FDA Warning and Removal of Rosiglitazone From VA National Formulary
Published Online: September 19, 2013
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
Before October 4, 2007, rosiglitazone was available on the Department of Veterans Affairs National Formulary (VANF) for treatment of type 2 diabetes mellitus (T2DM); pioglitazone could be obtained via the nonformulary request process. However, rosiglitazone use likely changed following the US Food and Drug Administration (FDA) safety alert issued May 21, 2007, regarding the potential increased risk of myocardial infarction (MI) and cardiovascular death in patients receiving rosiglitazone and the subsequent removal of rosiglitazone from the VANF on October 4, 2007.1 The FDA alert, which was sent to all Department of Veterans Affairs (VA) providers via established electronic distribution lists, was largely prompted by the online publication of a meta-analysis in which rosiglitazone was associated with increased MI risk (odds ratio = 1.43; 95% confidence interval [CI],1.03-1.98) compared with other diabetes medications or placebo.2 A subsequent meta-analysis of trials with 12 or more months of follow-up (vs 24 weeks in the previous meta-analysis) confirmed the increased MI risk (relative risk = 1.42; 95% CI, 1.06-1.91).3 The only other thiazolidinedione (TZD) available for T2DM treatment during this time was pioglitazone. A meta-analysis of pioglitazone versus non-TZDs showed a lower risk of the composite end point of death, MI, or stroke with pioglitazone (hazard ratio = 0.82; 95% CI, 0.72-0.94).4 In addition, a nested case-control study of older patients with T2DM showed that rosiglitazone monotherapy, but not pioglitazone, was associated with increased MI risk.5
Given these results, as well as similar findings in a retrospective cohort study conducted by the VA,6 regional pharmacy leaders and the VA Medical Advisory Panel removed rosiglitazone from the VANF at their October 4, 2007, meeting. Using the electronic distribution lists, VA prescribers were sent guidance recommending a discussion of the risks and benefits of continued rosiglitazone use with their patients. If patients and providers made an informed choice to continue TZD therapy, then patients could remain on rosiglitazone or change to pioglitazone. Pioglitazone was the only TZD available for new starts, but required completion of a nonformulary request.
Other studies examined the impact of safety warnings on rosiglitazone use, but none described changes in use based on its place in therapy for the treatment of T2DM.7-11 This is important because providers may be more likely to discontinue rosiglitazone if other options remain available for controlling blood glucose. In addition, our study describes the effect on glucose control (ie, glycated hemoglobin [A1C]) of removing rosiglitazone from the VANF. Formulary changes are frequently made within healthcare systems to promote the use of specific medications, but the clinical consequences of these decisions rarely are examined and reported.12-14
The 4 primary objectives of this study were to: (1) describe changes in rosiglitazone prescribing following the FDA warning of a potentially increased risk of MI and removal of rosiglitazone from the VANF; (2) describe these changes in the context of diabetes medications used concomitantly with rosiglitazone; (3) examine the medications replacing rosiglitazone; and (4) assess patient-level factors associated with rosiglitazone discontinuation. The secondary objective was to evaluate changes in A1C levels over time among patients who did and did not discontinue rosiglitazone.
PATIENTS AND METHODS
Study Setting and Population
The cohort included veterans with an active outpatient prescription for rosiglitazone in the VA on April 1, 2007, who were chronic users of the medication. Chronic use was defined as having another prescription for rosiglitazone within the 180 days preceding the release date of the prescription that was active on April 1. The release date is the date the prescription is mailed to the patient or picked up from the VA pharmacy. For each patient, the study period was the time between the baseline date of April 1, 2007, and June 30, 2008.
Data Sources and Data Collection
The study cohort was identified retrospectively using the Pharmacy Benefits Management Services’ database (version 3.0) for rosiglitazone prescriptions. The Pharmacy Benefits Management database also was used to obtain information on all antidiabetic medications prescribed in the VA during the study period. VA Medical SAS Datasets (Austin Information Technology Center, Austin, Texas) provided patient demographics and comorbidities. A1C values were obtained from the Decision Support Services database. All-cause mortality was identified from the VA Beneficiary Identification and Record Locator System files.
Discontinuation of the baseline rosiglitazone prescription during the study period was defined as a subsequent prescription for pioglitazone or no additional prescriptions for rosiglitazone during the 60 days following the end of the days of supply for the rosiglitazone prescription (ie, release date of rosiglitazone prescription plus days of supply plus 60 days).15
The place of rosiglitazone in therapy was defined in terms of concurrent prescriptions for antidiabetic medications that were active within 1 week of the baseline date. The place of rosiglitazone in therapy was categorized as; (1) first line if the patient had no concurrent medications at baseline (ie, monotherapy); (2) second line if the patient had concurrent metformin or sulfonylurea, but not both (with or without additional medications); (3) third line if the patient had concurrent metformin and sulfonylurea (with or without additional medications); (4) with insulin if the patient had concurrent insulin (with or without additional medications); or (5) other if the patient had concurrent medications other than those listed previously (eg, acarbose). For those patients discontinuing rosiglitazone, we assessed the medication(s) that replaced rosiglitazone (ie, the medications released within the time period of the days of supply of rosiglitazone plus 60 days, but not dispensed during the 180 days before the rosiglitazone release date). The secondary outcome was change in A1C. The baseline A1C value was the most recent result within 3 months of the baseline date. The follow-up A1C level was the most recent result within 3 to 9 months of stopping rosiglitazone (for those who discontinued rosiglitazone) or the most recent result within 3 to 9 months of June 30, 2008 (for those who continued rosiglitazone).
PDF is available on the last page.