Original Article
Safety and Cost Effectiveness of High-Osmolality as Compared with Low-Osmolality Contrast Material in Patients Undergoing Cardiac Angiography
N Engl J Med 1992; 326:425-430February 13, 1992
- Abstract
- Abstract
Background and Methods.
Low-osmolality contrast agents produce fewer hemodynamic and electrophysiologic alterations during cardiac angiography, but they are 20 times more expensive than high-osmolality contrast agents. In a randomized, double-blind trial comparing a nonionic, low-osmolality contrast agent (Omnipaque 350) with a high-osmolality agent that does not avidly bind calcium (Hypaque 76) in 505 patients undergoing cardiac angiography, we determined the incidence of minor, mild, moderate, and severe adverse reactions, identified risk factors for such reactions, and evaluated the cost effectiveness of various strategies for the use of contrast material.
Results.
The 253 patients who received a high-osmolality contrast agent were three times more likely to have a moderate adverse reaction (95 percent confidence interval for the relative risk, 1.6 to 5.5) but no more likely to have a severe reaction (95 percent confidence interval, 0.2 to 2.3) than the 252 patients who received a low-osmolality agent. All 10 severe reactions occurred in patients who were older than 60 years or had unstable angina. Patients with these characteristics were also 3.5 times more likely (95 percent confidence interval, 1.8 to 6.8) to have a moderate reaction (44 of 310 patients, or 14 percent) than those without either characteristic (8 of 195 patients, or 4 percent). We estimated that the incremental cost of each moderate reaction avoided would be $1,698 with a strategy that involved giving a low-osmolality contrast agent only to patients who were over 60 years of age or had unstable angina, instead of giving a high-osmolality agent to all patients. The incremental cost per moderate reaction avoided by giving a low-osmolality contrast agent to all patients rather than only to those over 60 or with unstable angina would be $5,842.
Conclusions.
The use of contrast agents with low rather than high osmolality during cardiac angiography reduces the risk of moderate, but not of severe, adverse reactions to the agent used. A strategy of reserving low-osmolality contrast agents for use in patients at high risk for adverse reactions would be more cost effective than one requiring their use in all patients. (N Engl J Med 1992;326:425–30.)
Media in This Article
Table 1
Characteristics of the Patients.*Table 2
Adverse Reactions in the Patients Undergoing Cardiac Angiography.*Article Activity
- Article
NUMEROUS studies have documented that in the performance of cardiac angiography, fewer hemodynamic and electrophysiologic changes result from the use of a nonionic, low-osmolality contrast agent than from the use of a high-osmolality contrast agent.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 A few studies have suggested that high-osmolality agents that bind calcium avidly cause more hemodynamic and electrophysiologic perturbations than those that bind calcium less avidly.17 18 19 Considerable controversy remains, however, about the use of the two types of contrast agents in cardiac angiography, because those with low osmolality are substantially more expensive than those with high osmolality. The use of 200 ml of a high-osmolality contrast agent during cardiac angiography, for example, costs our hospital $8, whereas an equal amount of a low-osmolality agent costs $170. Since cardiac angiography is performed 1.2 million times annually in the United States, over $195 million more would be spent each year if a low-osmolality contrast agent were universally used for these procedures instead of a high-osmolality agent.
We undertook a randomized, double-blind trial to compare the incidence of clinically important adverse reactions related to cardiac angiography performed with a low-calcium-binding, high-osmolality agent or a nonionic, low-osmolality agent. In addition, we identified potential risk factors related to the occurrence of such reactions and evaluated the cost effectiveness of alternative strategies for the use of contrast agents during cardiac angiography.
Methods
Study Design
The patients undergoing cardiac angiography were randomly assigned, with use of a random-number table, to receive either a high-osmolality contrast agent that binds little calcium and contains meglumine diatrizoate and sodium diatrizoate (Hypaque 76) or iohexol, a nonionic, low-osmolality contrast agent (Omnipaque 350). The agents used were provided in bottles of the same size and shape, with the contents of the bottles masked by foil. The investigators, the research nurse who followed the enrolled patients during and after cardiac angiography, the personnel involved in performing the procedures, and the enrolled patients were all blinded to the contrast medium used. Thus, all outcomes were ascertained and evaluated without knowledge of the medium used.
During cardiac angiography, the attending physician could request a change to an unmasked bottle of low-osmolality contrast agent if the physician thought the patient's condition warranted such a switch. In such circumstances, the attending physician did not know which type of contrast agent had been used before the switch occurred.
After each 100 procedures were performed, a safety-monitoring committee composed of a radiologist, a nephrologist, a cardiologist, and a biostatistician reviewed the results to advise the study team whether there was any reason to halt the study to protect the patients' safety. The study was approved by our institutional review board.
Population of Patients
Patients who underwent cardiac angiography during daytime hours (8 a.m. to 4 p.m.) from April 10, 1989, through December 31, 1990, were eligible for enrollment if they were currently hospitalized, were 18 years of age or older, and had none of the following conditions: hypotension or ischemia requiring the use of pressors or intraaortic balloon pumping, suspected critical aortic stenosis, previous serious reaction to contrast medium, pulmonary hypertension, sickle cell disease, use or anticipated use of contrast medium during the 72 hours before or the 48 hours after cardiac angiography, involvement in another research protocol using cardiac catheterization, inability to give informed consent, or a decision by the attending physician that it was necessary to use a low-osmolality contrast agent. Informed consent to participate was obtained from all patients.
Cardiac Angiography
The standard medication given before cardiac angiography included 25 or 50 mg of oral diphenhydramine hydrochloride and 5 or 10 mg of oral diazepam for sedation. Unless it was contraindicated, all patients received intravenous heparin, from 2000 to 3500 units, after the artery was entered. If a patient had a history of hives or bronchospasm with the administration of contrast material, 80 to 120 mg of oral prednisone was given prophylactically the evening before and the morning of the procedure. The mean (±SE) volume of intravenous fluid administered during the 12 hours before cardiac angiography was 380±17 ml. Coronary angiography was performed with standard techniques. Ventriculography was performed in most, but not all, patients; it was performed after coronary angiography.
Data Collection
A research nurse collected data from each enrolled patient's medical record, including the patient's age, sex, race, any underlying disease, concurrent medications, blood and urine laboratory values, heart rate, and blood pressure. Continuous two-minute blood-pressure and electrocardiographic tracings were begun five seconds before the first selective injection of contrast medium into the left coronary artery. The left ventricular systolic pressure and end-diastolic pressure were recorded immediately before and after ventriculography.
Patients who had adverse reactions were monitored for as long as the reactions affected their treatment. Base-line and 24-hour or 48-hour serum creatinine levels were available for 449 patients (89 percent), and all three measurements were available for 142 patients (28 percent).
In addition, through chart review and discussion with the physician or physicians for each patient with an adverse reaction, we identified all the resources, including tests, therapeutic interventions, and additional days spent in the hospital, that would not have been used if there had not been an adverse reaction related to the use of contrast material. Hospital cost-accounting reports, actual hospital charges, and cost-to-charge ratios specific to each revenue center were used to estimate the average cost to the hospital that was associated with the increase in resources used to manage adverse reactions.
Adverse Reactions
Definition
An adverse reaction was defined as any clinical event judged by five blinded physicians on the study team to be undesirable and potentially attributable to the administration of contrast material. Nephrotoxicity was defined as an elevation in the serum creatinine level within the 48 hours after the procedure that represented both an increase of 33 percent or more and an increase of 35 μmol per liter (0.4 mg per deciliter) or more above the base-line value.
Classification of Severity of Adverse Reactions
Explicit criteria were used to classify an adverse reaction according to clinical severity into one of four levels before the data were unblinded. (These criteria are available elsewhere.*) In general, level 1 (minor) reactions were those that required no treatment (such as self-limited episodes of chest pain); level 2 (mild) reactions, those that were treated with minimal therapy (such as chest pain treated with a single tablet of nitroglycerin); level 3 (moderate) reactions, those in which multiple doses of one or more drugs were administered (such as chest pain treated with multiple nitroglycerin tablets or morphine); and level 4 (severe) reactions, those that required intensive or prolonged therapy (such as a myocardial infarction). We also conducted a sensitivity analysis in which the criteria used to define an adverse reaction as severe were relaxed. Each reaction was graded individually, and the level of severity for a given patient was defined as the highest level assigned to any of the reactions in that patient.
*See NAPS document no. 04931 for four pages of supplementary material. Order from NAPS c/o Microfiche Publications, P.O. Box 3513, Grand Central Station, New York, NY 10163–3513. Remit in advance (in U.S. funds only) $7.75 for photocopies or $4 for microfiche. Outside the U.S. and Canada, add postage of $4.50 ($1.75 for microfiche postage). There is a $15 invoicing charge for all orders filled before payment.
Data Analysis
The characteristics of the patients in the two study groups were compared by either Student's t-test or the chi-square test, corrected for continuity. Relative risks (and 95 percent confidence intervals) of various types of adverse reactions were calculated for the patients in the two groups. The risk of a moderate or severe reaction (both of any type and limited to cardiac reactions only) was evaluated in relation to the type and amount of contrast material administered, the presence of clinical conditions before cardiac angiography, and the patient's use of medications before the procedure. Logistic regression was used to estimate the relative odds (and 95 percent confidence intervals) of the occurrence of moderate or severe reactions in association with various independent variables.20 In this analysis, the variables were entered into the model in an order that reflected the independent contribution of each variable to the likelihood of a moderate or severe reaction. The Wilcoxon rank-sum test was used to compare the average costs associated with the management of moderate and severe reactions in the patients in each study group. All P values were two-tailed.
Results
Eligibility and Enrollment
Of the 1955 hospitalized patients who underwent cardiac angiography during the study period, 1247 (64 percent) met the eligibility criteria for the study. Of these, 505 (40 percent) were enrolled. Of the 708 ineligible patients, 61 percent were ineligible because there was a high likelihood of their receiving contrast material during the 48 hours after cardiac angiography (primarily because coronary angioplasty was anticipated), 10 percent because they were thought to have a critical aortic stenosis, 9 percent because they were participating in another research protocol, 7 percent because they had had a previous serious reaction to contrast material, and 13 percent for miscellaneous reasons. Of the eligible patients, 742 were not enrolled, for the following reasons: the patient did not give informed consent (53 percent), the referring physician was unwilling to enroll the patient (13 percent), the cardiology fellow considered the patient to present too high a risk to receive a high-osmolality contrast agent (8 percent), there was an administrative error (19 percent), the patient's serum creatinine level was above 354 μmol per liter (4 mg per deciliter) (2 percent), the patient had a history of psychiatric problems or was considered too anxious to be asked for informed consent (2 percent), or for other reasons (3 percent).
Characteristics of the Patients
The patients in the study groups were similar, except that the proportion who had underlying renal insufficiency (defined as a base-line serum creatinine value of at least 133 μmol per liter [1.5 mg per deciliter]) and the proportion who were taking digoxin were higher in the group receiving a low-osmolality contrast agent (Table 1Table 1
Characteristics of the Patients.*).Adverse Reactions
One hundred eighty-one of the 505 enrolled patients (36 percent) had at least one adverse reaction. A total of 263 adverse reactions occurred among these 181 patients. The majority of the reactions (75 percent) were cardiac in nature. The relative risk of bradycardia was 17.9 (P<0.001), that of hypotension 6.3 (P<0.001), and that of angina 3.4 (P<0.001) among the patients who received a high-osmolality contrast agent, as compared with those who received a low-osmolality agent (Table 2Table 2
Adverse Reactions in the Patients Undergoing Cardiac Angiography.*).When we classified the adverse reactions according to severity, 24 percent of the patients had a minor or a mild reaction but nothing more severe, 10 percent had a moderate reaction but nothing more severe, and 2 percent had a severe reaction (Table 3Table 3
Severity of Adverse Reactions in the Patients Who Had Such Reactions, According to Type of Contrast Material Used.*). Of the 10 severe reactions that occurred, 3 were myocardial infarctions, and 1 was a stroke. No patient died. The patients who received a high-osmolality contrast agent were three to four times more likely (P<0.001) to have a mild or moderate reaction than those who received a low-osmolality agent. However, there was no statistically significant difference between the groups in the risk of a minor or a severe reaction. In the sensitivity analysis, we relaxed the criteria so that an adverse reaction for which a patient received furosemide, oxygen, morphine, or a thump to the chest or that caused a decline in renal function that exacerbated an underlying problem or increased the length of a patient's stay was classified as severe rather than moderate. In this analysis, the relative risk of a severe reaction among the patients who received a high-osmolality rather than a low-osmolality contrast agent increased to 1.6 (an incidence of 6 percent as compared with 4 percent), but this increase in the relative risk was not statistically significant (P = 0.29).Risk Factors for Moderate or Severe Reactions
In bivariate analyses, 10 variables were found to be associated with a statistically significant (P<0.05) increase in the risk of a moderate or severe adverse reaction: use of a high-osmolality contrast agent, female sex, the absence of steroid therapy, age over 45, age over 60, the amount of contrast medium received, and the presence of any form of diabetes, non-insulin-dependent diabetes mellitus, angina, or unstable angina. When we performed a stepwise logistic-regression analysis, only five of these variables remained significantly associated with an increase in the risk of a moderate or severe reaction (Table 4Table 4
Risk Factors for the Occurrence of a Moderate or Severe Adverse Reaction, According to Multivariate Logistic-Regression Analysis.*). These same five variables were the only ones associated significantly (P<0.05) with the occurrence of moderate or severe cardiac reactions, rather than moderate or severe reactions of any type.Three hundred ten of the 505 patients enrolled in our study (61 percent) were older than 60 years or had unstable angina. All 10 severe reactions observed in our study occurred in these patients. The patients who were more than 60 years old or had unstable angina were also 3.5 times more likely (95 percent confidence interval for relative risk, 1.8 to 6.8) to have a moderate adverse reaction (in 44 of 310 patients, or 14 percent) than the patients with neither of these characteristics (8 of 95, or 4 percent).
Cost Effectiveness
Given the rates of adverse reactions observed in our study, and considering patients at high risk to be those who were over 60 years of age or who had unstable angina, Table 5Table 5
Three Strategies for the Use of Contrast Material in Cardiac Angiography, the Frequency of Moderate or Severe Adverse Reactions Expected with Each, and the Associated Costs.* shows the expected frequency of moderate and severe reactions and the costs related to the use of contrast agents (both the costs of the material and average hospital costs associated with the management of contrast-related adverse reactions) at the Johns Hopkins Hospital (where cardiac angiography is performed 1200 times per year) for three different strategies related to the use of contrast material. The analogous costs for the 1.2 million cardiac angiographies performed annually nationwide would be 1000 times the costs shown in Table 5.If we assume that the true incidence of severe adverse reactions is 2 percent with both high-osmolality and low-osmolality contrast agents, as we observed in our primary analysis, the exclusive use of low-osmolality contrast agents for cardiac angiography at the Johns Hopkins Hospital would increase the costs related to the use of contrast material by $220,710 per year and would reduce the number of moderate adverse reactions by 130 per year (an incremental cost of $1,698 for each such reaction avoided). The use of low-osmolality contrast agents only in patients who are 60 years of age or older or have unstable angina, in comparison, would increase the costs related to the use of contrast material by only $127,242 and would reduce the number of moderate reactions by 114 per year (an incremental cost of $1,116 for each moderate reaction avoided). The incremental cost for each moderate reaction avoided by giving low-osmolality contrast agents to all patients rather than only to those over the age of 60 or with unstable angina would be $5,842.
If, however, the true incidence of a severe adverse reaction is 5.5 percent and 3.6 percent when a low-calcium-binding, high-osmolality contrast agent and a low-osmolality contrast agent, respectively, are used during cardiac angiography (as was the case in our study when a less strict definition of a severe reaction was used), then the use of a low-osmolality rather than a high-osmolality contrast agent in all patients would result in 28 fewer severe reactions and 94 fewer moderate reactions per year, and contrast-related costs would increase by only $32,333 per year once the costs associated with managing contrast-related adverse reactions were taken into account.
Discussion
Several interesting findings emerge from our analysis. Adverse reactions, particularly bradycardia, hypotension, and angina, occur substantially more often when a low-calcium-binding, high-osmolality contrast agent is used than when a nonionic, low-osmolality contrast agent is used during cardiac angiography, but almost all these adverse reactions are easily treated. In a study in which patients undergoing cardiac angiography were randomly assigned to receive either iopamidol (a nonionic, low-osmolality contrast agent) or diatrizoate (in either a high-calcium-binding or a low-calcium-binding formulation), Hlatky et al.3 made a similar finding— that bradycardia and angina were the two types of adverse reactions most commonly reduced in frequency by iopamidol.
Our study also demonstrates that severe adverse reactions occur infrequently and that they occur with equal frequency when either a low-calcium-binding, high-osmolality contrast agent or a nonionic, low-osmolality agent is used. Depending on the stringency with which one defines an adverse reaction as severe, we observed severe reactions in 2 percent to 6 percent of the patients receiving high-osmolality agents and in 2 percent to 4 percent of those receiving low-osmolality agents. There was no statistically significant difference in the incidence of such reactions when Hypaque rather than Omnipaque was used. However, the statistical power of our study to detect a true relative risk of severe reactions of 1.6 for Hypaque as compared with Omnipaque was only 24 percent.
The incidence of severe reactions in our study was similar to the 2 percent rate of such reactions observed with the use of Hexabrix (an ionic low-osmolality contrast agent) in a study of 82 high-risk patients undergoing cardiac angiography, but lower than the rate of severe reactions (16 percent) observed among the patients who received Renografin (a high-osmolality contrast agent that binds calcium avidly) in the same study.21 Hlatky et al. observed an 8 percent incidence of severe reactions among patients who received a high-osmolality contrast agent (some received a formulation that was low in calcium binding, whereas others received a formulation that bound calcium avidly) and a 5 percent incidence of severe reactions among patients who received a nonionic, low-osmolality contrast agent.3 In an observational study of 8517 patients who underwent cardiac catheterization with a nonionic, low-osmolality contrast agent, severe reactions were observed in about 1 percent of the patients.22
Few data are available that identify risk factors for clinically important adverse reactions among patients undergoing cardiac angiography. In a recent study by Hirshfeld et al.,8 only a high New York Heart Association functional class (e.g., III, IV, or V) or an elevated left ventricular end-diastolic pressure was found to predict major adverse reactions. Other studies have identified an age of more than 60 years and the presence of heart disease as risk factors for adverse reactions among patients receiving intravenous injections of contrast material.23
Our analysis of risk factors suggests that the use of a low-calcium-binding, high-osmolality contrast agent, female sex, age over 60 years, the presence of unstable angina, and the administration of more than 250 ml of contrast medium are each independently associated with increases ranging from 2.2 to 4.2 in the relative risk of a moderate or severe adverse reaction (either of any type or specifically a cardiac reaction). All the severe reactions and 85 percent of the moderate ones in our study occurred among patients who had unstable angina or were over the age of 60. Additional studies would need to be performed in a different sample of patients to confirm the predictive power associated with these characteristics.
Finally, on the basis of our results, we estimate that the incremental cost would be $1,116 for each moderate adverse reaction avoided if a low-osmolality contrast agent were used in patients who were over the age of 60 years or had unstable angina, instead of a high-osmolality agent in all patients, whereas if a low-osmolality agent were used in all patients, rather than only in high-risk patients, the incremental cost for each moderate reaction avoided would be $5,842. If, however, the true incidence of severe reactions is 6 percent and 4 percent with high-osmolality and low-osmolality contrast agents, respectively, as was the case when we defined a severe adverse reaction less strictly, our data suggest that the use of a low-osmolality contrast agent in all patients would substantially reduce the number of moderate and severe reactions, at minimal incremental cost. These estimates do not take into consideration the liability costs associated with the use of a high-osmolality rather than a low-osmolality contrast agent,24 but they do reflect the costs associated with managing adverse reactions related to contrast material. Our estimates of the latter costs, based on the results of this study, are higher than those from an earlier observational study in which only one severe reaction occurred.25 Considering that the use of low-osmolality contrast material in intravenous procedures reduces the risk of a serious reaction by only 0.18 percent,26 the use of these agents in cardiac angiography may be more cost effective than their use in intravenous procedures, such as contrast-enhanced computed tomography of the body or intravenous pyelography. Further research to validate or refine the risk factors we have identified would be beneficial, since the use of low-osmolality contrast agents in high-risk patients undergoing cardiac angiography would be more cost effective than the use of these expensive agents in all patients undergoing cardiac angiography.
Supported by a grant from Winthrop Pharmaceuticals, Inc. Dr. Moore is a Burroughs Wellcome Scholar in pharmacoepidemiology. Dr. Powe is a Research and Teaching Scholar of the American College of Physicians.
Presented in part at the 64th annual scientific session of the American Heart Association, Anaheim, Calif., November 11–14, 1991.
We are indebted to Bob Gayler, M.D., Alan Guerci, M.D., and Alan Watson, M.D., for their generous efforts as members of the Safety Monitoring Committee overseeing this clinical trial, and to Ellie Baker, R.N., and Beryl Stoler, R.N., for assistance in data collection and follow-up of patients.
Source Information
From the Departments of Medicine (E.P.S., R.D.M., N.R.P., R.G., J.A.B.) and Radiology (E.P.S.), the Johns Hopkins School of Medicine; the Departments of Health Policy and Management (E.P.S., N.R.P., A.J.D., S.G.) and Epidemiology (R.D.M.), the Johns Hopkins School of Hygiene and Public Health; the Johns Hopkins Program for Medical Technology and Practice Assessment (E.P.S., N.R.P., A.J.D., S.G.); and the Johns Hopkins Pharmacoepidemiology Unit (R.D.M., R.G.), all in Baltimore; and the Division of Cardiology, Baptist Hospital, Jacksonville, Fla. (M.L.). Address reprint requests to Dr. Steinberg at the Johns Hopkins University, 1830 E. Monument St., Rm. 8068, Baltimore, MD 21205.
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