Screening to identify signals of opioid drug interactions leading to unintentional traumatic injury.

BACKGROUND: Efforts to minimize harms from opioid drug interactions may be hampered by limited evidence on which drugs, when taken concomitantly with opioids, result in adverse clinical outcomes. OBJECTIVE: To identify signals of opioid drug interactions by identifying concomitant medications (precipitant drugs) taken with individual opioids (object drugs) that are associated with unintentional traumatic injury DESIGN: We conducted pharmacoepidemiologic screening of Optum Clinformatics Data Mart, identifying drug interaction signals by performing confounder-adjusted self-controlled case series studies for opioid + precipitant pairs and injury. SETTING: Beneficiaries of a major United States-based commercial health insurer during 2000-2015 PATIENTS: Persons aged 16-90 years co-dispensed an opioid and ≥1 precipitant drug(s), with an unintentional traumatic injury event during opioid therapy, as dictated by the case-only design EXPOSURE: Precipitant-exposed (vs. precipitant-unexposed) person-days during opioid therapy. OUTCOME: Emergency department or inpatient International Classification of Diseases discharge diagnosis for unintentional traumatic injury. We used conditional Poisson regression to generate confounder adjusted rate ratios. We accounted for multiple estimation via semi-Bayes shrinkage. RESULTS: We identified 25,019, 12,650, and 10,826 new users of hydrocodone, tramadol, and oxycodone who experienced an unintentional traumatic injury. Among 464, 376, and 389 hydrocodone-, tramadol-, and oxycodone-precipitant pairs examined, 20, 17, and 16 (i.e., 53 pairs, 34 unique precipitants) were positively associated with unintentional traumatic injury and deemed potential drug interaction signals. Adjusted rate ratios ranged from 1.23 (95 % confidence interval: 1.05-1.44) for hydrocodone + amoxicillin-clavulanate to 4.21 (1.88-9.42) for oxycodone + telmisartan. Twenty (37.7 %) of 53 signals are currently reported in a major drug interaction knowledgebase. LIMITATIONS: Potential for reverse causation, confounding by indication, and chance CONCLUSIONS: We identified previously undescribed and/or unappreciated signals of opioid drug interactions associated with unintentional traumatic injury. Subsequent etiologic studies should confirm (or refute) and elucidate these potential drug interactions.

Low rate of intraperitoneal port placement in ovarian cancer patients, a population-based assessment.

INTRODUCTION: The National Comprehensive Cancer Network (NCCN) guidelines recommend intraperitoneal chemotherapy in optimally debulked stage III ovarian cancer patients. The objective of this investigation was to determine the rate of intraperitoneal port placement in patients undergoing surgery for ovarian cancer in a national database maintained by the American College of Surgeons. METHOD: We identified ovarian cancer patients in the National Surgical Quality Improvement Program database from 2006 to 2012. Demographics, comorbidities, operative outcomes, and postoperative complications were abstracted. Descriptive analyses were conducted using Wilcoxon rank-sum and Chi square tests, and multivariate regression models were used to analyze pre-operative and post-operative variables associated with intraperitoneal port placement. RESULTS: We identified 2659 ovarian cancer patients who underwent primary surgical management. Of these patients, only 128 (4.8%) had an intraperitoneal port placed at the time of surgery. In multivariable analyses, intraperitoneal ports were associated with body mass index ≤25, disseminated cancer, later portion of the study period (2009-2012), and operative time >200 min. Intraperitoneal port placement was not associated with any difference in surgical site infection, wound disruption, major postoperative complication, readmission within 30 days, or death within 30 days. DISCUSSION: Recent investigation of practice at NCCN institutions between 2003 and 2012 found only 35% of eligible ovarian cancer patients received intraperitoneal chemotherapy. Using intraperitoneal port placement as a surrogate for intraperitoneal chemotherapy administration, our investigation suggests an even lower rate (4.8%) nationally.

Serious Hypoglycemia and Use of Warfarin in Combination With Sulfonylureas or Metformin.

Prior research suggests that warfarin, when given concomitantly with some sulfonylureas, may increase the risk of serious hypoglycemia. However, the clinical significance remains unclear. We examined rate ratios (RRs) for the association between serious hypoglycemia and concomitant use of warfarin with either sulfonylureas or metformin using a self-controlled case series design and US Medicaid claims (supplemented with Medicare claims) from 1999 to 2011. Across all risk windows combined, warfarin was associated with an elevated rate of serious hypoglycemia when given concomitantly with glimepiride (RR, 1.47; 95% confidence interval (CI), 1.07-2.02) and metformin (RR, 1.73; 95% CI, 1.38-2.16). Particularly in the late risk window (>120 days since beginning concomitancy), most of the RRs for warfarin were elevated: glipizide (RR, 1.72; 95% CI, 1.29-2.29), glyburide (RR, 1.57; 95% CI, 1.15-2.15), metformin (RR, 2.26; 95% CI, 1.67-3.05), and glimepiride (RR, 1.56; 95% CI, 0.97-2.50). These results are consistent with a previously hypothesized hypoglycemic effect of warfarin in patients with type 2 diabetes through inhibition of the carboxylation of osteocalcin.

Interaction between loop diuretic-associated mortality and blood urea nitrogen concentration in chronic heart failure.

OBJECTIVES: The purpose of this study was to investigate whether a surrogate for renal neurohormonal activation, blood urea nitrogen (BUN), could identify patients destined to experience adverse outcomes associated with the use of high-dose loop diuretics (HDLD). BACKGROUND: Loop diuretics are commonly used to control congestive symptoms in heart failure; however, these agents cause neurohormonal activation and have been associated with worsened survival. METHODS: Subjects in the BEST (Beta-Blocker Evaluation of Survival Trial) receiving loop diuretics at baseline were analyzed (N = 2,456). The primary outcome was the interaction between BUN- and HDLD-associated mortality. RESULTS: In the overall cohort, HDLD use (≥160 mg/day) was associated with increased mortality (hazard ratio [HR]: 1.56; 95% confidence interval [CI]: 1.35 to 1.80). However, after extensively controlling for baseline characteristics, this association did not persist (HR: 1.06; 95% CI: 0.89 to 1.25). In subjects with BUN levels above the median (21.0 mg/dl), both the unadjusted (HR: 1.59; 95% CI: 1.34 to 1.88) and adjusted (HR: 1.29; 95% CI: 1.07 to 1.60) risk of death was higher in the HDLD group. In patients with BUN levels below the median, there was no associated risk with HDLD (HR: 0.99; 95% CI: 0.75 to 1.34) and after controlling for baseline characteristics, the HDLD group had significantly improved survival (HR: 0.71; 95% CI: 0.49 to 0.96) (p interaction = 0.018). CONCLUSIONS: The risk associated with HDLD use is strongly dependent on BUN concentrations with reduced survival in patients with an elevated BUN level and improved survival in patients with a normal BUN level. These data suggest a role for neurohormonal activation in loop diuretic-associated mortality.