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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
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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
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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
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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
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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.
Objectives: To describe changes in rosiglitazone prescribing following the US Food and Drug Administration (FDA) warning of  potentially increased risk of myocardial infarction and removal from the Department of Veterans Affairs National Formulary (VANF), assess patient-level factors associated with rosiglitazone discontinuation, and evaluate changes in glucose control.

Study Design: Historical cohort.

Methods: Veterans with an active outpatient prescription for rosiglitazone on April 1, 2007, were followed until June 30, 2008. Incidence rate ratios (IRRs) of rosiglitazone discontinuation were compared over time using Poisson methods. We identified patient-level factors associated with stopping rosiglitazone using multivariable Poisson regression and compared glycated hemoglobin (A1C) values across time among patients who discontinued/continued rosiglitazone using linear mixed models.

Results: Of 95,539 veterans with an active outpatient rosiglitazone prescription, 86.7% discontinued rosiglitazone. Discontinuation rates increased significantly after the FDA warning, with IRRs from 1.6 to 1.8. After removal from the VANF, rosiglitazone discontinuation rates again increased significantly. Discontinuing rosiglitazone was associated with the FDA warning, removal from the VANF, female sex, black race, Hispanic ethnicity, comorbidity, A1C greater than 9%, and use of rosiglitazone as first- or second-line therapy. Among patients who did and did not receive a replacement medication, the mean  changes in A1C from baseline were 0.12% and 0.46%, respectively. For those who continued rosiglitazone, the mean change in A1C was –0.02%.

Conclusion: The rosiglitazone discontinuation rate increased following the FDA warning and increased further following removal of rosiglitazone from the VANF. Glucose control may have declined among those who discontinued rosiglitazone.

Am J Manag Care. 2013;19(9):748-758
After the US Food and Drug Administration (FDA) issued a safety alert in May 2007 regarding potentially increased risk of myocardial infarction in patients receiving rosiglitazone, the Department of Veterans Affairs (VA) removed it from its national formulary in October 2007.
  • The rosiglitazone discontinuation rate increased following the FDA warning and increased further after its removal from the VA formulary.

  • Patients receiving insulin concurrently tended to have the highest discontinuation rates, and patients receiving rosiglitazone as third-line agent had the lowest discontinuation rates.

  • Among patients who discontinued rosiglitazone and did not receive replacement medication, the mean change from baseline in glycated hemoglobin was 0.46%.
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.

Outcomes

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).

Outcomes were assessed in the context of 2 key events: the May 21, 2007, FDA safety warning and the removal of rosiglitazone from the VANF on October 4, 2007. The study period was split into 3 phases accordingly: pre-FDA warning (April 1, 2007, to May 20, 2007), post FDA warning (May 21,  2007, to October 4, 2007), and after removal from the VANF (October 5, 2007, to June 30, 2008).

Statistical Analysis

Patient baseline characteristics including demographics, comorbidities as defined in the adaptation by Deyo and colleagues of the Charlson Comorbidity Index (a weighted index in which a higher score is associated with an increased risk of health outcomes such as mortality and resource use based on comorbidities coded within the year prior to baseline),16 A1C, and place of rosiglitazone in therapy were described by rosiglitazone discontinuation status (yes or no). We compared baseline characteristics with x 2 or t tests, as appropriate.

We determined the monthly rosiglitazone discontinuation rates. Using Poisson methods, we compared monthly incidence rate ratios (IRRs) in the month prior to the FDA warning (May 2007) with the IRRs in the month prior to removing rosiglitazone from the VANF (September 2007) to assess the impact of the 2 events separately. We also examined the rosiglitazone discontinuation rates across time and described the proportions of patients receiving medications to replace rosiglitazone by the place of rosiglitazone in therapy at the index date. We estimated the intervention effects (IRRs for post FDA warning vs pre-FDA warning, after removal from the VANF vs pre-FDA warning, and after removal from the VANF vs post FDA warning) and identified patient-level factors associated with stopping rosiglitazone by using multivariable Poisson regression with a robust variance estimator and fixed effects for VA medical centers. Patients who died before rosiglitazone was discontinued were coded as continuing on rosiglitazone.

To evaluate the effect on glucose control of removing rosiglitazone from the VANF, we compared A1C levels across time among patients who discontinued and continued rosiglitazone. We used a linear mixed model to account for withinpatient correlation and conducted subgroup analyses of A1C levels according to insulin use at baseline. All P values were 2-sided, and P values less than .05 were considered statistically significant. Because most tests were statistically significant due to the large sample size, we focused our interpretation on differences of a clinically significant magnitude. We used Stata release 11 (StataCorp LP, College Station, Texas) to fit the Poisson models; the remaining analyses were conducted using SAS version 9.2 (SAS Institute Inc, Cary, North Carolina).

RESULTS

Baseline Characteristics by Rosiglitazone Discontinuation Status

On April 1, 2007, 95,539 veterans had an active outpatient prescription for rosiglitazone and were chronic users of the medication. The average age of the cohort was 67 years; 97.8% were male; 60% were white; 9.3% were black; and 30% were other/unknown race (Table 1). At baseline, the mean A1C was 7.4%, and 82.1% of patients received other antidiabetic medications concurrently with rosiglitazone. Rosiglitazone was first-line therapy in 17.9% of patients, second-line in 35.6%, third-line in 26.6%, used with insulin in 19.6%, and rarely prescribed with other medications not included in the second-line or third-line definitions (0.3%). By the end of the study period, 82,797 (86.7%) patients discontinued rosiglitazone. The baseline  characteristics of these patients were essentially the same as those of the total cohort. Patients who continued rosiglitazone were clinically similar to the patients who discontinued the medication, except that they were less likely to be black, have a baseline A1C value higher than 9%, or receive insulin concurrently at baseline, and relatively more likely to receive rosiglitazone as thirdline therapy.

Discontinuation of Rosiglitazone

 
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