Varenicline and Nicotine Replacement Use Associated With US Food and Drug Administration Drug Safety Communications.

Importance: Drug safety communications released by the US Food and Drug Administration (FDA) are often based on limited evidence on safety signals after approval. Varenicline may serve as a relevant case study because it was the target of several FDA communications in 2008 and 2009; ultimately, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) dismissed safety concerns on increased suicidal thoughts and aggressive and erratic behavior on December 16, 2016. Objective: To examine the association between FDA drug safety communications and the use of varenicline. Design, Setting, and Participants: Retrospective, longitudinal, cross-sectional study of Veterans Health Administration (VHA) outpatient data from October 1, 2001, through December 31, 2018, and Medicaid drug state use data from July 1, 2006, through September 30, 2018, on varenicline prescribing. Main Outcomes and Measures: Prescribing records for varenicline and nicotine replacement therapy (NRT) in the VHA were extracted, and the number of unique varenicline and NRT users in the VHA per quarter was measured. An interrupted time series analysis was performed to describe the association between FDA safety warnings and the use of varenicline and NRT. To test the generalizability of the findings, similar analyses were conducted using the number of prescriptions reimbursed for varenicline by Medicaid every quarter in 2006-2018. Results: After its addition to the VHA national drug formulary in January 2007, varenicline use presented a steady increase, reaching a peak of 32 581 quarterly unique users in the first quarter of 2008. Within 12 months of the February 1, 2008, public health advisory, quarterly varenicline use in VHA patients decreased by 68.7% (from 32 581 to 10 182 patients; P < .001 for slope change), and NRT use increased by 32.1% (from 55 728 to 73 629 patients; P < .001 for slope change). In Medicaid prescriptions, varenicline use decreased by 38.0% (from 109 308 to 67 761 prescriptions; P < .001 for slope change) within 12 months of the 2008 public health advisory. Twelve months after the publication of the EAGLES trial, which showed no significant increase in psychiatric/behavioral effects with varenicline relative to NRT, use of varenicline increased by 42.7% in VHA patients (from 9251 to 13 199 patients; P = .01 for slope change) and by 26.0% in Medicaid prescriptions (112 063 to 141 122; P = .26 for slope change ). Conclusions and Relevance: With use of varenicline as a case study, early communications from the FDA and VHA followed by a labeling change appeared to be associated with a considerable decrease in drug use, which may have been associated with negative public health consequences.

Provider Response to QTc Prolongation on Standard 12-Lead EKG: Do We Notice or Do We Care?

BACKGROUND: Drugs and electrolyte imbalances are widely recognized as common triggers of a prolonged QT interval. We conducted a chart review to assess provider response to prolonged QT reported on a standard 12-lead electrocardiogram (EKG). METHODS: We identified all Veterans Affairs Pittsburgh Healthcare System patients in a 6-month period with an EKG reporting a corrected QT (QTc) >500 ms. We excluded confounding or uninterpretable EKGs. Charts were reviewed to assess medications and electrolytes at the time of the EKG as well as the setting (inpatient vs outpatient) in which the EKG was obtained. Provider documentation of QTc and any corrective measures were sought. RESULTS: After exclusions, 106 patients were included in this analysis (87 [82%] inpatient and 19 [18%] outpatient). Most were male (101, 95%) with a mean age of 63.5 ± 10.6 years. At the time of index EKG, most patients were receiving at least one (72, 68%), and frequently two or more (35, 33%), QTc prolonging medications. Providers documented QTc prolongation in 20 inpatients (19%). Drugs were adjusted or discontinued in only two inpatients (2%). There were 14 patients (14%) with potassium level <3.6 mmol/L and 10 of 69 (14%) patients had a magnesium level <1.7 mg/dL. CONCLUSION: Patients with prolonged QTc on EKG were more likely to be inpatients than outpatients. Inpatients were more likely to be receiving multiple types and classes of QTc prolonging medications. In the vast majority of cases, providers did not address the prolonged QTc and only rarely initiated remedial actions.