Original Article
A Comparison of Nonionic, Low-Osmolality Radiocontrast Agents with Ionic, High-Osmolality Agents during Cardiac Catheterization
N Engl J Med 1992; 326:431-436February 13, 1992
- Abstract
- Abstract
Background.
Nonionic, low-osmolality radiocontrast agents are used frequently because they are believed to be safer than ionic, high-osmolality agents, but they are also more expensive. We conducted a randomized trial to compare the incidence of adverse events after the administration of ionic, high-osmolality and of nonionic, low-osmolality radiocontrast agents during cardiac angiography.
Methods.
We compared the need to treat patients for adverse reactions and the frequency and severity of specific hemodynamic, systemic, and symptomatic side effects in two groups of patients randomly assigned to receive either ionic, high-osmolality or nonionic, low-osmolality radiocontrast material, and also in 366 patients who could not be randomized.
Results.
Treatment for adverse events was required in 213 of 737 patients who received high-osmolality contrast agents (29 percent) but in only 69 of 753 patients who received nonionic agents (9 percent) (95 percent confidence interval for the percent difference, 15.9 to 23.6 percent). Hemodynamic deterioration and symptoms also occurred more often in the high-osmolality group, as did severe or prolonged reactions (2.9 percent, as compared with 0.8 percent in the nonionic group; P = 0.035). The severe reactions were largely confined to patients with severe cardiac disease. Multivariate analysis showed that the presence of severe coronary disease and unstable angina were predictors of clinically important adverse reactions. If all the patients in our randomized trial had been given nonionic contrast material, the incremental cost per procedure would have been $89.
Conclusions.
Nonionic, low-osmolality contrast material is better tolerated during cardiac angiography than ionic, high-osmolality contrast material. Since cost constraints may prevent the universal use of nonionic contrast material, its selective use in patients with severe cardiac disease could be considered. (N Engl J Med 1992;326: 431–6.)
Article Activity
- Article
CONVENTIONAL contrast agents used for intravascular imaging are solutions of sodium or meglumine salts. When they are injected into the intravascular space, two osmotically active particles are administered for every three iodine atoms. Thus, when sodium diatrizoate is administered in a formulation that has an iodine content of 37 percent (e.g., Renografin 76), the resulting solution has an osmolality about 5.8 times (1690 mOsm per liter) that of plasma, which may contribute to its adverse side effects. To reduce the osmolality of contrast material, several classes of new agents have been introduced. The nonionic monomers (e.g., iopamidol) have eliminated the sodium and meglumine ions while maintaining three iodine atoms per molecule. Thus, at an iodine content equivalent to that of Renografin 76, the osmolality of iopamidol is about 680 mOsm per liter.
Low-osmolality agents cause less discomfort, and their use may decrease the incidence of side effects during cardiac angiography.1 The incidence of hypotension, cardiac arrhythmias, and pulmonary edema may be reduced in patients at high risk, such as those with recent myocardial infarction, unstable angina, hypotension, or severe heart failure.2 Unfortunately, few randomized, controlled trials comparing high-osmolality with low-osmolality agents during cardiac angiography have been undertaken. Furthermore, the number of patients enrolled in such studies has been small, and some have not used clinically important outcome measures.3 , 4 Further trials have been recommended to determine whether nonionic agents actually perform better than high-osmolality ones and, if so, whether their benefits pertain to all patients or only to those at high risk.5
The principal problem with the new contrast agents is their cost — 10 to 20 times that of conventional agents in North America. Thus, cost needs to be considered as well as effectiveness in any decision about which material should be used and in which patients.6 Previous studies have suggested that the marginal increase in cost for nonionic agents is very high,7 amounting to $186 more per cardiac catheterization.8
Our randomized, controlled, double-blind clinical trial had the following objectives: to compare the incidence of important side effects after the intracardiac injection of high-osmolality, ionic contrast agents and low-osmolality, nonionic agents; to identify patients at high risk for adverse reactions; and to compare the cost effectiveness of low-osmolality, nonionic agents with that of high-osmolality, ionic agents.
Methods
Over a period of 17 months (ending in August 1990), 1856 consecutive adult patients who underwent cardiac catheterization without angioplasty during the working hours of the research nurses were considered for entry into the study. The only prespecified criteria for exclusion from the study were a history of anaphylactoid reaction to contrast material (in 32 patients) and a cardiac condition severe enough for the cardiologist to insist on the use of a nonionic contrast agent (188 patients). These conditions included low-output left ventricular failure, unstable angina, and myocardial infarction during the previous week. Not all the patients with these clinical conditions were excluded from the randomized trial. However, in 125 additional cases the cardiologist refused for other reasons to allow the patient to enter the study, and 21 patients declined to enter the study. Of 366 nonrandomized patients, 267 received nonionic contrast agents (72.9 percent), 56 received lowosmolality ionic agents (15.3 percent), and the remaining 43 received high-osmolality agents. All the nonrandomized patients were followed in the same manner as the patients in the randomized groups.
Seven hundred thirty-seven patients were randomly assigned to receive high-osmolality contrast material (either Renografin 76 or MD-76), and 753 patients were assigned to receive nonionic, low-osmolality contrast material (iohexol in 33 patients and iopamidol in 720). The outcomes of contrast infusion were determined by the doctor, the cardiopulmonary technician, and the patient, all of whom were unaware of the contrast agent that was being used. The research nurse was responsible for the assignment of contrast material and was also an unblinded recorder of events during and after the procedure, as reported by the patient, doctor, and technician. A questionnaire containing demographic data (age and sex), a clinical history (previous reactions to contrast material and a history of allergies, asthma, cardiac disease, renal impairment, diabetes mellitus, anxiety, and other illnesses), and a history of medications used was completed by the research nurse for each patient before randomization.
The serum creatinine concentration was measured on the day of each patient's procedure. Because the risk of clinically important contrast nephropathy is low in patients with normal renal function,9 the serum creatinine was measured again two days after the procedure, but only if the initial value was above 120 μmol per liter ( 1.36 mg per deciliter). One hundred fifty-three patients had elevated serum creatinine levels on the day of cardiac catheterization, and follow-up levels were obtained in 123 patients (80 percent).
After the insertion of the catheter, the patient's arterial blood pressure, heart rate, and heart rhythm were recorded continuously. The type and dose of contrast material were also recorded, as was the duration of catheterization. After the infusion of contrast material, the occurrence of asystole, hypotension, angina, arrhythmias, and any other adverse reactions was recorded, as was the type of treatment required to manage the reactions. After the procedure, the results of the coronary arteriography and left ventriculography were obtained. On leaving the cardiac catheterization laboratory, each patient was asked to complete a short questionnaire containing scales on which grades (from 0 for no symptoms to 10 for the most severe symptoms imaginable) were assigned to indicate the presence and severity of nine symptoms: pain, warmth, nausea, vomiting, sneezing, itching, shortness of breath, chest tightness, and any other symptom. Any side effect occurring during the 30 minutes after the procedure was also recorded.
The research protocol was approved by the Human Investigation Committee of Memorial University of Newfoundland. Informed consent was obtained from each patient.
Categories of Reaction
Four categories of adverse reactions to contrast material were distinguished among the patients studied. Category 1 included reactions requiring treatment by a doctor. This was the primary outcome of interest, and it was assigned if the patient received any treatment from a doctor for an adverse reaction to contrast material. Reactions severe enough to necessitate the unblinding of the cardiologist were included in this category. Standard criteria were not used in determining which patients required treatment. Category 2 included clinically important adverse events possibly related to the use of contrast material that were themselves life-threatening, possibly predictive of a life-threatening event, or sufficiently severe to be likely to interrupt or delay the completion of the angiography. These events were defined to include angina that was not relieved by the use of one nitroglycerin tablet, tachyarrhythmias of new onset that required treatment, bradyarrhythmias or conduction-system disturbances of new onset that required treatment, and a decrease in systolic blood pressure to less than 80 mm Hg for more than one minute or a decrease in blood pressure that required therapy. Category 3 included symptoms that were subjectively severe —i.e., those that were rated 5 or higher on the symptom scale. Category 4 included severe, prolonged reactions. Unlike those in the first three categories, these reactions were evaluated retrospectively by investigators unaware of the type of contrast agent prescribed. They included angina requiring the use of multiple drugs, ventricular fibrillation or severe tachyarrhythmia requiring treatment, prolonged hypotension requiring multiple interventions, and prolonged cardiac arrest.
Effect of Patients' Characteristics on the Incidence of Reactions
A number of covariates were examined to see whether they influenced the reaction rates. These included sex and age; any history of adverse reaction to contrast material, allergy, asthma, diabetes mellitus, impairment of renal function (as indicated by a serum creatinine level greater than 120 μmol per liter), cardiac failure, myocardial infarction, hypertension, intermittent claudication, or transient ischemic attacks; the presence and severity of coronary artery disease, left ventricular dysfunction, or valvular disease as determined during the catheterization; and the dose and type of contrast material infused. The effect of the potential covariates was analyzed by examining the frequency of the need to treat adverse reactions in the subgroup of patients corresponding to each covariate and also by combining the covariates in a multivariate analysis.
Cost Analysis
The records of all randomized patients who had a clinically important reaction during cardiac catheterization were reviewed to determine what changes in medical care were needed. The number of additional days spent in the coronary care unit or on the ward as a result of an adverse reaction to contrast medium was assessed without knowledge of the type of contrast material used, as was the number of additional medications and other treatments needed. The average cost to the hospital of extra days spent in the hospital was determined for each patient, as was the actual cost to the hospital of the resources used to treat an adverse event. The average increase in cost incurred when a patient spent a day in the coronary care unit rather than on a ward was used when appropriate. All hospital costs are stated in 1991 U.S. dollars.
Statistical Analysis
Continuous variables are presented as medians or means ±SD. All statistical tests were two-tailed, with a significance level of 0.05. The Bonferroni procedure10 was used to adjust for multiple comparisons. Incidence rates and relative risks are presented with 95 percent confidence intervals. The effect of nonionic contrast material on the rate of reactions and the effects of binary covariates were assessed by the chi-square test or Fisher's exact test.10 Continuous variables were compared by t-tests or Mann—Whitney U tests,10 depending on the distribution of the variables. A stepwise multiple logistic-regression analysis11 was performed with BMDP software to assess the effect of several potential predictors on the incidence of clinically important adverse events. The variables were added to the models and removed from them singly by both automated and deliberately determined stepping procedures to allow the detection of multicollinearity. All variables of potential clinical importance were examined in this fashion. The interactions between several variables were also assessed. The odds ratios presented are those obtained from a final model using all the independent variables hitherto found to have a predictive effect.
During the enrollment of the patients who underwent cardiac angiography, it became apparent that there was a high frequency of adverse cardiovascular events requiring therapy. The frequency of such events in the first 1490 patients enrolled was reported to the study's external adviser, who recommended that a full analysis of the data be performed. After this analysis, the cardiac-catheterization arm of the trial was stopped. Another arm of the study, investigating the systemic toxicity of intravenous contrast agents, was continued.12
Results
Status of Patients at Base Line
Randomized Trial
Table 1Table 1
Characteristics of the Patients in the Randomized Trial. shows the characteristics of the patients with regard to demographic status, clinical and medication history, and dose and type of contrast material infused, whereas Table 2Table 2
Results of Cardiac Catheterization in the Randomized Trial, According to the Degree of Cardiac Disease. shows the results of cardiac catheterization in the randomized patients. The two randomized groups were well matched with respect to demographic and clinical variables and types of drugs prescribed (Table 1) and the degree of cardiac disease at the time of catheterization (Table 2).Nonrandomized Patients
As compared with the randomized patients, the 220 patients who were excluded from the randomized trial for medical reasons had more severe previous cardiac illness (previous myocardial infarction in 140 patients, or 63 percent; and unstable angina in 146 patients, or 66 percent) and were more likely to be severely ill (95 patients, or 43 percent) or to have a history of adverse reaction to contrast material (36 patients, or 16.3 percent).
Adverse Reactions
The number of patients treated by the cardiologist for adverse reactions after the use of high-osmolality contrast material was high (28.9 percent), and the relative risk for such treatment was 3.1 (95 percent confidence interval, 2.5 to 4.1 ) when the high-osmolality group was compared with the nonionic group (Table 3Table 3
Adverse Reactions to Contrast Material in the Randomized Trial.*). In 29 patients assigned to receive high-osmolality contrast material, the only intervention was a switch to low-osmolality contrast material. In addition, the incidence of clinically important angina, hypotension, and bradycardia was substantially higher in the high-osmolality group (Table 3). Urticaria occurred in 20 patients in this group (2.7 percent) and was treated in 9 (1.2 percent), but only 1 patient assigned to nonionic contrast material had urticaria (0.1 percent; P<0.0001), and it was not treated. Nonionic contrast material was associated with a lower incidence of severe symptoms, particularly pain, chest tightness, and nausea (Table 4Table 4
Severe Symptoms after the Administration of Contrast Material.*).Severe or prolonged reactions (category 4) occurred in 21 patients in the high-osmolality group (2.9 percent) and 6 patients in the nonionic group (0.8 percent) (Table 3). In the high-osmolality group, these reactions included angina requiring treatment with multiple drugs (11 patients), ventricular fibrillation (5 patients), prolonged hypotension requiring multiple interventions (4 patients), and prolonged cardiac arrest (1 patient). In the nonionic group, four of the six patients had angina requiring the use of morphine (one of whom had a myocardial infarction during cardiac catheterization), one had ventricular tachycardia requiring lidocaine, and one had atrial fibrillation requiring verapamil and digoxin.
All but three of the patients who had severe or prolonged reactions had severe coronary disease, advanced valvular disease, or poor left ventricular function. Of the 27 severe events, 22 occurred in patients who could have been identified in advance as being at high risk because of unstable angina, current heart failure, previous coronary-artery bypass grafting, or known three-vessel coronary disease. There were no deaths related to the procedure, and no episodes of permanent disability or damage were attributable to the administration of contrast material in the study.
The average time from the insertion of the catheter to its removal was similar in the two randomized groups (13.7±8.8 minutes in the high-osmolality group and 13.6± 10.6 minutes in the low-osmolality group).
Sixty-four patients who received high-osmolality contrast material had elevated serum creatinine levels on the day of the cardiac catheterization, and follow-up serum creatinine levels were obtained in these patients. Three patients in this group (5 percent) had increases in their serum creatinine levels of at least 25 percent but less than 50 percent, and another three patients had increases of more than 50 percent. Of 59 patients who randomly received nonionic contrast material and had serum creatinine levels above 120 μmol per liter before the procedure, 2 patients (3 percent) had increases in their serum creatinine levels of more than 25 percent but less than 50 percent, and 1 patient (2 percent) had an increase of more than 50 percent. Given the relatively small sample and the low incidence of contrast-related nephropathy, these differences were not significant. A more detailed analysis of patients with contrast nephropathy after intravascular infusion of contrast material will be published separately.13
The patients who were excluded from the randomized trial for medical reasons had a higher incidence of most adverse reactions than the patients randomly assigned to receive nonionic contrast material; in 17 percent as compared with 9.2 percent, respectively (P = 0.002), treatment for an adverse reaction was required. Despite being at higher risk, the patients excluded from randomization for medical reasons had a lower incidence of adverse reactions than the patients randomly assigned to receive high-osmolality contrast material.
Effect of Covariates
A univariate analysis of all the covariates mentioned above revealed that the only patients who derived a higher-than-average relative benefit from the use of nonionic contrast material were those with diabetes mellitus (relative risk, 6.6; 95 percent confidence interval, 2.7 to 16.3) and those with a previous adverse reaction to contrast material (relative risk, 7; 95 percent confidence interval, 1 to 50). Patients who were severely ill needed treatment more frequently in both study groups (40.5 percent of patients in the high-osmolality group and 12.6 percent in the nonionic group). With increasing severity of coronary disease, there was an increase in the number of patients requiring treatment (for single-vessel disease, 27.1 percent in the high-osmolality group and 4.2 percent in the nonionic group; for two-vessel disease, 35.7 and 11.1 percent; for three-vessel disease, 39.1 and 17.9 percent; and for disease of the left main coronary artery, 38.2 and 22.0 percent).
In the multiple logistic-regression analysis, the following independent variables were found not to be associated with adverse events of clinical importance (category 2): age; sex; a previous adverse reaction to contrast material; a history of allergy or asthma; the presence of impaired renal function, valvular heart disease, or diabetes; the degree of left ventricular dysfunction; and the dose of contrast material.
The best predictors of a clinically important adverse reaction were the presence of severe coronary disease (disease of the left main coronary artery, three-vessel disease, or coronary-artery bypass grafting) (odds ratio, 1.5; 95 percent confidence interval, 1.2 to 1.8) and unstable angina (odds ratio, 1.2; 95 percent confidence interval, 1.03 to 1.5). When these variables were combined, there was little additional predictive association with the occurrence of an adverse reaction.
Cost
The length of the hospital stay was the same (median, five days) in the two randomized groups. The stays of the patients excluded from the randomized trial for medical reasons were significantly longer (median, 11 days; P<0.0001 for the comparison with the randomized groups).
With respect to the medical care required to treat adverse events possibly related to the use of contrast agents, the differences between the two randomized groups included 20 days spent in the coronary care unit rather than on a ward, 1 day spent on a ward rather than as an outpatient, the insertion and maintenance of two pacemakers, and many different medications. In all, the cost of these interventions was $6,000. For the high-osmolality group, contrast material cost $16,333 (including the cost of the nonionic material provided to the patients whose treatment was switched), whereas for the same number of patients in the nonionic group, the contrast material cost $87,843. Thus, the incremental cost of nonionic contrast material was $65,509, or $89 per patient undergoing cardiac catheterization. Thirty-nine percent of the patients in the randomized groups had heart failure at the time of the procedure, myocardial infarction within the previous two weeks, unstable angina, previous coronary-artery bypass grafting, known three-vessel coronary disease, or advanced valvular disease. If only these "high-risk" patients had been given nonionic contrast material, the marginal cost would have been $114 for each high-risk patient undergoing catheterization.
If all the patients in the trial had been given nonionic contrast material, it would have been necessary to treat 50 patients to prevent one serious or prolonged adverse reaction, and the marginal cost for each such reaction prevented would have been $4,450 (Table 5Table 5
Cost Effectiveness of Nonionic Contrast Material in the Randomized Trial, According to the Group of Patients Chosen to Receive It.). If only the high-risk patients had been given nonionic contrast material, it would have been necessary to treat 27 patients to prevent one such reaction, and the marginal cost of preventing that reaction would have been $2,363 (Table 5).Discussion
There have been persistent requests for trials to provide better information about the benefits of using expensive nonionic contrast agents. To date, few large randomized trials have been reported,3 and many have not commented on the clinical consequences of the adverse reactions.
We observed a high frequency of adverse reactions requiring treatment after the use of high-osmolality contrast material. The rate of such events was higher than that reported by Hirshfeld et al. in a similar population of patients given high-osmolality contrast agents.5 This may be because we included as events treatment given for angina or bradycardia and requests for unblinding. In fact, many of the adverse effects seen with the use of contrast material in our trial were relatively minor and short-lived. Nevertheless, more clinically important adverse events also occurred. The incidence of serious arrhythmias and prolonged angina in our study was similar to that noted in others.5 , 14 Severe, prolonged reactions were infrequent, but they were also more likely when high-osmolality contrast material was used.
The particular formulations of high-osmolality contrast material used in our trial contained calcium-chelating additives. These agents have been associated with a significantly higher incidence of ventricular fibrillation than have similar high-osmolality agents that do not chelate calcium.15 , 16 Although the use of a non-calcium-chelating formulation of high-osmolality contrast material might have prevented some of the episodes of ventricular fibrillation seen only after the use of high-osmolality contrast material in our study, there is no evidence that the non-calcium-chelating high-osmolality material can prevent other contrast-related reactions. Nor has there been any adequate comparison between nonionic contrast material and non-calcium-chelating formulations of high-osmolality agents.
Virtually all patients undergoing cardiac catheterization were eligible for this trial, but the cardiologists excluded many who they believed would be at excessive risk with the use of high-osmolality contrast material. These patients were more seriously ill and had more adverse reactions than those randomly assigned to the same nonionic contrast agent. However, they had fewer adverse events than the patients who received high-osmolality contrast material in the randomized trial. Nearly all the most serious adverse reactions to either contrast agent occurred in patients with advanced cardiac disease, and the multivariate analysis of the randomized groups identified severe coronary disease and unstable angina as risk factors for clinically important adverse events in this already selected group.
We found that the universal use of nonionic contrast material for the type of patients included in our randomized trial would have cost an extra $89 per patient undergoing the procedure. In the United States, nonionic contrast material costs up to 20 times as much as high-osmolality agents. The figure of $186 was reported as the added cost of iopamidol over diatrizoate in a recent U.S. trial.8 Of course, if nonionic contrast material was given selectively only to those at higher risk for adverse reactions, the cost effectiveness would improve.
The results of this trial underscore the problem confronting those who determine health policy when a new therapy is found to be superior to a conventional one but at higher cost. No formal guidelines have been agreed on to aid in deciding how much society is willing to pay to achieve a given degree of improvement in the health status of its members. Analyses of cost effectiveness alone cannot usually be used to compare disparate and competing health care programs. Decisions about which programs should be funded are often influenced by factors other than their cost effectiveness.6 , 7
We conclude that nonionic contrast material is better tolerated during cardiac angiography than a calcium-chelating formulation of high-osmolality contrast material, but the universal use of nonionic contrast material would be expensive. It may be possible to use it selectively in the patients at highest risk for serious adverse effects — a more economical policy. Should the price of nonionic agents decrease, their universal use in the cardiac catheterization laboratory would become more feasible.
Supported by grants from Health and Welfare Canada; the General Hospital; and the General Hospital Health Foundation. Dr. Barrett is a Kidney Foundation of Canada Fellow, and Mr. O'Dea was supported by the Federal Challenge '90 program.
We are indebted to the following cardiologists who participated in this study: Drs. E. Stone, C. McCallum, B. Sussex, M. Furey, A. Williams, B. Rose, and S. Missan; and to Dr. J.D. Harnett of the Health Sciences Centre, St. John's, who was the external adviser to the trial.
Source Information
From the Division of Nephrology (B.J.B., P.S.P., H.M.V., F.O., G.K.) and the Division of Cardiology (E.S.), Department of Medicine, the General Hospital, the Health Sciences Centre, Memorial University, St. John's, Newf., Canada. Address reprint requests to Dr. Parfrey at the Division of Nephrology, The Health Sciences Centre, St. John's, NF A1B 3V6. Canada.
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