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Brief Report |

Liver Enzyme Monitoring in Patients Treated With Troglitazone FREE

David J. Graham, MD, MPH; Carol R. Drinkard, MPH, PhD; Deborah Shatin, PhD; Yi Tsong, PhD; Margaret J. Burgess
[+] Author Affiliations

Author Affiliations: Office of Postmarketing Drug Risk Assessment (Dr Graham) and Office of Biostatistics (Dr Tsong), Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, Md; and Center for Health Care Policy and Evaluation, UnitedHealth Group, Minneapolis, Minn (Drs Drinkard and Shatin and Ms Burgess).


JAMA. 2001;286(7):831-833. doi:10.1001/jama.286.7.831.
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Context Soon after initial marketing in March 1997, troglitazone, the first thiazolidinedione antidiabetic agent, was found to cause life-threatening acute liver failure. The drug was removed from the market in March 2000.

Objective To evaluate the effect of US Food and Drug Administration (FDA) risk management efforts, including repeated labeling changes and "Dear Healthcare Professional" letters, on periodic liver enzyme monitoring of patients taking troglitazone.

Design, Setting, and Participants Claims data from a large, multistate managed care organization were used to establish 4 cohorts of patients (N = 7603) with at least 90 days of health plan enrollment before first troglitazone prescription during 4 consecutive periods spanning April 1997 to September 1999 and representing 4 progressively stringent liver monitoring recommendations.

Main Outcome Measures Percentage of eligible troglitazone users in each cohort with baseline, monthly (for up to 6 months of continuous use), and complete (baseline and monthly) enzyme monitoring, based on computerized records of laboratory claims.

Results Baseline testing increased from 15% before any FDA monitoring recommendations (cohort 1) to 44.6% following 4 separate FDA interventions (cohort 4; P<.001). In cohort 4, 33.4% of users had follow-up testing after 1 month of therapy, falling to 13% after 5 months of continuous use. In all cohorts, less than 5% received all recommended liver enzyme tests by the third month of continuous use.

Conclusions The FDA risk management efforts did not achieve meaningful or sustained improvement in liver enzyme testing. Evaluation of the impact of regulatory actions is needed before such actions can be regarded as effective or sufficient.

Figures in this Article

Troglitazone is a thiazolidinedione antidiabetic agent that decreases insulin resistance. It was approved by the US Food and Drug Administration (FDA) in January 1997 for treatment of type 2 diabetes mellitus. During premarketing clinical trials, serum liver transaminase elevations exceeding 3 times the upper limit of normal were observed in 1.9% of troglitazone-treated patients vs 0.6% in comparators.1 Of 2510 patients treated with troglitazone in these trials, 2 were hospitalized with drug-associated hepatitis and 2 developed jaundice.

From March 1997, when marketing began, through the end of October 1997, there were no recommendations in product labeling that liver enzymes should be monitored. Soon thereafter, cases of acute liver failure (ALF) began to be reported among patients taking troglitazone. In response to a steadily increasing number of reported cases, 4 separate "Dear Healthcare Professional" letters were sent by the manufacturer to US physicians nationwide, each successively recommending an increase in liver enzyme monitoring.25 Despite these warnings, as well as a widely publicized FDA advisory meeting in March 1999, cases of ALF continued to be reported.613 In mid-1999, 2 other thiazolidinediones were approved. By March 2000, when troglitazone was removed from the market, 94 cases of liver failure had been reported.

The issuance of successive warning letters and associated changes in labeling for liver enzyme monitoring provided an opportunity to study their impact on physician and patient behavior and to assess their effectiveness as a risk management tool.

UnitedHealth Group is a national health care company that includes 43 health plans across the United States. A historical cohort study of troglitazone recipients was performed using longitudinal claims data from 12 UnitedHealth Group–affiliated health plans covering about 3 million persons from 10 different states. Data consisted of separate files (pharmacy, facility, physician, and enrollment) linked by unique encrypted identifiers, protecting patient confidentiality.

Members with at least 1 troglitazone prescription between April 1, 1997, and September 24, 1999, and with at least 90 days of continuous enrollment before their first (index) prescription were selected for study (n = 9136). The prior enrollment requirement ensured that the index prescription was the patient's first prescription. Enrolled patients were assigned to time-specific cohorts based on the date of their index prescription and were followed for up to 6 months while taking the drug. Four study cohorts were established, correlating with specific FDA regulatory actions and liver enzyme monitoring recommendations (Table 1). Patients whose index dates fell outside the inclusion dates for cohorts 1 through 4 were excluded (n = 1533).

Table Graphic Jump LocationTable 1. Description of Study Cohorts With Respect to Period Covered, Liver Enzyme Monitoring Recommendations in Place, and Number of Patients Under Observation

Longitudinal claims were screened for testing of alanine aminotransferase or aspartate aminotrasferase, either specifically or as part of a multitest panel. Baseline liver enzyme monitoring was defined as a laboratory claim within 30 days before to 7 days after the index troglitazone prescription. Monthly follow-up liver enzyme monitoring was defined as a claim from 14 days before to 14 days after the 30-day calendar "anniversary" date following the index prescription for up to 6 months of use. During the study period, none of the 12 health plans limited the number of liver enzyme tests that could be performed.

Liver enzyme monitoring completeness at baseline and after each month of troglitazone use was calculated as the percentage of eligible patients with a laboratory claim at each relevant time point. Statistical analysis of differences in degree of enzyme testing was performed using the χ2 test with adjustment for multiple comparisons according to Hochberg.14,15 Statistical analyses were performed using SAS version 6.12 (SAS Institute Inc, Cary, NC).

There were 7603 first-time troglitazone recipients enrolled in the 4 study cohorts. The proportion of patients undergoing baseline liver enzyme testing rose from 15% in cohort 1 to 44.6% in cohort 4 (χ23 = 429; P<.001). Monthly follow-up enzyme monitoring at 1 month of therapy increased from 3.8% for cohort 1 to 33.4% for cohort 4 (Figure 1; χ23 = 325; P<.001). This level of monitoring was not maintained in cohort 4, falling to 13% by 5 months.The largest increase in monthly testing occurred between cohorts 1 and 2, with successively smaller increases between subsequent cohorts. For the first 5 months of treatment, monthly testing was generally 3- to 4-fold higher in cohort 2 than cohort 1 (P<.001 at each month). There was no difference between these cohorts in the sixth month. Monthly testing in cohort 3 was 1.7-fold higher than cohort 2 in the first month (P<.001). With each successive month, the differences in monitoring completeness decreased and were gone by month 5. There was no statistical difference in monthly monitoring between cohorts 3 and 4 in any month. Although one third or fewer of patients underwent follow-up testing in any month, the same patients were not typically tested each month. For example, among patients in cohort 4 treated with troglitazone for 3 months, only 10% had all 3 follow-up tests performed, while 60% had at least 1.

Figure. Performance of Follow-up Liver Enzyme Testing During Each Month of Continuous Troglitazone Use Among Eligible Patients by Period (Cohort) of Troglitazone Initiation
Graphic Jump Location
The number of patients in each cohort at each month is shown in Table 2.

Complete adherence to monitoring requirements occurred at low levels (Table 2). In cohort 4, only 18.4% of patients had a liver enzyme test at both baseline and month 1. By 3 months of use, less than 5% of patients in any cohort received the full complement of recommended testing.

Table Graphic Jump LocationTable 2. Percentage of Patients Undergoing All Liver Enzyme Monitoring for Which They Were Eligible (Baseline and Testing Each Month)*

Liver transaminase monitoring was infrequently and irregularly performed despite repeated FDA regulatory interventions, including labeling changes, "Dear Healthcare Professional" letters to physicians, and heightened national publicity and awareness of liver failure risk associated with troglitazone.213 Although baseline testing increased from 15% to 45%, more than half of the patients who started taking troglitazone during the last period did so without a baseline test. Monthly follow-up testing also increased somewhat between the baseline and last period studied, but was modest and not sustained. Differences in testing rates between cohorts quickly waned and were indistinguishable by months 5 or 6 of continued use.

Liver enzyme monitoring was chosen by the FDA as the primary means of reducing ALF risk with troglitazone. Testing was not performed consistently or frequently enough to provide meaningful protection to patients. It is unknown whether monthly monitoring would have prevented the development of ALF had it been performed as recommended. A review of 43 ALF cases reported to the FDA found 12 in which monthly monitoring was performed.13 Of these, 9 (75%) went from normal enzyme levels to irreversible liver injury within a 1-month interval. In the other 3, troglitazone use continued for a month beyond the first detected abnormality, so that it is unknown whether ALF would have been avoided had the drug use been stopped a month earlier. Also, 1 case of ALF occurred in each of 3 separate postmarketing studies, despite monthly monitoring. These data call into question the utility of enzyme monitoring for the prevention of ALF with troglitazone. In addition, the risk of ALF did not abate with continued use of the drug, suggesting that if monitoring were capable of preventing liver failure, it would need to be performed at high levels of completeness for as long as patients continued treatment.13 If monitoring were shown to be protective against ALF, linkage of drug dispensing with normal laboratory test results might be considered. This approach worked well in reducing the incidence of agranulocytosis with clozapine.16,17

The influence of labeling recommendations and warning letters on physician and patient behavior is poorly understood. Walker et al18 found that the cumulative incidence of liver function testing during the first 8 weeks of diclofenac use was below 20%, despite recommendations in the "warnings" section of its label. Recently, Smalley et al19 found that an FDA "black box" warning for cisapride, with an accompanying "Dear Healthcare Professional" letter, did not meaningfully reduce the high level of contraindicated use of this product.

There are several potential study limitations. Data were obtained from computerized claims, and it is possible that not all laboratory claims were submitted to UnitedHealth Group. However, because facility reimbursement depends on filing of claims, this probably did not occur frequently. Claims lag is another means by which laboratory tests might be undercounted. To minimize this, data collection was performed 6 months after the end of the final cohort period. More than 95% of facility claims typically are filed within 6 months of the date of service.

This study suggests that labeling changes, including "black-box warnings" and instructions to monitor patients closely, as well as repeated "Dear Healthcare Professional" letters to physicians, cannot be assumed to be effective means of risk management. More effective strategies are needed if drug risk management programs are to benefit patient safety. Such methods should be pilot-tested and evaluated before they are presumed successful.

 Rezulin. In: Physicians' Desk Reference. Montvale, NJ: Medical Economics Co; 1998:2218-2221.
Sigmund WR. Important drug warning for troglitazone (Rezulin) ["Dear Healthcare Professional" letter]. Morris Plains, NJ: Parke-Davis/Warner Lambert; October 28, 1997. Available at: http://www.fda.gov/medwatch/safety/1997/rezuli.htm. Accessed November 28, 2000.
Sigmund WR. Important drug warning for troglitazone (Rezulin) ["Dear Healthcare Professional" letter]. Morris Plains, NJ: Parke-Davis/Warner Lambert; December 1, 1997. Available at: http://www.fda.gov/medwatch/safety/1997/rezul3.htm. Accessed November 28, 2000.
Sigmund WR. Important drug warning for troglitazone (Rezulin) ["Dear Healthcare Professional" letter]. Morris Plains, NJ: Parke-Davis/Warner Lambert; July 28, 1998. Available from: http://www.fda.gov/medwatch/safety/1998/rezuli.htm. Accessed November 28, 2000.
Sigmund WR. Important prescribing information for troglitazone (Rezulin) ["Dear Healthcare Professional" letter]. Morris Plains, NJ: Parke-Davis/Warner Lambert; June 17, 1999. Available from: http://www.fda.gov/medwatch/safety/1999/rezuhp.htm. Accessed November 28, 2000.
Stolberg SG. Stricter rules are urged on use of a diabetic drug.  New York Times.March 27, 1999:A-9.
Gitlin N, Julie NL, Spurr CL, Lim KN, Juarbe HM. Two cases of severe clinical and histologic hepatoxicity associated with troglitazone.  Ann Intern Med.1998;129:36-38.
Neuschwander-Tetri BA, Isley WL, Oki JC.  et al.  Troglitazone-induced hepatic failure leading to liver transplantation: a case report.  Ann Intern Med.1998;129:38-41.
Shibuya A, Watanabe M, Fujita Y.  et al.  An autopsy case of troglitazone-induced fulminant hepatitis.  Diabetes Care.1998;21:2140-2143.
Herrine SK, Choudhary C. Severe hepatotoxicity associated with troglitazone [letter].  Ann Intern Med.1999;130:163-164.
Murphy EJ, Davern TJ, Shakil AO.  et al.  Troglitazone-induced fulminant hepatic failure.  Dig Dis Sci.2000;45:549-553.
Jagannath S, Rai R. Rapid-onset subfulminant liver failure associated with troglitazone [letter].  Ann Intern Med.2000;132:677.
Graham DJ, Green L. Epidemiology of hepatotoxicity with troglitazone: FDA Metabolic-Endocrine Drugs Advisory Committee Meeting, Bethesda, Md, March 26, 1999. Transcript available at: http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3499t1a.pdf. Accessed November 28, 2000.
Hochberg Y, Tamhane HE. Multiple Comparison ProceduresNew York, NY: Wiley & Sons; 1987.
Hochberg Y. A sharper Bonferroni procedure for multiple tests for significance.  Biometrika.1988;75:800-802.
Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA. Clozapine-induced agranulocytosis: incidence and risk factors in the United States.  N Engl J Med.1993;329:162-167.
Honigfeld G, Arellano F, Sethi J, Bianchini A, Schein J. Reducing clozapine-related morbidity and mortality: 5 years of experience with the Clozaril National Registry.  J Clin Psychiatry.1998;59(suppl 3):3-7.
Walker AM, Bortnichak EA, Lanza L, Yood RA. The infrequency of liver function testing in patients using nonsteroidal anti-inflammatory drugs.  Arch Fam Med.1995;4:24-29.
Smalley W, Shatin D, Wysowski DK.  et al.  Contraindicated use of cisapride: impact of Food and Drug Administration regulatory action.  JAMA.2000;284:3036-3039.

Figures

Figure. Performance of Follow-up Liver Enzyme Testing During Each Month of Continuous Troglitazone Use Among Eligible Patients by Period (Cohort) of Troglitazone Initiation
Graphic Jump Location
The number of patients in each cohort at each month is shown in Table 2.

Tables

Table Graphic Jump LocationTable 1. Description of Study Cohorts With Respect to Period Covered, Liver Enzyme Monitoring Recommendations in Place, and Number of Patients Under Observation
Table Graphic Jump LocationTable 2. Percentage of Patients Undergoing All Liver Enzyme Monitoring for Which They Were Eligible (Baseline and Testing Each Month)*

References

 Rezulin. In: Physicians' Desk Reference. Montvale, NJ: Medical Economics Co; 1998:2218-2221.
Sigmund WR. Important drug warning for troglitazone (Rezulin) ["Dear Healthcare Professional" letter]. Morris Plains, NJ: Parke-Davis/Warner Lambert; October 28, 1997. Available at: http://www.fda.gov/medwatch/safety/1997/rezuli.htm. Accessed November 28, 2000.
Sigmund WR. Important drug warning for troglitazone (Rezulin) ["Dear Healthcare Professional" letter]. Morris Plains, NJ: Parke-Davis/Warner Lambert; December 1, 1997. Available at: http://www.fda.gov/medwatch/safety/1997/rezul3.htm. Accessed November 28, 2000.
Sigmund WR. Important drug warning for troglitazone (Rezulin) ["Dear Healthcare Professional" letter]. Morris Plains, NJ: Parke-Davis/Warner Lambert; July 28, 1998. Available from: http://www.fda.gov/medwatch/safety/1998/rezuli.htm. Accessed November 28, 2000.
Sigmund WR. Important prescribing information for troglitazone (Rezulin) ["Dear Healthcare Professional" letter]. Morris Plains, NJ: Parke-Davis/Warner Lambert; June 17, 1999. Available from: http://www.fda.gov/medwatch/safety/1999/rezuhp.htm. Accessed November 28, 2000.
Stolberg SG. Stricter rules are urged on use of a diabetic drug.  New York Times.March 27, 1999:A-9.
Gitlin N, Julie NL, Spurr CL, Lim KN, Juarbe HM. Two cases of severe clinical and histologic hepatoxicity associated with troglitazone.  Ann Intern Med.1998;129:36-38.
Neuschwander-Tetri BA, Isley WL, Oki JC.  et al.  Troglitazone-induced hepatic failure leading to liver transplantation: a case report.  Ann Intern Med.1998;129:38-41.
Shibuya A, Watanabe M, Fujita Y.  et al.  An autopsy case of troglitazone-induced fulminant hepatitis.  Diabetes Care.1998;21:2140-2143.
Herrine SK, Choudhary C. Severe hepatotoxicity associated with troglitazone [letter].  Ann Intern Med.1999;130:163-164.
Murphy EJ, Davern TJ, Shakil AO.  et al.  Troglitazone-induced fulminant hepatic failure.  Dig Dis Sci.2000;45:549-553.
Jagannath S, Rai R. Rapid-onset subfulminant liver failure associated with troglitazone [letter].  Ann Intern Med.2000;132:677.
Graham DJ, Green L. Epidemiology of hepatotoxicity with troglitazone: FDA Metabolic-Endocrine Drugs Advisory Committee Meeting, Bethesda, Md, March 26, 1999. Transcript available at: http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3499t1a.pdf. Accessed November 28, 2000.
Hochberg Y, Tamhane HE. Multiple Comparison ProceduresNew York, NY: Wiley & Sons; 1987.
Hochberg Y. A sharper Bonferroni procedure for multiple tests for significance.  Biometrika.1988;75:800-802.
Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA. Clozapine-induced agranulocytosis: incidence and risk factors in the United States.  N Engl J Med.1993;329:162-167.
Honigfeld G, Arellano F, Sethi J, Bianchini A, Schein J. Reducing clozapine-related morbidity and mortality: 5 years of experience with the Clozaril National Registry.  J Clin Psychiatry.1998;59(suppl 3):3-7.
Walker AM, Bortnichak EA, Lanza L, Yood RA. The infrequency of liver function testing in patients using nonsteroidal anti-inflammatory drugs.  Arch Fam Med.1995;4:24-29.
Smalley W, Shatin D, Wysowski DK.  et al.  Contraindicated use of cisapride: impact of Food and Drug Administration regulatory action.  JAMA.2000;284:3036-3039.
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