiography

interventional coronary arteriography


Intravenous DSA


Computed tomography



Cavernosography


Total

787” 265 33.7’%,

795” 445 56.(Y%,

576 276 48.0%

I21 120 99.2%

138” 44 3 I .9%

681” 197 28.9%

498 435 87.3’%1

346” 243 70.2%

449 430 95X%1

130 130 IOO%

I46 I46 lW%l

286” 285 99.7’%1

4953” 3016 60.9%

277 35.2%

263 33.1% 267

46.4% 1

0.8% 53

38.4% 307

45. I’%, 42

8.4’%, 77 22.3% I5 3.5%

1302 26.3’%,

210 26.7%

74 9.3’%1

27 4.7’%1

39 28.3’X I61 23.6%

I5 3.@%l 22 6.4’%, 4 0.9’%1

552 11.1%

32 4. I’%,

8 I.@%, 2

0.31%)

2 I .4’%1 I2 I .8’%>

I 0.2% 4 I .2% 95

I 0.3”X

62 I .3’%1

3 0.4’%,

5 0.6% 4

0.7%

4 0.6%

5 I .O’%I

21 0.4%

“Including multiple nominations.

and low concentrations shows a clear difference in favour of iomeprol 400 (Table 5).

Heat sensation perceived as severe occurred most often (4.1%) in conventional peripheral arteriography

and at a rate of less than 2% in all the other procedures (Table 6). This result is understandable, as experience has shown that injections of contrast medium into the femoral artery and brachial artery cause a strong heat

Table 7 Frequency and intensity of heat sensation of different iomeprol concentrations

Concentration

I50 mgl/ml

200 mgI/ml

250 mgI/ml

300 mgI/ml

350 rngI/ml

400 mgI/ml

N

428

536

I50

1961

II23

755

Absent

354 97.4%

436 81.3%

II8 78.7% II94 60.9% 594 52.9%

320 42.4%

Mild

68 15.9% 79

14.7% I7

11.3% 479 24.4% 384 34.2% 275 36.4%

Moderate

4 0.9%

I8 3.4%

IO 6.7% 255 13.0% I25 II.l% I40 18.5%

Severe

I 0.2%

2 0.4%

I 0.7% 25 1.3% I6 1.4% 17 2.3%

Missing data

I 0.2% I 0.2% 4 2.7’%, 8 0.4% 4 0.4% 3 0.4%

Total 4953”


4748 102 84 I6 3 95.9% 2.1% I .7% 0.3% 0.1%

s102 E. Schmiedel/ Eur. J. Rudiol. 18 Suppl. (1994) S97-SlO3

Table 8 Pain on injection of iomeprol

Indication N Absent Mild Moderate Severe Missing data

Conventional angiography

Intraarterial DSA

Selective coronary arteriography + angiocardiography

Interventional coronary arteriography


Intravenous DSA


Computed tomography

Urography


Cavemosography


Total

787’

795’

576

121

138”

681’

498

346”

449

130

146

286”

682 86.7%

778 97.9%

568 98.6%

120 99.2%

II9 86 2% 664

97.5’% 492

98.8% 344

99.4% 443

98.7% 130

100% 141

96.6% 267

93.3%

4748 102 84 I6 95.7% 2. I’% I .I’%, 0.3%

49 6.2%

7 0.9%

5 0.9%

IO 7.2%

I3 1.9%

3 0.6%

I 0.3%

3 0.7%

3 2 2.1% I .4’%,

8 8 2.8% 2.8%

47 6.0%

8 1 .O’%, 3

0.5% I

0.8% 8

5.8% 2

0.3% 1

0.2% I

0.3% 3

0.7%

9 1.1%

I 0. I’%

I 0.7%

2 0.3%

I 0.2%

2 0.7%

I 0. I ‘%,

I 0.2%

I 0.3%

3 0. I%


sensation and because iomeprol400 was one of the con- tion was observed more often with iomeprol400 (2.3%) centrations tested in peripheral arteriography. The than with iomeprol 150 (0.2%) (Table 7). sensation of heat depends particularly on the osmolality A comparable result is shown clearly by the distribu- of the contrast medium. Therefore, a severe heat sensation of intensity in the symptom pain, even though

Table 9 Frequency and intensity of pain of different iomeprol concentrations

Concentration N Absent Mild Moderate Severe Missing data

150 mgl/mt 428 417 6 97.4% I .4’%

200 mgl/ml 536 526 4 98.1% 0.7%

250 mgl/ml I50 149 I 99.3% O.?“/;I

300 mgl/ml 1961 1897 41 96.7% 2. I”/;,

350 mgl/ml 1123 1068 22 95. I % 2.0%

400 mgl/ml 155 691 28 91.5% 3.7%

3 0.7%

5 0.9%

21 6 2 1.1% 0.3% 0. I ‘%I 26 1 I 2.3% 0.1% 0. I ‘%I 29 7 3.8% 0.9%

Total 4953’


4748 102 84 I6 3 95.7% 2. I % I . 7% 0.3% 0. I ‘%I

E, Schmiedel/Eur. J. Radiol. 18 Suppl. (1994) S97-S103

severe pain was reported relatively rarely overall. As expected, it was recorded most often in conventional peripheral arteriography, at 1.1% (Table 8). Even with injection of iomeprol400, severe pain occurred in only 0.9% of cases (Table 9).

4. Diioll

The aim of the Phase III clinical trial was to evaluate the 6 available concentrations of iomeprol in all the common radiographical methods within a large nonselected patient population (n = 48 11) from over 150 study centres. The main parameters were the evaluation of adverse reactions [3] and the contrast density.

The nonselected patient population showed a high proportion of risk factors, such as cardiovascular diseases (45.3%), allergic predisposition (22.0%) and kidney diseases (15.1%). High total doses of the contrast medium were used, in some cases over 300 ml iomeprol.

The contrast density was evaluated as good or satisfactory in 99% of cases (3980/4020). In 1.9% of the patients, it was not possible to make a radiological diagnosis; the investigators attributed this to the contrast medium in only 0.2% of cases. The local tolerance of iomeprol is extremely good. Severe heat sensations were reported by only 1.25% of patients, although the highly- concentrated iomeprol 400 had been injected in 15.7% and iomeprol 350 had been injected in 23.3% of the patients. This result is confirmed by the evaluation of the parameter pain. Severe pain was reported by only 0.3% and moderate pain by only 1.7% of the total patient

SlO3

population during and after injection of the contrast medium.

A critical note on the value of open studies is called for in this connection. Open studies are still necessary to show that a new contrast medium has been clinically tested in all the common radiological techniques, rather than establishing dose recommendations. The doses of contrast medium which give optimal contrast density depend mainly on the iodine content and the known injection data, so recourse can be made to clinico- radiological experience with other nonionic contrast media. Nevertheless open studies with a large sample give reliable assessment of the symptoms and frequency of side effects. Comparison with other nonionic contrast media can only be made in controlled studies, the results of which will be reported elsewhere.

5. References

Felder E, Gallotti A, Favilla A. Molecular rearrangement of 5- (a-hydroxyalkanoylaminol-2,4,6 triiodo-isophtalic acid amides. Invest Radio1 1988; 23 Suppl I: SIOI-106. Davies A, Felder E, Tirone P. Iomeprol. Drugs Future 1990; 15: 1074-1076 Schmiedel E. Evaluation of the adverse effects of iomeprol. Em J Radio1 1994; 18 Suppl I: SlO4-SlO8. Guglielmino L, Minguzszi P. Piscitelli G, Rosati GF. lomeprol, A new nonionic low osmolar contrast medium for intravascular use: Report of phase I and phase II clinical trials. Presented at the 17th International Congress of Radiology, Paris, July l-8 1989. Abstract Book; No. 3565, 1989; 344.

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Evaluation of the contrast density of iomeprol