Since ketorolac has been marketed, it has been widely used in clinical settings other than clinical trials. As have other NSAIDs [14-18], ketorolac has been associated with acute renal failure [19-27]. The appropriate role of ketorolac and all NSAIDs has consequently been questioned, especially for patients who are considered to be at high risk for acute renal failure [13, 14].

We did a large cohort study to evaluate the effects (including nephrotoxicity) of parenteral ketorolac in the postmarketing clinical setting. We previously reported on the risks for gastrointestinal bleeding and surgical-site bleeding associated with ketorolac [28]. We now compare the potential risk for acute renal failure after administration of ketorolac with the risk after administration of opioids among hospitalized patients.

Methods

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Study Sample

This retrospective cohort study was done using 35 community-based and tertiary care hospitals in the Philadelphia area. Data collection began on 18 November 1991 and ended on 31 August 1993. All patients who were identified from hospital pharmacy records as having received parenteral ketorolac during the data collection period were potentially eligible for inclusion in the group receiving ketorolac, regardless of whether they had concomitantly received opioids. The comparison group consisted of patients who received parenteral opioids (without ketorolac) and was matched to the ketorolac group by hospital, admitting service (any medical service compared with any surgical service), and date on which therapy was initiated. Use of ketorolac or opioids was verified by examining medication administration records. Patients who were receiving long-term dialysis were excluded.

A course of ketorolac or opioids was defined as the time from administration of the first dose through the third day after administration of the final dose. If more than 3 days had elapsed between consecutive doses, a new course was defined as starting after the lapse. We collected data on all courses of ketorolac. Data on repeated courses of opioids were not abstracted because the purpose of the "unexposed" comparison group was to serve as a control group that had indications similar to those of the group receiving ketorolac and not to identify all adverse events that occurred in patients receiving opioids. If more than one course of opioids was available, we chose the course that had the initiation date closest to that of the matched patient's course of ketorolac.

Data were abstracted from the hospital charts of 9850 patients who had received 10 219 courses of ketorolac and of 10 145 patients who had received 10 145 courses of opioids. Only 326 of the 9850 patients receiving ketorolac (3.3%) received more than one course. Of these patients, 291 received two courses, 27 received three courses, and 8 received four courses. All analyses are presented by treatment course because each course represented a separate opportunity for an adverse outcome. However, separate analyses of each patient's first course alone yielded nearly identical results.

Data Collection

Trained nurses used a computer-based data entry system to abstract data from hospital charts. The data collected included demographic characteristics, medical history, dose and duration of ketorolac or opioid therapy, occurrence of surgery, use of concomitant medication, laboratory data, and adverse events (regardless of whether the hospital staff or the abstracter thought that these events were caused by the drug).

Definitions of Acute Renal Failure

The principal definition of acute renal failure was a peak serum creatinine concentration that was 50% greater than the baseline value and 1) an absolute increase of at least 44.2 µmol/L if the baseline concentration was less than 132.6 µmol/L or 2) an absolute increase of at least 88.4 µmol/L if the baseline concentration was 132.6 µmol/L or greater. Patients for whom baseline serum creatinine values were not available did not meet the definition of acute renal failure even if their peak serum creatinine concentration was abnormally elevated. Our secondary definition required, in addition to laboratory evidence, a notation in the hospital chart that acute renal failure had occurred during the course of therapy with the analgesic drug. Unless otherwise stated, the results presented are those obtained using our principal definition.

Statistical Analysis

Data on demographic characteristics and medical history were compared between the two groups using the independent sample t-test for continuous variables and the chi-square statistic [29] for discrete variables. The proportion of patients in each group for whom data on serum creatinine concentration were included in the medical record was described.

Both matched and unmatched analyses were done. Because point estimates and 95% CIs did not greatly differ between the two types of analysis, we report the results of the unmatched analyses [30].

We did a survival analysis using Cox proportional-hazards regression to explore the association of ketorolac administration with the rate of acute renal failure [30, 31]. Survival was defined as the interval from the initiation of analgesic drug therapy until either acute renal failure or the end of the course (3 days after the end of drug therapy), whichever occurred first. Unadjusted rate ratios comparing the rate of acute renal failure in patients receiving ketorolac with the rate in patients receiving only opioids were calculated using standard proportional hazards methods and are reported with 95% CIs [30, 31]. Multivariate proportional hazards models were fit, with simultaneous adjustment for the influence of potential confounding variables that were defined a priori. These variables included age; type of pain (acute or chronic) that served as the indication for analgesic administration; medical admission; admission to an intensive care or trauma unit; concomitant use of NSAIDs other than ketorolac, aminoglycoside antibiotics and other antibiotics, or angiotensin-converting enzyme inhibitors and other antihypertensive drugs; and a history of cancer, congestive heart failure, kidney disease, diabetes mellitus, hypertension, NSAID use, drug abuse, or cirrhosis. A time-dependent covariate that indicated the duration of analgesic therapy was incorporated into all models.

We did a sensitivity analysis to assess the potential effect of the fact that a smaller proportion of patients in the ketorolac group had serum creatinine values measured during their treatment course. In this analysis, we recalculated the unadjusted relative risk for acute renal failure under the assumption that the risk for acute renal failure among study patients without measures of serum creatinine was the same as the risk among patients in the same group who did have measures recorded. This assumption is extreme because it assigns the risk for acute renal failure that was seen among patients who had laboratory data to patients who did not have laboratory data and thus probably had low morbidity.

Because we were interested in the possible nephrotoxicity of ketorolac in patients who had a high risk for acute renal failure, we evaluated the interactions between the administration of ketorolac and coexisting conditions that may have predisposed patients to acute renal failure. These coexisting conditions include congestive heart failure; cirrhosis; a history of renal disease, diabetes mellitus, or hypertension; age older than 65 years; and heart failure, cirrhosis, or a history of renal disease [13]. We also explored potential interactions between ketorolac and the concomitant use of either aminoglycoside antibiotics or angiotensin-converting enzyme inhibitors. Finally, we explored the potential interaction of ketorolac with the presence of any condition known to predispose patients to acute renal failure or the concomitant administration of aminoglycoside antibiotics or angiotensin-converting enzyme inhibitors. Interactions were assessed on the basis of the statistical significance of the relevant product term in the multivariate models.

Duration of analgesic therapy was defined as the number of days during which the analgesic drug was administered (in patients who did not have renal failure and in those whose event occurred after the last day of therapy) or the number of days from the onset of therapy until renal failure. The interaction between duration of therapy and choice of analgesic agent was analyzed in two ways.

First, a set of proportional hazards models was fit; each model included patients who had received analgesic therapy for no longer than a specified duration (that is, those receiving therapy for as many as 2 days, as many as 3 days, and so forth). In any given model, patients who received an analgesic drug for longer than the specified duration for that model were included, but their follow-up was censored at that specified duration. For example, a patient who received analgesic therapy for 5 days was included in the model of "as many as 4 days of analgesic therapy" but was censored in that analysis at day 4. If such patients had acute renal failure during a 3-day window after day 4 (that is, if a patient had an episode of acute renal failure on day 6, within the 3-day window after day 4 of therapy), this renal failure was counted when that model was fitted, consistent with the principal definition of a course of therapy. We also fit similar models in which we did not count such events, but we do not report these analyses because they yielded nearly identical results.

Second, we decided a priori to examine the rate ratio for patients who received therapy for more than 5 days, the maximum recommended duration of ketorolac therapy in the United States.

Using proportional hazards regression, we examined the effects of the average daily dose of ketorolac, defined as the total cumulative dose divided by the number of days of administration. If acute renal failure occurred before ketorolac therapy was discontinued, the total cumulative dose was calculated only on the basis of doses given before the event. We included a term in our models to indicate average daily dose. Because total cumulative dose was highly correlated with duration of course (R = 0.87; P < 0.001), no further analysis of cumulative dose was done.

All analyses were done using SAS software, version 6.08 (SAS Institute, Cary, North Carolina).

Results

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Forty percent of patients receiving ketorolac were men, 87% were white, and 9% were black. Their mean age (±SD) was 51 ± 20 years. Forty-three percent of patients in the opioid group were men, 87% were white, and 9% were black. Their mean age was 52 ± 21 years. A history of acute renal failure was recorded before 0.22% of courses of ketorolac and 0.23% of courses of opioids only (P > 0.2). A history of chronic renal failure was recorded before 0.84% of courses of ketorolac but before 1.33% of courses of opioids only (P = 0.001). A history of papillary necrosis was recorded before 0% of courses of ketorolac but before 0.10% of courses of opioids only (P = 0.002). A history of the nephrotic syndrome was recorded before 0.21% of courses of ketorolac but before 0.38% of courses of opioids only (P = 0.02).

Serum creatinine concentrations were measured at least once during 39.0% of courses of ketorolac and 45.2% of courses of opioids. The percentages of courses during which the serum creatinine concentration was abnormal but for which no baseline value had been measured were low: 1.3% for ketorolac and 1.2% for opioids. Acute renal failure occurred during 109 courses of ketorolac (1.07%) and during 113 courses of opioids alone (1.11%). Among patients in the ketorolac group who had acute renal failure, the mean peak serum creatinine concentration (±SD) was 230.7 ± 118.5 µmol/L and the median peak serum creatinine concentration was 185.6 µmol/L (range, 97.2 to 636.5 µmol/L). In the opioid group, the analogous peak serum creatinine concentration was 285.5 ± 173.3 µmol/L and the median was 229.8 µmol/L (range, 106.1 to 972.4 µmol/L). The mean increase in the serum creatinine concentration that indicated acute renal failure was 126.4 ± 102.5 µmol/L in the ketorolac group and 155.6 ± 126.4 µmol/L in the opioid group.

Acute renal failure occurred more often in the presence of hypertension (multivariate adjusted rate ratio, 1.56 [CI, 1.15 to 2.11]; P < 0.01), chronic renal disease (rate ratio, 3.07 [CI, 1.86 to 5.07]; P < 0.01), cirrhosis (rate ratio, 3.54 [CI, 1.55 to 8.10]; P < 0.01), admission to an intensive care unit (rate ratio, 1.93 [CI, 1.45 to 2.58]; P < 0.01), cancer (rate ratio, 1.74 [CI, 1.30 to 2.34]; P < 0.01), concomitant use of aminoglycoside antibiotics (rate ratio, 3.22 [CI, 2.36 to 4.40]; P < 0.01) or other antibiotics (rate ratio, 1.38 [CI, 0.98 to 1.96]; P = 0.07), and medical admission (rate ratio, 1.69 [CI, 1.12 to 2.27]; P < 0.01). The risk for acute renal failure increased with age (rate ratio, 1.37 [CI, 1.25 to 1.50] per 10-year increase in age; P < 0.01). Renal failure was seen in no patients younger than 15 years of age, in 0.6% of patients 15 to 64 years of age, and in 2.1% of patients 65 years of age or older. A history of diabetes mellitus (P = 0.17) or congestive heart failure (P = 0.19) was also associated with an increased rate of acute renal failure, but these associations did not achieve conventional levels of statistical significance.

Ketorolac was not associated with acute renal failure, with or without multivariate adjustment (P > 0.2 for both) (Table 1). Analyses that were done using our secondary definition of acute renal failure (laboratory evidence and physician diagnosis) yielded similar results. No statistically significant difference in the risk for acute renal failure was seen between our study groups (rate ratio, 1.11 [CI, 0.94 to 1.32]), even under the extreme conditions of our sensitivity analysis.

Analysis of the interaction between the effect of ketorolac and congestive heart failure, cirrhosis, diabetes, hypertension, previous renal disease, age older than 65 years, surgery, need for admission to an intensive care unit, concomitant use of aminoglycoside antibiotics, or concomitant use of angiotensin-converting enzyme inhibitors did not identify any subgroup at particular risk for nephrotoxicity from ketorolac. In addition, analysis of the interaction of ketorolac with the presence of either congestive heart failure, cirrhosis, or previous renal disease did not identify important interactions. Finally, an analysis of the interaction of ketorolac with congestive heart failure, cirrhosis, diabetes, hypertension, previous renal disease, surgery, need for admission to an intensive care unit, use of aminoglycosides, or use of angiotensin-converting enzyme inhibitors did not identify an important interaction (P > 0.12 for all tests of interaction).

Despite the similarity between the opioid and ketorolac groups in overall distribution of the duration of therapy, the events of acute renal failure occurred later for the ketorolac group than for the opioid group (Table 2). Whereas 6 episodes of acute renal failure (5.3% of 113 episodes) occurred after day 6 of opioid therapy, 18 episodes (16.5% of 109 episodes) occurred after day 6 of ketorolac therapy. Analysis of the effects of duration of treatment on acute renal failure showed no increased rate of renal failure for duration of therapy as long as 6 days (Table 3). However, when we focused on durations of therapy longer than 5 days, the rate ratio for acute renal failure associated with ketorolac compared with that associated with opioids was 2.08 (CI, 1.08 to 4.00; P = 0.03). When we used our secondary definition of disease, we also saw an increased rate of acute renal failure with more than 5 days of analgesic therapy (rate ratio, 3.58 [CI, 0.95 to 13.5]; P = 0.06).

Seventeen of the 222 cases of acute renal failure (7.7%) were accompanied by acute gastrointestinal bleeding that was clinically serious and required prolonged hospitalization, caused residual disability, or was life threatening (9 of 17 [52.9%] cases in the ketorolac group and 8 of 17 [47.1%] cases in the opioid group). However, the increased risk for acute renal failure with prolonged use of ketorolac was not caused by the previously documented increased risk for gastrointestinal bleeding [28] because the number of episodes of gastrointestinal bleeding in patients in whom acute renal failure occurred after 5 days of therapy was similar in the two study groups.

Finally, we evaluated the relation of the average daily dose of ketorolac in the ketorolac group with the principal and secondary definitions of acute renal failure (Table 4). Analyses among all patients receiving ketorolac and analyses among patients receiving ketorolac for more than 5 days showed no statistically significant relation.

Discussion

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We have shown that the overall incidence of acute renal failure after a course of analgesics was low, even in ill, hospitalized patients. In addition, the overall incidence of renal failure among patients receiving parenteral ketorolac was similar to that among patients receiving opioids. The analysis among patients who received prolonged analgesic therapy suggests that with therapy lasting more than 5 days, ketorolac may be associated with a higher incidence of acute renal failure than are opioid analgesics. We found that the incidence of acute renal failure increased with several predisposing conditions, including congestive heart failure, chronic renal disease, cirrhosis, and hypertension. However, we could not identify a clinically distinct subgroup with a particular risk for ketorolac nephrotoxicity. Nonetheless, given our limited power to identify subgroups at high risk, the potentially additive effect of ketorolac and other conditions that predispose patients to renal failure should be considered when ketorolac is prescribed for prolonged durations.

To our knowledge, nine case series reporting a total of 19 cases of renal failure that were presumed to have been caused by parenteral ketorolac have been published [19-27]. In only 2 of these reported cases was ketorolac administered for more than 5 days [21]. No previous study has compared the rate of acute renal failure in patients receiving ketorolac with the rate in appropriate controls to isolate the effects of ketorolac from those of other risk factors for nephrotoxicity. Thus, none of these case reports could exclude the possibility that acute renal failure was caused by underlying illness and that ketorolac use was incidental. Although ketorolac theoretically may worsen renal perfusion by inhibiting the biosynthesis of vasodilatory prostaglandins [1, 2], especially in clinical states characterized by high circulating levels of norepinephrine and angiotensin II (such as volume depletion, cirrhosis, and congestive failure), appropriate comparison groups are crucial because acute renal failure occurs in these conditions even in the absence of exposure to NSAIDs. Our findings do not eliminate the possibility that these cases of acute renal failure were truly caused by ketorolac; rather, these cases show that, overall, the rate of renal failure in patients treated with ketorolac is low and is indistinguishable from that of patients treated with opioids.

It is important to interpret our results in light of the possibility that our study groups are not comparable because this study was not a randomized, clinical trial. However, we did match patients by hospital, admitting service, and date of initiation of therapy, and we did extensive multivariate regression analyses, adjusting for known risk factors for renal disease. Overall, illness burden was similar in the two study groups. Because previous renal disease was slightly more common in patients treated with opioids, we cannot rule out the possibility that our finding of no overall difference between ketorolac and opioids resulted from bias caused by unmeasured confounders. However, because adjustment for previous renal disease and other variables resulted in no important changes in the results, this potential bias is extremely unlikely.

Although one might expect physicians to screen for renal failure with laboratory tests more often in the group receiving ketorolac because of concern about renal disease induced by NSAID use, patients receiving ketorolac actually had their serum creatinine concentrations measured less frequently than did patients receiving opioids. Our sensitivity analysis showed that even under extreme assumptions about the rate of renal failure among patients for whom laboratory data were not collected, the unequal collection of such data across our study groups had little effect on our results.

Our analyses of duration of therapy suggest that the risk for acute renal failure associated with prolonged administration of ketorolac may be higher than the risk associated with opioid analgesics. In view of the lack of difference between our study groups overall, several explanations for this subgroup finding must be considered. First, this finding may represent true nephrotoxicity resulting from long-term therapy with ketorolac. Extended use of ketorolac by ill, hospitalized patients conceivably increases the probability that the drug's pharmacologic effects will occur simultaneously with volume depletion sufficient to cause acute renal failure. Second, the increased risk for acute renal failure associated with prolonged ketorolac use could be caused by ketorolac's known propensity for causing gastrointestinal bleeding and the increased risk for gastrointestinal bleeding associated with an increased duration of therapy [28]. However, we did not find evidence showing that bleeding, a possible cause of volume depletion in patients receiving ketorolac, accounted for the disproportionate amount of renal failure seen among patients who were treated with ketorolac for more than 5 days. Finally, we cannot rule out that this subgroup finding was a chance occurrence; therefore, we believe that additional research is warranted.

In conclusion, our study shows that, overall, the incidence of acute renal failure in a hospitalized group of patients receiving parenteral ketorolac is low and is no greater than that in a group of patients receiving opioids. Our findings suggest that ketorolac may be associated with a greater risk for renal failure when therapy is prolonged. This finding is consistent with the pharmacologic activity of ketorolac and the toxicity profiles of other NSAIDs that have been associated with acute renal failure [3-7]. Although we could not define a specific threshold for duration of therapy beyond which ketorolac increases the risk for acute renal failure, our data show that, when used for 5 days or less (as recommended on the drug's U.S. label), ketorolac does not increase the risk for acute renal failure.

Pennsylvania: Doylestown Hospital, Lower Bucks Hospital, Grandview Hospital, North Penn Hospital, Phoenixville Hospital, Southern Chester County Medical Center, Paoli Memorial Hospital, Taylor Hospital, Thomas Jefferson University Hospital, Montgomery Hospital, Delaware County Memorial Hospital, Hahnemann University Hospital, Riddle Memorial Hospital, Pottstown Hospital, Lancaster General Hospital, Community Hospital of Lancaster, Ephrata Community Hospital, St. Joseph's Hospital of Reading, Community Osteopathic Hospital of Harrisburg, the Hospital of the University of Pennsylvania, Brandywine Medical Center, Albert Einstein Medical Center, Hershey Medical Center, and Polyclinic Medical Center of Harrisburg.

New Jersey: Community Medical Center of Toms River, Memorial Hospital of Salem County, Shore Memorial Hospital, Elmer Community Hospital, Hunterdon Medical Center, Burdette Tomlin Memorial Hospital, Cooper Hospital/University Medical Center, and Monmouth Medical Center.

Delaware: Kent General Hospital.

The authors also thank Connie Marrone, RN, project coordinator; John Holmes, MS, medical informatician; Tikkana Akurati, MS, programmer analyst; and the nurse abstracters.

Ms. Kinman: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Medical Center, 423 Guardian Drive, 826 Blockley Hall, Philadelphia, PA 19104-6021.

Dr. Berlin: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Medical Center, 423 Guardian Drive, 815 Blockley Hall, Philadelphia, PA 19104-6021.

Dr. Hennessy: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Medical Center, 423 Guardian Drive, 832 Blockley Hall, Philadelphia, PA 19104-6021.

Dr. Kimmel: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Medical Center, 423 Guardian Drive, 717 Blockley Hall, Philadelphia, PA 19104-6021.

Dr. Farrar: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Medical Center, 423 Guardian Drive, 813 Blockley Hall, Philadelphia, PA 19104-6021.

Dr. Carson: University of Medicine and Dentistry of New Jersey, 125 Paterson Street, 2nd Floor, New Brunswick, NJ 08903-0019.

Dr. Strom: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Medical Center, 423 Guardian Drive, 824 Blockley Hall, Philadelphia, PA 19104-6021.