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Contrast Media Gianpaolo Pirovano, MD Daniel B. Goodman, MD Usha Halemane, MA, MBA Carole Venetianer, RN, MS Miles A. Kirchin, PhD Alberto Spinazzi, MD
Index terms: Contrast media, comparative studies Coronary vessels, diseases Electrocardiography Published online before print 10.1148/radiol.2332031802 Radiology 2004; 233:555–565 Abbreviations: CAD ⫽ coronary artery disease CI ⫽ confidence interval ECG ⫽ electrocardiographic 1
From Worldwide Medical Affairs, Bracco Diagnostics, Princeton, NJ (G.P., U.H., C.V., A.S.); Department of Medical Affairs, Covance Central Diagnostics, Reno, Nev (D.B.G.); and Worldwide Medical Affairs, Bracco Imaging, Via E. Folli 50, 20134 Milan, Italy (M.A.K., A.S.). Received November 7, 2003; revision requested January 28, 2004; revision received February 13; accepted March 23. Address correspondence to M.A.K. (e-mail:
[email protected]).
Author contributions: Guarantors of integrity of entire study, A.S., G.P., D.B.G.; study concepts and design, G.P., D.B.G.; literature research, C.V., M.A.K.; clinical studies, G.P., D.B.G.; data acquisition, all authors; data analysis/interpretation, C.V.; statistical analysis, U.H., C.V.; manuscript preparation, M.A.K.; manuscript definition of intellectual content, M.A.K., G.P., A.S.; manuscript editing, G.P., M.A.K.; manuscript revision/review, all authors; manuscript final version approval, A.S., M.A.K. ©
RSNA, 2004
Cardiac Electrophysiologic Monitoring after Injection of Gadobenate Dimeglumine versus Placebo in Healthy Volunteers and Patients with Cardiovascular Disease1 PURPOSE: To prospectively compare intraindividual effects of 0.2 mmol/kg gadobenate dimeglumine and placebo (saline) on cardiac electrophysiology in healthy volunteers and patients with coronary artery disease (CAD). MATERIALS AND METHODS: Gadobenate dimeglumine and saline placebo were injected intravenously approximately 72 hours apart in randomized crossover fashion in 24 healthy volunteers and 23 patients with CAD. Twelve-lead ambulatory (Holter) electrocardiographic (ECG) monitoring was performed from 3 hours preinjection to 24 hours postinjection. Quantitative and qualitative evaluation was performed with automated algorithmic interpretations and blinded assessment by one cardiologist. Possible QT-interval prolongation was evaluated after correction for heart rate on an individualized basis and by means of Bazett formula. Statistical analyses based on two-sided confidence intervals (CIs) were performed by using a linear model for a two-period crossover design. All subjects were monitored for vital signs, laboratory variables, and adverse events. RESULTS: Placebo was administered before contrast agent in 12 volunteers and 12 patients and after contrast agent in 12 volunteers and 11 patients. For mean increase in QTc interval from baseline, a nonsignificant difference of 3.1 msec was noted between gadobenate dimeglumine and placebo (95% CI: ⫺1.8, 8.0) after individualized correction. Overcorrection for heart rate was noted with Bazett formula (mean difference, 5.6 msec; 95% CI: ⫺2.2, 13.5). Cardiologist findings were consistent with automated readings. Similar findings were noted for healthy volunteers and patients with CAD. No differences between treatments were noted for any evaluation, although more frequent qualitative changes were noted in patients with CAD. Adverse events were noted in seven of 47 (15%) subjects after gadobenate dimeglumine injection and in five of 47 (11%) subjects after injection of placebo. CONCLUSION: Injection of 0.2 mmol/kg gadobenate dimeglumine has no detrimental effect on cardiac electrophysiology or other safety parameters in healthy volunteers or patients with CAD. ©
RSNA, 2004
Pharmaceutical agents that prolong cardiac repolarization became a concern when the antihistamine terfenadine was suspected of causing a potentially fatal arrhythmia known as torsade de pointes. Terfenadine and certain other nonsedating antihistamines prolong the cardiac QT interval by inhibiting potassium channel repolarization (1). In addition to terfenadine, more than 50 compounds, including antimicrobials and antimalarials, H1 555
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antihistamines, antiarrhythmics, vasodilators and/or antiischemics, psychotropics, and a few other miscellaneous agents have been reported to cause potentially fatal arrhythmias (2,3). In view of a drug’s potential to prolong the QT interval, regulatory authorities now require that all new drugs undergo a rigorous evaluation for potential QT interval prolongation prior to the granting of marketing approval. Gadolinium-based contrast agents for magnetic resonance (MR) imaging are not among the list of agents reported to cause torsade de pointes. Nevertheless, as with therapeutic drugs, these agents now require screening for the potential to cause malignant arrhythmias. The label for the most recently marketed gadolinium-based agent indicates that discretion be used when administering the agent to patients who receive medications or who have cardiac, metabolic, or other abnormalities that may predispose them to cardiac arrhythmias (4). Gadobenate dimeglumine (MultiHance; Bracco Imaging, Milan, Italy) is a gadolinium-based agent that is approved in Europe, several Asian countries, South Africa, and Australia for contrast material– enhanced MR imaging of the central nervous system and liver. This product is currently undergoing investigation for contrast-enhanced MR angiography and MR imaging of the breast. Clinical studies conducted in more than 2500 subjects have shown that gadobenate dimeglumine is at least as safe as other approved gadoliniumbased agents in terms of the incidence and type of adverse events reported (5). Analysis of electrocardiographic (ECG) data collected at intermittent time points up to 24 hours after injection by using a conventional 12-lead ECG system revealed no marked differences between gadobenate dimeglumine and another gadolinium-based agent (gadodiamide) or between gadobenate dimeglumine and saline placebo (5). Few differences between pre- and postinjection mean values were considered clinically meaningful, and few ECG-related adverse events were reported after gadobenate dimeglumine injection (5). The purpose of our study, however, was to prospectively compare intraindividual effects of 0.2 mmol per kilogram of body weight gadobenate dimeglumine and placebo (saline) on cardiac electrophysiology in healthy volunteers and patients with coronary artery disease (CAD). 556
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MATERIALS AND METHODS The present placebo-controlled crossover clinical trial was granted institutional review board approval prior to commencement and was conducted in accordance with the Declaration of Helsinki (Helsinki, Finland, 1964) and subsequent amendments (Tokyo, Japan, 1975; Venice, Italy, 1983; Hong Kong, 1989; and Somerset West, Republic of South Africa, 1996). Written informed consent was obtained from all subjects prior to inclusion in the study.
Subjects Both male and female subjects were enrolled. Healthy volunteers were included if they were between 18 and 40 years of age and were in good health, as determined by means of medical history, physical examination, ECG findings at rest, serum chemistry, hematology, urinalysis, and serology. Patients with CAD were included if they were at least 18 years of age and had documented diagnosis of CAD with or without a history of myocardial infarction, as determined by means of ECG, nuclear medicine, or coronary angiography. Patients confirmed to have CAD were recruited from general medicine outpatient clinics. Subjects were excluded if they had received (a) gadobenate dimeglumine or another investigational compound within 30 days of contrast agent administration in the present study or (b) another contrast agent within 1 week before contrast agent administration in the present study. Subjects with a history of clinically important allergic disease, multiple drug allergies, or hypersensitivity to metals or gadolinium chelates were also excluded, as were subjects with unstable, clinically important systemic disease or any other medical condition or circumstances that would decrease the chances of obtaining reliable data or completing the study. Finally, pregnant or nursing women were excluded. In addition, volunteers were excluded for the following reasons: if they had unstable clinically important cardiovascular disease; had taken prescription medications within 4 weeks prior to contrast agent administration or had taken nonprescription systemic or topical medication that, in the opinion of the principal investigator at the center at which the study was conducted, would interfere with the study procedure or compromise safety; had taken megadose vitamin therapy or received any treatment agents known to alter major organs or systems
within 30 days prior to study agent administration; had received or donated blood or blood products in excess of 500 mL within the 3 months preceding contrast agent administration; had a clinically important illness within 4 weeks of contrast agent administration; were known to have serum hepatitis or were carriers of the hepatitis B surface antigen (HbsAg) or hepatitis C antibody; had a positive test for human immunodeficiency virus, or HIV, antibodies; or admitted to belonging to a high-risk group for contraction of HIV. Additional exclusion criteria for patients with CAD were clinically important cardiovascular disease (unstable angina or congestive heart failure [New York Heart Association Classification III or IV]) and/or unstable arrhythmias or arrhythmias for which the patient was receiving treatment (eg, atrial fibrillation, atrial flutter, bundle branch block, intraventricular conduction disorders with QRS ⬎ 0.11 second, and sustained nonsinus mechanism).
Contrast Agent Administration Each subject received in randomized fashion a single 0.2-mmol/kg bolus injection of 0.5 mol/L gadobenate dimeglumine (0.4 mL/kg) and a single bolus injection of placebo (commercially available 0.9% saline; 0.4 mL/kg). The injections were administered intravenously at a rate of 2 mL/sec on days 1 and 4 of the study (ie, the two were separated by approximately 72 hours) and in each case were followed by a 10-mL saline flush at the same injection rate. The randomization schedule that listed the sequence of agent administration (placebo administered either first or last) was stratified within the study population (ie, healthy volunteers or patients with CAD) and between sexes to ensure an equal distribution of the sequences.
Cardiac Electrophysiologic Assessments Conventional 12-lead ECG was performed for screening purposes prior to inclusion of subjects into the study. For the study itself, 12-lead Holter ECG data were recorded as continuous individual 10-second ECGs (ie, six individual 10second 12-lead ECGs per minute) by using a Holter device (SEER MC; GE Medical Systems, Milwaukee, Wis). Each of the subjects in each study session wore the Holter device from 3 hours prior to injection until 24 hours after inPirovano et al
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jection. The device recorder collected each 10-second ECG during the 27hour period, with the exception of a brief pause (approximately 5 minutes) to change the data card approximately 11 hours after injection. To minimize movement artifact, the limb leads were placed on the lateral clavicles and lower anterior torso. The subjects were instructed to remain recumbent and quiet at specified time points designated in advance as critical for evaluation of ECG data. These time points occurred each minute during the first 15 minutes after injection (period 1); at 30 and 45 minutes and at 1, 1.25, 1.5, 1.75, and 2 hours during the time period from 15 minutes to 2 hours after injection (period 2); at 2.5, 3, 3.5, 4, 4.5, 5, 5.5, and 6 hours during the time period from 2 to 6 hours after injection (period 3); and at 8, 10, 12, 14, 16, 18, 20, 22, and 24 hours during the time period from 6 to 24 hours after injection (period 4). The ECG data acquired during the first two periods were averaged over 1-minute time frames to give final values that were the average of six 10-second tracings. The data acquired during the third and fourth time periods were averaged over 5-minute time frames to give final values that were the average of 30 10-second tracings. The ECG parameters for the 10-second tracings were interpreted automatically by means of an integrated electronic software system (12SL Marquette interpretive software; GE Medical Systems). The compilation and averaging of values over the 1- and 5-minute time frames was performed by a central reading service (Covance Central Diagnostics, Reno, Nev). Each ECG waveform was screened automatically and manually for technical artifact or failure. Automated screening led to the rejection of grossly noisy tracings, while manual screening led to the rejection of all ECGs more than 6 kB in size. Manual screening for technical adequacy was conducted at the central reading service by one technician with 3 years of experience who was blinded to the identity of both the agent administered and the subject. ECGs with an uninterpretable signal-to-noise ratio that arose from motion artifact, somatic muscle signal, electric interference, electric failure, or recorder failure were excluded from the analysis. All ECGs that were technically adequate were included for analysis.
Quantitative ECG Assessment Selected technically adequate 10-second individual ECGs were printed and Volume 233
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subjected to manual review and interpretation by an independent board-certified cardiologist with 25 years of experience who was unaffiliated with the study site and was blinded to the identity and clinical profile of the subjects and to the agent administered. The printed ECGs were systematically sampled at the midpoint of each analysis period for reference and quality control purposes and for comparison with the values calculated by the automated software. The quantitative data collected for automated and blinded cardiologist analysis comprised heart rate, R-R interval (60/heart rate), PR interval, QRS interval, and QT interval. Correction for the QTc interval (QT interval corrected to a standardized heart rate of 60 beats per minute) was determined initially by using the Bazett formula (6): QTc ⫽ QT/公R-R. However, the Bazett formula is known to overcorrect at elevated heart rates and to undercorrect at reduced heart rates (7,8). Consequently, additional individualized corrections for the QTc interval were performed, as proposed previously (9). For this evaluation, a correction factor for each subject was determined on the basis of the individual 10-second QT and R-R data for the entire 3-hour baseline period (ie, six values per minute for the 3-hour period ⫽ 1080 values for each subject). A nonlinear regression model (QT ⫽  䡠 R-R␣) was fitted, where  is the location parameter and the slope ␣ is an estimate of the individualized correction factor for each subject (9). Individualized QTc (QTcI) values were then determined from the individual 10-second QT values by means of the following formula: QTcI ⫽ QT/R-R␣. After correction for heart rate, the quantitative QTc data from both the automated read and blinded cardiologist assessment were analyzed to determine possible differences between gadobenate dimeglumine and placebo in terms of the mean maximum increase in QTc interval from baseline. Additional analysis of the automated read data was performed to determine whether the comparative effects of gadobenate dimeglumine and placebo on the QTc interval were influenced by subject sex or the presence of CAD. Finally, changes in heart rate and QTc interval of potential clinical importance (heart rate higher than ⫾10 beats per minute and QTc interval from ⫾30 – 60 msec and greater than ⫾60 msec) after administration of gadobenate dimeglumine and placebo were compared according to population.
Since the PR and QRS intervals are not considered markers of the potential of a drug to cause malignant arrhythmias, less emphasis was placed on the evaluation of these data. Nevertheless, changes of potential clinical importance (⬎32 and ⬎16 msec, respectively) over the course of the 24-hour monitoring period were noted, and comparisons were made between gadobenate dimeglumine and placebo.
Qualitative ECG Assessment Qualitative assessment of each technically adequate ECG recording was performed by the cardiologist for the presence or absence of pathologic U waves, abnormal T-wave morphology, postinjection arrhythmias, and postinjection QT dispersion (ie, QT dispersion [difference between longest single QT value on the tracing and shortest QT value in any other lead for the same beat] ⬎ 100 msec). Clinically important T-wave morphology included waves that were tall (amplitude ⱖ 10 mm), flat (amplitude ⬍ 1 mm), diphasic (positive ⫺ negative—that is, amplitude ⱖ positive 1 mm, followed by amplitude ⱖ negative 1 mm but ⬍ negative 5 mm; or negative ⫺ positive—that is, amplitude ⱖ negative 1 mm but ⬍ negative 5 mm, followed by amplitude ⱖ positive 1 mm), slightly negative (amplitude ⱖ negative 1 mm but ⬍ negative 5 mm without diphasic T waves), or deeply negative (amplitude ⱖ negative 5 mm with or without diphasic T waves). Notched (transient change in sign of the slope) and low (T/R ratio ⬍ approximately 1:10) T waves were considered “borderline” and not clinically important. Finally, the off-site cardiologist also made an overall evaluation of the ECGs to determine if they were normal or abnormal, and if they were abnormal, whether they were possibly clinically important.
Other Safety Assessments The principal investigator at the center in which the study was performed (a dedicated clinical trials unit) monitored all subjects for adverse events from the time of the signing of the consent form until the end of the 24-hour postinjection follow-up period for each agent administered. The investigator was blinded to the drug administered but not to clinical information or the medical history of the subject. Adverse events were classified as Cardiac Electrophysiologic Monitoring
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either serious (ie, causing death, life threatening, requiring or prolonging hospitalization, or resulting in persistent or substantial disability or incapacity) or not serious (rated as mild, moderate, or severe). The relationship of each adverse event to the study agent was classified as probable, possible, not related, or unknown. Safety was also evaluated in terms of changes in vital signs (blood pressure, heart rate, and respiratory rate) and laboratory variables (hematology, blood chemistry, and urinalysis) from the time of physical examination before injection. Physical examination was performed at screening, within 24 hours prior to agent administration, and at 24 hours after administration of each agent. Measurement of vital signs was performed at screening; 10 minutes, 20 minutes, and 3 hours before injection; immediately after injection; and 5, 10, and 20 minutes and 1, 2, 4, 8, and 24 hours after injection. Laboratory evaluations were performed with blood and urine samples obtained at screening, at 4 hours before injection, and at 1, 8, and 24 hours after injection. The principal investigator evaluated all pre- to postinjection changes in physical chemistry, vital signs, and laboratory parameters for clinical relevance and determined whether they met the definition of an adverse event.
Statistical Methods For primary analyses, differences in mean QTc values from baseline were determined at the time points specified earlier. A linear model for a two-period crossover design was used for the assessment of the mean maximal increase in QTc interval from baseline. Subject, period, and treatment effects were included in the model. A two-sided confidence interval (CI) for the difference between gadobenate dimeglumine and placebo was constructed by using the standard error obtained from the linear model. Secondary analyses included graphic and tabular displays of summary statistics for QT and other ECG parameters (heart rate, PR, QRS) and also included qualitative analyses of subjects identified with specified ECG morphology. Sample size was determined by using the method of Kupper and Haffner (10) for estimation of a tolerance interval. The primary hypothesis was that the mean maximal increase in the QTc interval from before injection of gadobenate dimeglumine to after injection is similar to the mean maximal increase in the QTc 558
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TABLE 1 Subject Information Parameter
No. of Healthy Volunteers
No. of Patients with CAD
No. of Total Subjects
Randomization Placebo given first Placebo given last Subjects given injections Men Women Study completed Study discontinued Included in primary ECG analysis After contrast agent After placebo Included in other ECG evaluations After contrast agent After placebo Included in other safety evaluations After contrast agent After placebo
24 12 12 24 12 12 24 0 23 23 23 24 24 23 24 24 24
23 12 11 23 11 12 23 0 20 20 20 23 23 21 23 23 23
47 24 23 47 23 24 47 0 43 43 43 47 47 44 47 47 47
interval from before injection of placebo to after injection. A two-sided 95% CI was constructed by using the estimated difference in least squares means and the standard error obtained from the linear model. For a two-sided 95% CI for the difference in the mean maximal increase in QTc interval between the study agents, a sample size of 44 subjects provided 80% coverage probability for a CI for which the half-width is equal to 33% of the true standard deviation in this difference. For example, if the standard deviation is 15 msec, then the half-width of the CI for this difference would be 5 msec with 80% coverage probability. The comparability of the two study groups (placebo administered first and placebo administered last) in terms of mean (⫾ standard deviation) subject age and population was confirmed statistically by means of a t test and a 2 test, respectively.
RESULTS Subjects A total of 129 subjects signed the consent form, and 47 subjects were randomized and received the injections. One subject, a 67-year-old man with CAD, was mistakenly enrolled in the study twice; only data from the first randomization were pooled with the data from the other subjects and used in the overall analysis. Of the 82 subjects not randomized, 46 subjects did not show up to be admitted to the clinic for study participation, 27 subjects were screened as alternates, six subjects had laboratory abnor-
malities at screening that disqualified them as participants, two female subjects were disqualified because pregnancy could not be excluded, and one subject withdrew consent. The 47 randomized subjects comprised 24 healthy volunteers (12 men, 12 women; mean age, 33 years ⫾ 4.6; range, 25– 40 years) and 23 patients with CAD (11 men, 12 women; mean age, 62 years ⫾ 7.0; range, 48 –73 years). Twenty-four subjects (six healthy men, six healthy women, six men with CAD, and six women with CAD; mean age, 47 years ⫾ 16; range, 28 –73 years) were randomized to receive placebo first, then gadobenate dimeglumine. Twenty-three subjects (six healthy men, six healthy women, five men with CAD, and six women with CAD; mean age, 47 years ⫾ 15.3; range, 25–70 years) were randomized to receive gadobenate dimeglumine first, then placebo. There was no statistically significant difference between the two groups in terms of either age (P ⫽ .867) or the numbers of patients and healthy volunteers (P ⫽ .882). The disposition of subjects according to treatment group is summarized in Table 1. All randomized subjects completed the study (ie, received both gadobenate dimeglumine and placebo and underwent postinjection evaluations) and were included in the assessment of all parameters; however, three subjects (one healthy volunteer and two patients with CAD) did not have technically adequate 12-lead ECG baseline data after the administration of placebo and were included only in the assessment of cardiac electrophysiology after administration of Pirovano et al
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interval) because the patient did not have technically adequate QTc data after administration of placebo for at least two time points between 11 and 15 minutes after injection.
Cardiac Electrophysiology
Figure 1. Graphs show mean pre- to postinjection changes, as determined with automated reading. A, Changes in heart rate. B, Changes in QT interval. Despite a slightly faster mean heart rate in the first 30 minutes after gadobenate dimeglumine (E) administration compared with that of placebo (f), mean change from baseline for uncorrected QT interval was more negative in the first minutes after gadobenate dimeglumine administration. bpm ⫽ beats per minute.
Figure 2. Graphs show mean pre- to postinjection changes, as determined with automated reading. A, Changes in QTc interval after Bazett correction. B, Changes in QTc interval after individualized correction. Overcorrection of QT interval for heart rate was apparent when the Bazett formula was used but not when individualized correction was used. There was no significant difference in QTc interval prolongation between gadobenate dimeglumine (E) and placebo (f) compared with baseline.
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from the primary analysis of cardiac electrophysiology (maximum change in QTc
Quantitative results.—The mean pre- to postinjection changes in heart rate and QT interval, as determined by means of automated readings throughout the 24hour monitoring period, are shown in Figure 1. Changes in mean heart rate from mean baseline values ranged between ⫺2.9 and 2.2 beats per minute during the first 4 hours after placebo administration. After administration of gadobenate dimeglumine, a mean maximal change from baseline of 8.3 beats per minute was noted within the first 5 minutes, but by approximately 30 minutes after injection, the difference compared with placebo had disappeared. The mean changes in QT interval during the first 4 hours after injection were similarly small and constant after administration of placebo, ranging between ⫺4.5 and 7.4 msec. In comparison, slightly more negative mean changes were apparent during the first 30 minutes after gadobenate dimeglumine administration, but after this time point, the profiles for gadobenate dimeglumine and placebo were similar for the remainder of the 24-hour monitoring period. Determination of the QTc interval on an individualized basis and by means of the Bazett formula is shown in Figure 2. With the Bazett formula, the mean changes from baseline after placebo administration were small, ranging between ⫺3.4 and 6.1 msec at each of the postinjection time points. In comparison, transient mean increases (3.9 –11.3 msec) were noted within the first 5 minutes after gadobenate dimeglumine administration. Thereafter, the profile for gadobenate dimeglumine resembled that of placebo, with only small mean changes of between ⫺3.6 and 4.3 msec observed at any time point during the remainder of the 24-hour monitoring period. In comparison, the postinjection changes in QTc interval obtained by means of individualized correction were smaller for both placebo and gadobenate dimeglumine, reflecting the more accurate correction for heart rate with this technique. With placebo, overall changes in QTc interval ranging between ⫺17.0 and 7.5 msec were observed during the 24-hour monitoring period when individualized correction was used. Conversely, with gadobenate dimeglumine, Cardiac Electrophysiologic Monitoring
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Note.—Numbers in parentheses are 95% CIs. Normal range for QTc interval is 320 – 450 msec. SD ⫽ standard deviation, SE ⫽ standard error. * Baseline is the mean of all recorded values from 15 to 30 minutes before injection. † Postinjection value from 1 minute to 2 hours, where the maximum increase from baseline occurred, and maximum postinjection increase from baseline from 1 minute to 2 hours. ‡ Least squares, based on analysis of variance model that includes study agent and period as fixed effects and subject as random effect. § Difference is gadobenate dimeglumine minus placebo.
⫺2.6 ⫾ 3.1 (⫺8.9, 3.7) 1.8 ⫾ 4.4 (⫺7.1, 10.6) 3.1 ⫾ 2.4 (⫺1.8, 8.0) 5.6 ⫾ 3.9 (⫺2.2, 13.5) Difference§ in Mean Change‡ ⫾ SE
31.3 ⫾ 2.2 (26.8, 35.9) 33.9 ⫾ 2.2 (29.4, 38.4) 46.0 ⫾ 3.2 (39.5, 52.5) 44.2 ⫾ 3.2 (37.8, 50.7) 16.2 ⫾ 2.0 (12.1, 20.3) 25.6 ⫾ 2.8 (19.9, 31.3) Mean change‡ ⫾ SE
20.0 ⫾ 2.8 (14.3, 25.7)
13.1 ⫾ 2.0 (9.0, 17.2)
31.3 ⫾ 15.5 33.9 ⫾ 14.2 46.0 ⫾ 21.4 44.2 ⫾ 21.0 16.2 ⫾ 13.8 25.6 ⫾ 20.6 20.0 ⫾ 16.1 Maximum increase from baseline (mean ⫾ SD)†
13.1 ⫾ 12.6
454.3 ⫾ 22.6 455.5 ⫾ 26.4 477.3 ⫾ 27.3 475.2 ⫾ 28.2 432.3 ⫾ 24.8 451.0 ⫾ 29.1 445.6 ⫾ 29.2 Postinjection value (mean ⫾ SD)†
427.6 ⫾ 26.4
423.0 ⫾ 21.9 431.3 ⫾ 23.3 431.0 ⫾ 23.3 425.4 ⫾ 18.6 425.6 ⫾ 19.3 Baseline (mean ⫾ SD)*
414.5 ⫾ 19.7
416.1 ⫾ 18.8
421.5 ⫾ 24.4
Contrast Agent (n ⫽ 44) Placebo (n ⫽ 44) Contrast Agent (n ⫽ 44) Placebo (n ⫽ 44) Contrast Agent (n ⫽ 43) Placebo (n ⫽ 43) Contrast Agent (n ⫽ 43) Placebo (n ⫽ 43) Parameter
Individual Correction Bazett Correction
Off-Site Cardiologist Assessment Automated Reading
Individual Correction Bazett Correction
TABLE 2 Maximum Increase in QTc Interval from Baseline within First 2 Hours after Injection as Determined by Means of Automated Reading and Off-Site Blinded Cardiologist Assessment
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minor increases ranging between 0.6 and 4.4 msec were noted within the first 5 minutes after injection, followed by overall decreases in the range between ⫺15.6 and ⫺0.2 msec for the remainder of the 24-hour monitoring period. The changes in PR and QRS intervals from baseline were minimal over the course of the 24-hour monitoring period, and few differences between placebo and gadobenate dimeglumine were apparent. The trends were similar for all quantitative parameters for both healthy volunteers and patients with CAD. Analysis of maximal increases in QTc interval from baseline during the first 2 hours after injection is shown in Table 2 for the automated read and the off-site blinded cardiologist assessment. Although slight differences in baseline QTc values were apparent between the automated and blinded cardiologist reads and within each assessment for values corrected on an individual basis or by means of the Bazett formula, no marked postinjection differences between gadobenate dimeglumine and placebo were observed in either assessment. The differences (gadobenate dimeglumine ⫺ placebo) in mean changes from baseline, as determined by means of least squares fitting, were 5.6 msec (95% CI: ⫺2.2, 13.5) and 3.1 msec (95% CI: ⫺1.8, 8.0) for automated values corrected by means of the Bazett formula and on an individualized basis, respectively, and 1.8 msec (95% CI: ⫺7.1, 10.6) and ⫺2.6 msec (95% CI: ⫺8.9, 3.7), respectively, for evaluations performed by the blinded cardiologist. The 95% CIs for the small differences between placebo and gadobenate dimeglumine in each case contained zero. These differences were therefore not statistically significant and were not considered to be of clinical concern. Automated evaluation of the mean maximum change in QTc interval from baseline revealed slightly lower mean QTc values (a) for healthy volunteers than for patients with CAD and (b) for men than for women (Table 3). With Bazett correction, the mean maximum increase in QTc interval from baseline was similar among the two population subgroups and was comparable to that of the population as a whole, ranging from 24.6 to 26.7 msec after administration of gadobenate dimeglumine and from 18.3 to 22.0 msec after administration of placebo. With the more accurate individual correction, smaller mean maximum increases in QTc interval from baseline were seen when compared with Bazett
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TABLE 3 Maximum Increase in QTc Interval from Baseline within First 2 Hours after Injection as Determined by Means of Automated Reading according to Population and Subject Sex
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A: Maximum Increase according to Subject Population Healthy Volunteers (n ⫽ 23) Parameter Bazett correction Baseline* Postinjection value† Maximum increase from baseline† Individual correction Baseline* Postinjection value† Maximum increase from baseline†
Patients with CAD (n ⫽ 20)
Placebo
Contrast Agent
Placebo
Contrast Agent
416.9 ⫾ 12.6 435.2 ⫾ 17.8 18.3 ⫾ 10.0
417.0 ⫾ 11.6 441.6 ⫾ 28.1 24.6 ⫾ 22.1
435.5 ⫾ 21.1 457.6 ⫾ 35.2 22.0 ⫾ 21.3
435.0 ⫾ 20.6 461.8 ⫾ 27.0 26.7 ⫾ 19.2
406.6 ⫾ 12.8 417.2 ⫾ 16.4 10.6 ⫾ 8.3
408.3 ⫾ 9.4 420.4 ⫾ 16.9 12.1 ⫾ 13.9
423.6 ⫾ 22.6 439.5 ⫾ 30.9 16.0 ⫾ 15.9
425.0 ⫾ 22.8 445.9 ⫾ 25.6 20.9 ⫾ 12.4
B: Maximum Increase according to Subject Sex Male (n ⫽ 22) Parameter Bazett correction Baseline* Postinjection value† Maximum increase from baseline† Individual correction Baseline* Postinjection value† Maximum increase from baseline†
Female (n ⫽ 21)
Placebo
Contrast Agent
Placebo
Contrast Agent
417.9 ⫾ 17.3 435.3 ⫾ 22.0 17.3 ⫾ 11.1
418.3 ⫾ 15.7 444.3 ⫾ 26.1 26.0 ⫾ 21.4
433.6 ⫾ 18.3 456.4 ⫾ 32.3 22.9 ⫾ 20.0
432.8 ⫾ 18.8 458.0 ⫾ 31.0 25.2 ⫾ 20.2
409.5 ⫾ 17.0 419.6 ⫾ 21.1 10.1 ⫾ 8.6
410.6 ⫾ 16.4 427.2 ⫾ 23.2 16.6 ⫾ 15.9
419.7 ⫾ 21.4 435.9 ⫾ 29.3 16.3 ⫾ 15.3
421.8 ⫾ 19.8 437.6 ⫾ 25.8 15.7 ⫾ 11.6
Note.—Values are mean ⫾ standard deviation. Normal range for QTc interval is 320 – 450 msec. * Baseline is the mean of all recorded values from 15 to 30 minutes before injection. † Postinjection value from 1 minute to 2 hours, where the maximum increase from baseline occurred, and maximum postinjection increase from baseline from 1 minute to 2 hours.
correction, and more marked increases were noted for patients with CAD (20.9 msec for gadobenate dimeglumine, 16.0 msec for placebo) than for healthy volunteers (12.1 msec for gadobenate dimeglumine, 10.6 msec for placebo). Few differences between male and female subjects were noted when mean changes in QTc interval were evaluated according to subject sex, although the increases were again smaller with individualized correction than with Bazett correction. Slightly greater increases were noted on the basis of data of the off-site blinded cardiologist. Similar overall patterns were observed, however, particularly with regard to individual correction producing smaller increases than Bazett correction (maximal increases from baseline of 35.5 msec ⫾ 14.1 and 32.3 msec ⫾ 14.4 after placebo administration and 28.8 msec ⫾ 17.4 and 34.0 msec ⫾ 12.8 after gadobenate dimeglumine administration in healthy volunteers and patients with CAD, respectively, following individualized correction, compared with 51.2 msec ⫾ 23.5 and 36.7 msec ⫾ 14.9 after placebo administration and 44.6 msec ⫾ 22.6 and 47.5 msec ⫾ 20.4 after gadobenate dimeglumine administration, respectively, after Bazett correction was performed). Volume 233
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With regard to individual changes in QTc intervals, many subjects had both increases and decreases of the same magnitude within the same measured time frame, indicating the normal fluctuations in QTc intervals that might be expected over a period of time. In most subjects, the fluctuations from baseline were less than 30 msec over the course of the 24-hour monitoring period, and among these subjects, more than half of the changes were less than 20 msec in magnitude. For QTc intervals determined by using individualized correction, increases of potential clinical concern (⬎30 msec) were considerably less frequent than decreases of the same magnitude after administration of both placebo and gadobenate dimeglumine. The opposite trend was apparent when using Bazett correction, however. With this approach, increases in the QTc interval of potential clinical concern (⬎30 msec) were more frequent than decreases of the same magnitude after administration of both gadobenate dimeglumine and placebo. The difference between the two correction techniques was clearly apparent for increases of the QTc interval of more than 60 msec. With individualized correction, only one increase (one of 47 sub-
jects, 2%) of more than 60 msec was noted after gadobenate dimeglumine administration (between 15 minutes and 2 hours after injection) within the 24-hour monitoring period, compared with two increases (two of 44 subjects, 4%) after placebo administration (one between 15 minutes and 2 hours after injection and the other between 2 and 24 hours after injection). Conversely, with Bazett correction, nine occurrences of QTc prolongations of more than 60 msec were reported within the 24-hour monitoring period, of which three (three of 44 subjects, 7%) occurred after placebo administration, and six (six of 47 subjects, 13%) occurred after gadobenate dimeglumine administration. Quantitative changes in heart rate and QTc intervals of potential clinical importance, as determined by means of automated read for healthy volunteers and patients with CAD, are summarized in Table 4. Transient increases in heart rate of more than 10 beats per minute were noted in almost all healthy volunteers and patients with CAD after both gadobenate dimeglumine and placebo administration at some point during the 24hour monitoring period. Although more subjects reported transient increases in heart rate after gadobenate dimeglumine Cardiac Electrophysiologic Monitoring
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TABLE 4 Summary of QTc Changes of Potential Clinical Importance according to Population
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Healthy Volunteers Time Point
Change
Placebo (n ⫽ 23)
Patients with CAD
Contrast Agent (n ⫽ 24)
Placebo (n ⫽ 21)
Contrast Agent (n ⫽ 23)
3 (14) 6 (28) 5 (24) 11 (52) 6 (28) 20 (95)
3 (13) 9 (39) 5 (22) 16 (70) 6 (26) 23 (100)
2 (10) 0 2 (10) 1 (5) 3 (14) 1 (5) 2 (10) 1 (5) 4 (19) 3 (14) 4 (19) 2 (10)
3 (13) 0 2 (9) 0 5 (22) 0 4 (17) 0 11 (48) 0 8 (35) 0
1 (5) 1 (5) 2 (10) 2 (10) 2 (10) 1 (5) 2 (10) 2 (10) 1 (5) 2 (10) 3 (14) 3 (14)
1 (4) 0 6 (26) 2 (9) 1 (4) 0 7 (30) 2 (9) 2 (9) 0 8 (35) 4 (17)
Heart Rate (beats per minute) 1–15 min postinjection 1 min to 2 h postinjection 1 min to 24 h postinjection
Decrease ⬎ 10 Increase ⬎ 10 Decrease ⬎ 10 Increase ⬎ 10 Decrease ⬎ 10 Increase ⬎ 10
3 (13) 8 (35) 4 (17) 15 (65) 7 (30) 23 (100)
0 15 (62) 4 (17) 16 (67) 10 (42) 23 (96)
QTc Interval (msec), Individual Correction 1–15 min postinjection
1 min to 2 h postinjection
1 min to 24 h postinjection
Decrease ⬎ 30–60 Decrease ⬎ 60 Increase ⬎ 30–60 Increase ⬎ 60 Decrease ⬎ 30–60 Decrease ⬎ 60 Increase ⬎ 30–60 Increase ⬎ 60 Decrease ⬎ 30–60 Decrease ⬎ 60 Increase ⬎ 30–60 Increase ⬎ 60
2 (9) 0 0 0 3 (13) 0 0 0 9 (39) 1 (4) 4 (17) 0
2 (8) 0 0 0 3 (12) 0 1 (4) 1 (4) 7 (29) 0 3 (12) 1 (4)
QTc Interval (msec), Bazett Correction 1–15 min postinjection
1 min to 2 h postinjection
1 min to 24 h postinjection
Decrease ⬎30–60 Decrease ⬎ 60 Increase ⬎ 30–60 Increase ⬎ 60 Decrease ⬎ 30–60 Decrease ⬎ 60 Increase ⬎ 30–60 Increase ⬎ 60 Decrease ⬎30–60 Decrease ⬎ 60 Increase ⬎ 30–60 Increase ⬎ 60
1 (4) 0 3 (13) 0 1 (4) 0 3 (13) 0 2 (9) 0 6 (26) 0
0 0 4 (17) 0 0 0 3 (12) 2 (8) 1 (4) 0 7 (29) 2 (8)
Note.—Numbers in parentheses are percentages.
administration than after placebo administration within the first 15 minutes after injection, this was less apparent at time points beyond 15 minutes after injection. Overall, few differences were apparent between healthy volunteers and patients with CAD, in terms of either the incidence of subjects with changes of potential clinical importance or the effects of the two agents. Decreases of QTc intervals of potential clinical importance (⬎30 – 60 msec or ⬎60 msec) occurred more frequently than increases of the same magnitude when determined by using individualized correction. The trends were similar for healthy volunteers and patients with CAD, and no marked differences were evident between gadobenate dimeglumine and placebo. Conversely, increases of potential clinical concern were more frequent than decreases of the same magnitude, after both gadobenate di562
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meglumine and placebo administration, when Bazett correction was used. Particularly noteworthy was the difference between individualized correction and Bazett correction within the first 15 minutes after injection. Whereas individualized correction revealed an increase of more than 60 msec in one patient with CAD who received placebo, Bazett correction resulted in increases of more than 60 msec in four patients overall (two after placebo administration and two after gadobenate dimeglumine administration). Similarly, increases from 30 – 60 msec were noted in considerably fewer subjects after individualized correction than after Bazett correction. Overall, increases of more than 60 msec during the 24-hour monitoring period were noted for just three subjects after individualized correction (one healthy volunteer who received gadobenate dimeglumine and two patients
with CAD who received placebo). Conversely, increases of more than 60 msec during the 24-hour monitoring period were observed for nine subjects when Bazett correction was used (two healthy volunteers and four patients with CAD after gadobenate dimeglumine administration and three patients with CAD after placebo administration). Few subjects overall had changes in PR and QRS intervals that met the criteria of potential clinical importance (⬎32 msec and ⬎16 msec, respectively), and changes that were observed occurred more frequently after placebo administration than after gadobenate dimeglumine administration, in both healthy volunteers and patients with CAD. From measurements taken throughout the 24-hour postinjection monitoring period, seven of 44 (16%) subjects after placebo administration and two of 47 (4%) subjects after gadobenate dimeglumine administration Pirovano et al
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TABLE 5 Summary of Qualitative Changes in ECG as Determined by Off-Site Cardiologist Healthy Volunteers (n ⫽ 24) Parameter T waves* Any T wave* 1–15 min postinjection 30 min to 2 h postinjection 2.5–6 h postinjection 8–24 h postinjection Flat or slightly negative 1–15 min postinjection 30 min to 2 h postinjection 2.5–6 h postinjection 8–24 h postinjection Pathologic U waves㛳 1–15 min postinjection 30 min to 2 h postinjection 2.5–6 h postinjection 8–24 h postinjection Postinjection arrhythmia 1–15 min postinjection 30 min to 2 h postinjection 2.5–6 h postinjection 8–24 h postinjection
Patients with CAD (n ⫽ 23)
Placebo
Contrast Agent
Placebo
Contrast Agent
5 (22)† 4 (17) 13 (54) 11 (46)
7 (29) 5 (22)† 12 (52)† 10 (42)
13 (62)‡ 13 (62)‡ 12 (60)§ 15 (65)
11 (48) 11 (48) 16 (70) 16 (70)
5 (22)† 4 (17) 12 (50) 11 (46)
6 (25) 5 (22)† 12 (52)† 10 (42)
12 (57)‡ 13 (62)‡ 12 (60)§ 15 (65)
11 (48) 11 (48) 16 (70) 16 (70)
4 (17)† 2 (8) 9 (38) 9 (38)
6 (25) 3 (13)† 8 (35)† 10 (42)
10 (48)‡ 9 (43)‡ 10 (50)§ 10 (43)
9 (39) 9 (39) 13 (56) 11 (48)
1 (4)† 0 2 (8) 0
0 0 0† 1 (4)
4 (19)‡ 3 (14)‡ 2 (10)§ 3 (13)
3 (13) 3 (13) 1 (4) 3 (13)
Note.—Numbers in parentheses are percentages. * Clinically important T-wave morphologic findings. † n ⫽ 23. ‡ n ⫽ 21. § n ⫽ 20. 㛳 Presence of U waves in conjunction with clinically important T-wave morphologic findings.
demonstrated decreases in the PR interval of more than 32 msec, compared with three of 44 (7%) subjects (placebo) and one of 47 (2%) subjects (gadobenate dimeglumine) that demonstrated increases of the same magnitude. With regard to the QRS interval, two of 44 (4%) subjects (placebo) and one of 47 (2%) subjects (gadobenate dimeglumine) demonstrated decreases of potential clinical importance during the 24-hour monitoring period, compared with six of 44 (14%) subjects (placebo) and two of 47 (4%) subjects (gadobenate dimeglumine) that demonstrated increases of potential clinical importance. Qualitative results.—A summary of the most frequent clinically important qualitative ECG changes noted by the off-site blinded cardiologist is presented in Table 5. The frequency of reports of clinically important T-wave morphologic findings, pathologic U waves, and postinjection arrhythmias was greater among patients with CAD than among healthy volunteers, but within these populations, no differences between gadobenate dimeglumine and placebo were apparent. Flat or slightly negative T waves were the most frequent T-wave morphologic findings noted, and these were noted more frequently more than 2 hours after injecVolume 233
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tion than before 2 hours after injection in both study populations. Reports of clinically important tall, deeply negative, and diphasic T waves were infrequent over the course of the 24-hour monitoring period. They occurred overall just one (tall), three (deeply negative), and six (diphasic) times after placebo administration and zero (tall), two (deeply negative), and three (diphasic) times after gadobenate dimeglumine administration. Whereas U waves were noted in nearly all of the subjects over the course of the 24-hour monitoring period for each agent administered, the presence of pathologic U waves (U waves in conjunction with clinically important T-wave morphologic findings) was noted in fewer than half of the subjects. No differences between gadobenate dimeglumine and placebo were apparent, although a slight tendency for more reports among patients with CAD than among healthy volunteers was noted, particularly during the first 2 hours after injection. Reports of postinjection arrhythmias were infrequent, occurring in three healthy volunteers (ectopic atrial rhythm in each case) and seven patients with CAD (atrial premature systoles in four subjects; junctional rhythm and atrial
premature systoles in one subject; atrial and ventricular premature systoles in one subject; and ectopic atrial rhythm in one subject). The postinjection arrhythmias in the seven patients with CAD were observed in one patient after gadobenate dimeglumine administration only, in two patients after placebo administration only, and in the remaining four patients after both gadobenate dimeglumine and placebo administration. The arrhythmias in the healthy volunteers were observed in two volunteers after placebo administration and in one volunteer after gadobenate dimeglumine administration.
Other Safety Results A total of 13 adverse events were reported overall by seven of 47 (15%) subjects after gadobenate dimeglumine administration, while nine adverse events were reported by five of 47 (11%) subjects after placebo administration. One of the 12 subjects to experience an adverse event did so after administration of both gadobenate dimeglumine and placebo. The percentage of subjects with adverse events was comparable between the two randomized sequences (placebo first, six of 24 subjects, 25%; gadobenate dimeglumine first, five of 23 subjects, 22%). Most adverse events (17 of 22, 77%) were reported after the administration of the first agent in the randomized sequence. The most frequently reported event was hypertension, which was reported by four of 47 (8%) subjects after administration of both gadobenate dimeglumine and placebo. Headache was also reported by two of 47 (4%) subjects after placebo administration. No clinically meaningful differences between mean pre- and postinjection values for vital signs parameters were noted after placebo or gadobenate dimeglumine administration at any of the postinjection time points. Similarly, the mean and median pre- to postinjection changes in laboratory values did not indicate any clinically meaningful trends for hematology, serum chemistry, or urinalysis parameters after administration of either agent, and no adverse events were reported.
DISCUSSION ECG data acquired previously by using conventional 12-lead ECG recording equipment at intermittent time points up to 24 hours after injection revealed that shifts from normal range and changes of potential clinical importance Cardiac Electrophysiologic Monitoring
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occurred infrequently after administration of gadobenate dimeglumine (5). When they did occur, such changes tended to be distributed evenly between small increases and small decreases, with no discernable pattern or trend. In these earlier evaluations, which were conducted during the course of clinical trials of gadobenate dimeglumine, the pattern of change was similar in patients who received gadobenate dimeglumine and those who received an active comparator (gadodiamide) or placebo (saline). Generally, any minor changes observed reflected the normal variability associated with acquisition of ECGs in conjunction with MR imaging procedures, especially when exacerbated by anxiety or claustrophobic reactions (5). An important feature of the present study was the use of continuously recorded automated ECG measurements in the absence of association with any imaging procedure. This approach permitted the collection of robust QTc data during the rapid changes in gadobenate dimeglumine concentration. No potential transient effects were overlooked. The large number of data points permitted averaging of individual QTc values, thereby reducing the effects of biologic variation of the QTc interval. The study, which was conducted in a highly standardized and rigorous manner in the absence of other possibly stressful diagnostic procedures, permitted a full and accurate assessment of the temporal profile during a 24-hour monitoring period. Further, the parallel information from the blinded cardiologist confirmed the validity of the conclusions drawn from the automated data. The results of the present study confirm the conclusions of ECG evaluations conducted previously (5) in that gadobenate dimeglumine has no detrimental effect either on cardiac electrophysiology in general or the QTc interval in particular. Principal among the various ECG parameters for these purposes is the QTc interval, since abnormal QTc interval prolongation is recognized as a major surrogate marker of potential proarrhythmic activity (11). The association between treatment-related QTc interval prolongation and proarrhythmic cardiac toxicity of new drugs has been reported previously for both cardiac and noncardiac compounds (1–3,12). In the present study, no evidence for proarrhythmic cardiac toxicity was apparent; the difference in mean maximum increase from baseline between gadobenate dimeglu564
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mine and placebo for the QTc interval was not statistically significant, regardless of whether correction was performed on an individualized basis (3.1 msec ⫾ 2.4) or by means of the Bazett formula (5.6 msec ⫾ 3.9). Furthermore, the mean values for the QTc interval in the study remained stable over the course of the 24 hours for both study agents, and the small number of subjects for whom the QTc interval increased by more than 60 msec was distributed evenly after gadobenate dimeglumine and placebo administration. With individualized correction, mean maximal QTc interval increases of only 13.1 and 16.2 msec were recorded after the administration of placebo and gadobenate dimeglumine, respectively. These values and those obtained when using Bazett correction (20.0 and 25.6 msec, respectively) may result not only from the fact that there is a distribution of normal values among different individuals but also from the fact that measurements in the same individual may fluctuate greatly over the course of a 24-hour period. In this regard, it has been shown that the QTc interval may vary from as little as 15 msec to as much as 70 msec in the same subject (13). Holter studies have showed the variability in QTc interval to be as much as 76 msec ⫾ 19 from day to night in healthy subjects, with maximum QTc values of more than 500 msec (14). These variations may be even greater in patients with cardiovascular disease (15). It has been demonstrated that sympathetic and parasympathetic tone alter the relation between QT interval and heart rate. As a result, QTc values vary with changes in autonomic tone (13). It should also be noted that while considerable effort was made to limit the stress incurred during the study, a limited amount of stress associated with study procedures is inevitable. Given the above considerations and the fact that QTc prolongation is not generally a potential clinical risk unless it exceeds 60 msec (11), a transient nonsignificant alteration of 3.1 msec compared with that of placebo (5.6 msec by means of Bazett correction) cannot be considered a clinical concern. As discussed in the Food and Drug Administration concept article (16) and in a recent meeting of the Cardiovascular and Renal Drug Advisory Committee (17), minimal changes of this type are not considered to represent an increased risk for development of torsade de pointes. Support for the absence of any effect of gadobenate dimeglumine on the QTc interval comes from
the fact that gadolinium-based contrast agents of this type are not among the list of drugs known to cause torsade de pointes (2,3,18). More specifically, no torsade de pointes or other events suggestive of prolongation of ventricular repolarization have been reported either during the clinical development program for gadobenate dimeglumine in Europe and the United States (5) or during postmarketing surveillance of approximately 500,000 patients across Europe and Asia (Bracco, unpublished data, 2003). Particularly noteworthy in the present study is the marked difference in QTc values for QT intervals corrected for heart rate on an individual basis, compared with QT intervals corrected by using the Bazett formula. Until recently, the Bazett formula was implemented in many clinical studies (7,19) of QTc prolongation for the determination of QTc values, despite the fact that this approach is known to overcorrect at elevated heart rates and to undercorrect at reduced heart rates (7,8). An alternative approach to correction of the QT interval for heart rate involves the use of the technique of Fridericia (20). However, the correction achieved with this formula has also been shown to be variable (8). In the present study, there were no healthy volunteers or patients with CAD for whom heart rate was elevated excessively after gadobenate dimeglumine compared with placebo: The mean maximal change from baseline within the first 5 minutes after gadobenate dimeglumine administration was 8.3 beats per minute. Nevertheless, this minimal alteration of heart rate, which can be attributed in large part to anxiety in subjects undergoing study procedures of this type, led not only to overcorrected QTc values during the first 5 minutes after injection but also to considerably more reports of prolongations of QTc interval with potential clinical importance (⬎60 msec) during the 24-hour monitoring period: Nine occurrences were reported when Bazett correction was implemented, compared with three when individualized correction was used. Not unexpectedly, comparison of the QTc interval of healthy volunteers with that of patients with CAD showed higher mean baseline and postinjection values for the latter after both placebo and gadobenate dimeglumine were administered. A similar pattern was noted for female subjects compared with male subjects. Patients with CAD were generally heavier and older than the healthy volunteers, which may have put these Pirovano et al
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subjects at increased risk for changes in cardiac electrophysiology. Notably, female sex and prolonged QT duration at baseline are background factors thought to be associated with abnormal repolarization and possibly increased incidence of malignant arrhythmias (2). The results of the other safety evaluations demonstrate that gadobenate dimeglumine injected as a bolus dose of 0.2 mmol/kg is well tolerated in both healthy volunteers and patients with CAD. There were no clinically meaningful trends in vital signs or clinical laboratory results, and any individual abnormalities that were noted were attributed to concomitant illnesses or medications. Shifts from baseline were generally comparable after administration of gadobenate dimeglumine and placebo and between healthy volunteers and patients with CAD. The overall incidence and type of adverse events reported were similar to those reported previously for the gadobenate dimeglumine clinical program as a whole (5). Of particular interest is the fact that more than 75% of the reported adverse events occurred after administration of the first agent in each randomized sequence and that the overall incidences of adverse events for the two sequences were similar (placebo first, 25%; placebo last, 22%). Not surprisingly, the proportion of subjects with adverse events was higher in the patients with CAD (gadobenate dimeglumine, 22%; placebo, 18%) than in the healthy volunteers (gadobenate dimeglumine, 8%; placebo, 4%). The patients with CAD often had cardiovascular medical histories accompanied by type II diabetes or lipid abnormalities; thus, it was not unexpected that the higher incidence of adverse events comprised mainly cardiovascular symptoms. The present study was designed to be as comprehensive, robust, and accurate an evaluation of the potential effects of gadobenate dimeglumine on cardiac electrophysiology parameters as possible. However, whereas the evaluation of 47 subjects according to a fully randomized intraindividual crossover protocol provided sufficient power to meet the objectives of the study fully in terms of confirming that gadobenate dimeglumine
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has no significant effect on QTc interval prolongation compared with placebo, it was perhaps insufficient to permit conclusions to be drawn regarding the absence of potential adverse effects on secondary safety parameters. On the other hand, a full safety evaluation of gadobenate dimeglumine based on clinical trials in almost 3000 subjects for a number of possible indications has been published recently (5) and indicates that the overall incidence of adverse events associated with gadobenate dimeglumine is at least as good as that observed with other available gadolinium-based agents. In conclusion, the results of the present study indicate that a dose of 0.2 mmol/kg gadobenate dimeglumine is safe and well tolerated with respect to both quantitative (heart rate, QT, QTc, PR, and QRS intervals) and qualitative (presence of U waves, clinically important T-wave changes, postinjection arrhythmias) determinants of cardiac electrophysiology, both in healthy volunteers and in patients with CAD. In particular, it is the absence of any significant effect on the QTc interval relative to placebo in these subjects that extends the previously established safety profile of this agent and confirms its suitability for intravenous administration in human subjects. Acknowledgments: The authors thank Nalina Dronamraju, PhD, Ningyan Shen, MD, PhD, and Deborah Hoss, BSc, of Bracco Diagnostics, Princeton, NJ, and Mark Donovan, MS, of Covance, Princeton, NJ, for their contributions to the acquisition and analysis of data. References 1. Yap YG, Camm AJ. The current cardiac safety situation with antihistamines. Clin Exp Allergy 1999; 29(suppl 1):15–24. 2. Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and proarrhythmia by non-antiarrythmic drugs: clinical and regulatory implications. Eur Heart J 2000; 21:1216 –1231. 3. Priori SG. Exploring the hidden danger of noncardiac drugs. J Cardiovasc Electrophysiol 1998; 9:1114 –1116. 4. OptiMark [package insert]. St Louis, Mo: Mallinckrodt, 1999. 5. Kirchin MA, Pirovano G, Venetianer C, Spinazzi A. Safety assessment of gadobenate dimeglumine (Multihance): extended clinical experience from phase I studies to post-marketing surveillance. J Magn Reson Imaging 2001; 14:281–294. 6. Bazett HC. An analysis of time relations of
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