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The American Journal of Managed Care September 2013
Referring Patients for Telephone Counseling to Promote Colorectal Cancer Screening
Roger Luckmann, MD, MPH; Mary E. Costanza, MD; Milagros Rosal, PhD; Mary Jo White, MS, MPH; and Caroline Cranos, MPH
Improving BP Control Through Electronic Communications: An Economic Evaluation
Paul A. Fishman, PhD; Andrea J. Cook, PhD; Melissa L. Anderson, MS; James D. Ralston, PhD, MPH; Sheryl L. Catz, PhD; David Carrell, PhD; James Carlson, PharmD; and Beverly B. Green, MD, MPH
Risk-Stratification Methods for Identifying Patients for Care Coordination
Lindsey R. Haas, MPH; Paul Y. Takahashi, MD; Nilay D. Shah, PhD; Robert J. Stroebel, MD; Matthew E. Bernard, MD; Dawn M. Finnie, MPA; and James M. Naessens, ScD
Out-of-Pocket Costs and Prescription Reversals With Oral Linezolid
Margaret K. Pasquale, PhD; Anthony M. Louder, PhD, RPh; Michael C. Deminski, MS, RPh; Richard B. Chambers, MSPH; and Seema Haider, MSc
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FDA Warning and Removal of Rosiglitazone From VA National Formulary
Sherrie L. Aspinall, PharmD, MSc; Xinhua Zhao, PhD; Chester B. Good, MD, MPH; Roslyn A. Stone, PhD; Kenneth J. Smith, MD, MS; and Francesca E. Cunningham, PharmD
Improving Pneumococcal and Herpes Zoster Vaccination Uptake: Expanding Pharmacist Privileges
Michael S. Taitel, PhD; Leonard E. Fensterheim, MPH; Adam E. Cannon, MPH; and Edward S. Cohen, PharmD
Testimonials Do Not Convert Patients From Brand to Generic Medication
John Beshears, PhD; James J. Choi, PhD; David Laibson, PhD; Brigitte C. Madrian, PhD; and Gwendolyn Reynolds, MTS
Outpatient Parenteral Antimicrobial Therapy at Large Veterans Administration Medical Center
Andrew Lai, MD; Thuong Tran, PharmD; Hien M. Nguyen, MD; Jacob Fleischmann, MD; David O. Beenhouwer, MD; and Christopher J. Graber, MD, MPH
Adherence, Persistence, and Switching Patterns of Dabigatran Etexilate
Kimberly Tsai, PharmD; Sara C. Erickson, PharmD; Jianing Yang, MS; Ann S. M. Harada, PhD, MPH; Brian K. Solow, MD; and Heidi C. Lew, PharmD

FDA Warning and Removal of Rosiglitazone From VA National Formulary

Sherrie L. Aspinall, PharmD, MSc; Xinhua Zhao, PhD; Chester B. Good, MD, MPH; Roslyn A. Stone, PhD; Kenneth J. Smith, MD, MS; and Francesca E. Cunningham, PharmD
After the FDA warning and removal of rosiglitazone from the VA National Formulary, glucose control may have declined among those discontinuing rosiglitazone without receiving replacement medication.
The rosiglitazone discontinuation rate over the entire study period was 4.0 per 1000 person-days, which means that during 1000 days of observation (eg, 10 patients on rosiglitazone for100 days), 4 would have discontinued the medication. The period-specific rosiglitazone discontinuation rates were about 2.3 per 1000 person-days of rosiglitazone use before the FDA warning, 3.9 per 1000 person-days after the FDA warning, and 5.3 per 1000 person-days after removal from the VANF (Table 2). Discontinuation rates increased significantly during the 4 months following the May 21, 2007, FDA warning, with the IRRs ranging from 1.6 to 1.8 (Table 2, Figure 1A). After removal from the VANF on October 4, 2007, discontinuation rates increased significantly through May 2008; compared with September 2007, the monthly IRRs ranged from 1.2 to 1.6. Discontinuation rates returned to the September 2007 level in June 2008. Rosiglitazone discontinuation rates varied with the place of rosiglitazone in therapy at the baseline date (Figure 1B). Patients receiving insulin concurrently tended to have the highest discontinuation rates,  and those on rosiglitazone as a third-line agent had the lowest discontinuation rates.

Medications Replacing Rosiglitazone

When rosiglitazone was discontinued, the proportions of patients who received another medication in its place ranged from 17.1% pre-FDA warning to 22.5% post FDA warning and 37.8% after the VANF removal. An abrupt increase in the proportion of patients starting pioglitazone in place of rosiglitazone, from 1% or fewer pre-FDA warning to 22% after VANF removal of rosiglitazone, accounts for the large increase in the proportion of patients receiving prescriptions for replacement medications (Figure 2A). In addition, patients receiving rosiglitazone as first-line therapy were most likely to receive a replacement  medication, whereas those receiving insulin concurrently at baseline were least likely (Figure 2B).

Factors Associated With Discontinuation of Rosiglitazone

Compared with the pre-FDA warning period, patients were more likely (IRR = 1.81; 95% CI, 1.77-1.85) to have rosiglitazone discontinued after the FDA warning (Table 3). During the post VANF removal period, patients were more than twice as likely to discontinue rosiglitazone relative to baseline (IRR = 2.73; 95% CI, 2.67-2.79). The discontinuation rate was significantly higher after rosiglitazone was removed  from the formulary than it was immediately after the FDA warning (IRR = 1.51; 95% CI, 1.49-1.53).

In the multivariable model (Table 3), rosiglitazone was more likely to be discontinued for patients who were female (IRR = 1.10; 95% CI, 1.05-1.15) or black (IRR = 1.05; 95% CI, 1.03-1.08). A 1-point increase in the Charlson Comorbidity Index score was associated with a 3% increase in the risk of discontinuing rosiglitazone. Compared with patients whose baseline A1C was within the range of 7% to 9%, patients whose A1C was less than 7% were less likely (IRR = 0.91, 95% CI, 0.89-0.92), and patients whose A1C was greater than 9% were more likely (IRR = 1.24; 95% CI, 1.2-1.27), to have rosiglitazone discontinued. Patients who were not receiving rosiglitazone as third-line therapy at the index date were 11% to 24% more likely to have it discontinued.

Change in A1C

Among patients who had rosiglitazone discontinued and received replacement medication(s), mean A1C values at baseline and after discontinuation were 7.4% and 7.5%, respectively (Table 4). For those patients who had rosiglitazone discontinued and received no new medication, mean A1C values were 7.4% at baseline and 7.9% after discontinuation. Among patients who remained on rosiglitazone, mean A1C values were the same at baseline and the end of the study (ie, 7.3% vs 7.3%). In the subset of patients who did not receive insulin concurrently  at baseline, those who had rosiglitazone discontinued and received a replacement medication had mean A1C values of 7.3% at baseline and 7.5% after discontinuation. Those who did not receive a replacement medication had mean A1C values at baseline and after discontinuation of 7.2% and 7.7%, respectively. Patients who received insulin concurrently with rosiglitazone had higher A1C values on average. Among those taking insulin who received other medication(s) to replace rosiglitazone, the mean A1C values were comparable at baseline and after discontinuation of rosiglitazone (7.9% vs 8.0%). For patients receiving insulin at baseline who had rosiglitazone discontinued and received no new medication, mean A1C values were 7.9% at baseline and 8.3% after discontinuation.


Similar to previous studies,7-11 we found an increase in the rosiglitazone discontinuation rate following the May 21, 2007, FDA warning.1 The rate increased still more following the removal of the medication from the VANF; 86.7% of the VA cohort had rosiglitazone discontinued, which is higher than the 62% reported in a similar study by Orrico and colleagues.9 However, our overall follow-up period was longer (13 vs 5 months), and we further assessed rosiglitazone use following its change in formulary status. We conducted a similar study of an intervention to decrease glyburide use in elderly veterans with renal insufficiency; in that study, the baseline glyburide discontinuation rate was approximately 3 per 1000 person-days in the preintervention period and 6.1, 4.8, and 4.2 per 1000 person-days at 1, 2, and 3 months, respectively, after the intervention.17 Although the antidiabetic  medications and “interventions” were different, the discontinuation rates in the glyburide and rosiglitazone studies (ie, 2.3 per 1000 person-days at baseline and 4.6, 5.4, and 6.0 per 1000 person-days at 1, 2, and 3 months, respectively, after removal from the VANF) are fairly similar.

We also found important differences in the discontinuation rates according to rosiglitazone’s place in therapy, which was not evaluated in prior studies. The discontinuation rate was lowest when rosiglitazone was used as third-line therapy and generally highest when it was used in combination with insulin. Patients receiving rosiglitazone in combination with metformin and a sulfonylurea (ie, third-line therapy) likely had long-standing and more difficult to control diabetes and may have preferred to avoid insulin, so providers may have been reluctant to stop rosiglitazone. Among patients receiving concomitant insulin, providers could increase the dose of insulin as necessary when rosiglitazone was discontinued. Also, the FDA warned of an increased MI risk in patients on both insulin and rosiglitazone on November 19, 2007; this warning did not apply to pioglitazone.18

For patients who had rosiglitazone discontinued, approximately 29% received another medication in its place during the time periods before and after the FDA warning. The FDA warning increased the rosiglitazone discontinuation rate, but did not markedly influence the rate of replacement of rosiglitazone with other medications. However, this replacement rate increased sharply to 37.8% when rosiglitazone was removed from the VANF because providers could switch patients to pioglitazone without completing a nonformulary request. This made prescribing pioglitazone easier and accounted for the observed increase during the period after the VANF removal as the proportions of patients prescribed metformin, a sulfonylurea, or insulin in place of rosiglitazone decreased slightly. It is somewhat surprising that the proportion of patients who received pioglitazone  was not higher; it is possible that some medical centers did not follow VA guidelines and limited the availability of pioglitazone.

Because of the huge sample size, all factors assessed, except for age, were statistically associated with discontinuing  osiglitazone in the multivariable model. However, the effects of the FDA warning and removal of rosiglitazone from the VANF, baseline glucose control, and rosiglitazone’s place in therapy were most strongly associated with discontinuation. Providers were more likely to discontinue rosiglitazone after the FDA warning and were even more apt to do so after removal from the VANF. Although providers were notified of the FDA warning via e-mail, the change in formulary status and associated recommendations for using the medication likely resulted in a greater response because additional information regarding MI risk with the TZDs had been published.3-5 Furthermore, VA providers were urged to discuss the risks and benefits of continuing rosiglitazone with their patients and make a decision about continued TZD use. Thus, a concrete action was required with the change in formulary status. Studies have found that formularies can be effective in shifting prescribing practices toward preferred, or formulary, medications.19,20 Providers also were more likely to discontinue rosiglitazone if the glucose was less   well controlled (ie, baseline A1C >9% vs 7%-9%). It is possible that providers thought rosiglitazone was not contributing much to the antidiabetic regimen. Providers also were more likely to discontinue rosiglitazone when it was not being used as third-line therapy. Again, providers may have been more willing to stop the medication when other options were available.

The increase in A1C was statistically and potentially clinically significant when another medication was not prescribed in place of rosiglitazone (mean change of 0.35% in those receiving insulin concurrently at baseline and 0.5% in those not receiving insulin). Because of measurement error, some have suggested that a change of 0.5% or greater over time is clinically significant.21 In the study by Shi and colleagues10 of the effect of TZD safety warnings on glycemic control, the group of veterans who discontinued rosiglitazone or pioglitazone without receiving another antidiabetic medication in its place had a mean increase in their A1C of 0.27%. However, those patients who were changed to a non-TZD therapy also had an increase in their A1C (ie, 0.33%). Similar to the results of our study, patients who remained on rosiglitazone or pioglitazone had almost no change in their A1C (ie, –0.06%).10 We used the most recent A1C result within 3 to 9 months of stopping rosiglitazone, so  glucose control may have improved over time if antidiabetic medications were changed after the provider assessed the effect of discontinuing rosiglitazone.


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