Liver Enzyme Monitoring in Patients Treated With Troglitazone FREE

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.^2- 5 Despite these warnings, as well as a widely publicized FDA advisory meeting in March 1999, cases of ALF continued to be reported.^6- 13 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).

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.

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.

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.^2- 13 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.