Objective Opioid analgesics are a mainstay for acute pain management, but postoperative opioid administration has risks. We examined the prevalence, risk factors, and consequences of opioid-related adverse drug events (ORADEs) in a previously opioid-free surgical population. Methods A retrospective, observational, cohort study using administrative, billing, clinical, and medication administration data from two hospitals. Data were collected for all adult patients who were opioid-free at admission, underwent surgery between October 1, 2015, and September 30, 2016, and received postoperative opioids. Potential ORADEs were determined based on inpatient billing codes or postoperative administration of naloxone. We determined independent predictors of ORADE development using multivariable logistic regression. We measured adjusted inpatient mortality, hospital costs, length of hospital stay, discharge destination, and readmission within 30 days for patients with and without ORADEs. Results Among 13,389 hospitalizations where opioid-free patients had a single qualifying surgery, 12,218 (91%) received postoperative opioids and comprised the study cohort. Of these, we identified 1111 (9.1%) with a potential ORADE. Independent predictors of ORADEs included older age, several markers of disease severity, longer surgeries, and concurrent benzodiazepine use. Opioid-related adverse drug events were strongly associated with the route and duration of opioids administered postoperatively: 18% increased odds per day on intravenous opioids. In analyses adjusted for several covariates, presence of an ORADE was associated with 32% higher costs of hospitalization, 45% longer postoperative length of stay, 36% lower odds of discharge home, and 2.2 times the odds of death. Conclusions We demonstrate a high rate and severe consequences of potential ORADEs in previously opioid-free patients receiving postoperative opioids. Knowledge of risk factors and predictors of ORADEs can help develop targeted interventions to minimize the development of these potentially dangerous and costly events.

Aim: We describe the real-world utilization and outcomes associated with managing oral factor Xa inhibitor (FXai)-related major bleeds. Materials & methods: Electronic records from 45 US hospitals were queried (ICD-10-CM billing codes D68.32, T45.515x or T45.525x) to identify major bleed hospitalizations related to FXai use. Patient demographics, bleed type (intracranial hemorrhage, gastrointestinal, critical compartment, traumatic, other), FXai taken, reversal or replacement agents administered (including andexanet alfa, four-factor prothrombin complex concentrate, fresh frozen plasma, others), in-hospital mortality and length of stay were recorded. Results: Of 3030 FXai-related hospitalizations for major bleeds, patients averaged 68 years old and 47% were women. In-hospital mortality was highest for intracranial hemorrhage (23%, n = 507) and lowest for gastrointestinal bleeds (4%, n = 1453). In-hospital mortality was lowest (4%) for bleeds managed with andexanet alfa (n = 342), compared with 10% for four-factor prothrombin complex concentrate (n = 733), 11% for fresh frozen plasma (n = 925) and 8% for both other agents (n = 794) and no agents (n = 438). Median length of stay was 5 days across all agents, while ICU length of stay was shorter andexanet alfa (2 days) compared with other agents (3 days). Conclusion: In-hospital mortality differed by bleed type and agents administered. Andexanet alfa was associated with the lowest rate of in-hospital mortality across all bleed types.

Background Andexanet alfa is approved (FDA “accelerated approval”; EMA “conditional approval”) as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH). Methods This two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban < 24 h prior to the bleed were included. Patients with a Glasgow Coma Scale (GCS) score < 7, hematoma volume > 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression. Results The study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16–6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13–0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC. Conclusions In this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC. Trial registration NCT02329327; registration date: December 31, 2014.

Objectives: Hepatorenal Syndrome (HRS) is characterized by renal failure in patients with advanced chronic liver disease (CLD) and is the leading cause of hospitalizations in CLD. This study examines the clinical and economic burden, outcomes, and unmet need of HRS treatment in US hospitals. Method: A retrospective cohort study was conducted based on a large electronic health records database (Cerner HealthFacts) with records for hospitalized HRS patients from January 2009-June 2015. Demographics, clinical characteristics, treatment patterns, and economic outcomes were analyzed. Prognostic indicators of cirrhosis, kidney injury, end-stage liver disease, and acute-on-chronic liver failure were used to determine mortality risk. Results: A total of 2,542 patients hospitalized with HRS were identified (average age ¼ 57.9 years, 61.8% males, 74.2% Caucasian), with an average total hospital charge of $91,504 per patient and a mean length of stay (LOS) of 30.5 days. The mortality rate was 36.9% with 8.9% of patients discharged to hospice. Of all patients, 1,660 patients had acute kidney injury, 859 with Stage 3 disease, and 26.7% had dialysis. The 30-day readmission rate was 33.1%, 41% of which were unplanned. Nearly one-third of study patients had commercial insurance (30.2%), followed by Medicare (29.9%); hospital charges varied by LOS, receipt of dialysis, and discharge status. Regression analysis demonstrated that HRS costs are associated with LOS, dialysis, and hospital mortality. Conclusion: HRS is associated with poor outcomes and high hospital costs. Analysis of HRS cost drivers demonstrated an unmet need for additional treatment options to improve outcomes in this patient population.

Background: Recovery from spine surgery is oriented toward restoring functional health outcomes while reducing resource use. Optimal pain management is a key to reaching these objectives. We compared outcomes of spine surgery patients who received standard pain management including intravenous (IV) acetaminophen (APAP) vs. oral APAP. Methods: We performed a retrospective analysis of the Premier database (January 2012 to September 2015) comparing spine surgery patients who received pain management with IV APAP to those who received oral APAP, with no exclusions based on additional pain management. We performed multivariable logistic regression for the discharge and all cause 30-day readmission to the same hospital outcomes and instrumental variable regressions using the quarterly rate of IV APAP use for all hospitalizations by hospital as the instrument in two-stage least squares regressions for length of stay (LOS), hospitalization costs, and average daily morphine equivalent dose (MED) outcomes. Models adjusted for age, gender, race, admission type, 3M All Patient Refined Diagnosis Related Group severity of illness and risk of mortality, hospital size, and indicators for whether the hospital was an academic center and whether it was urban or rural. Results: We identified 112,586 spine surgery patients with 51,835 (46%) having received IV APAP. Subjects averaged 57 and 59 years of age respectively in the IV APAP and oral APAP cohorts and were predominantly non-Hispanic Caucasians and female. In our adjusted models, IV APAP was associated with 0.68 days shorter LOS (95% CI: À0.76 to À0.59, p < .0001), $1175 lower hospitalization costs (95% CI: À$1611 to À$739, p < .0001), 13 mg lower average daily MED (95% CI: À14 mg to À12 mg, p < .0001), 34% lower risk of discharge to a skilled nursing facility (95% CI: 0.63 to 0.69, p < .0001), and 13% less risk of 30-day readmission (95% CI: 0.73 to 1.03). Conclusions: Compared to oral APAP, managing post-spine-surgery pain with IV APAP is associated with less resource use, lower costs, lower doses of opioids, and improved discharge status.

HRS imposes a significant economic burden.

Oral factor Xa (FXa) inhibitors significantly reduce incidence of stroke and thromboembolic events in patients with atrial fibrillation or venous thromboembolism. Due to various factors and the lack of a randomized controlled trial comparing andexanet alfa to usual care, non-specific replacement agents including 4 F-PCC are still used off-label for FXa inhibitor bleed management. Clinical and mortality data were extracted from the inpatient medical data and Veteran Affairs (VA) vital status files over the time of March 2014 through December 2020. Propensity score-weighted models were used for this retrospective cohort study using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). The study included 255 patients (85-andexanet alfa and 170-4 F-PCC) exposed to an oral factor Xa inhibitor and hospitalized with an acute major, gastrointestinal (GI), intracranial (ICH) or other bleed. In-hospital mortality was significantly lower in the andexanet alfa cohort compared to the 4 F-PCC cohort (10.6% vs. 25.3%, p = 0.01). Propensity score–weighted Cox models reveal a 69% lower hazard of in-hospital mortality for those treated with andexanet alfa (HR 0.31, 95% CI 0.14–0.71) compared to those treated with 4 F-PCC. Additionally, those treated with andexanet alfa had a lower 30-day mortality rate and lower 30-day hazard of mortality in the weighted Cox model (20.0% vs. 32.4%, p = 0.055; HR 0.54, 95% CI 0.30–0.98) compared to those treated with 4 F-PCC. Among 255 US veterans with major bleeding in the presence of an oral factor Xa inhibitor, treatment with andexanet alfa was associated with lower in-hospital and 30-day mortality than treatment with 4 F-PCC.

Use of post-surgical OFA was limited overall and was not favored in some patient groups prone to ORADEs, indicating missed opportunities to reduce opioid use and ORADE incidence. A substantial proportion of OFA patients was contributed by a few hospitals with especially high rates of OFA, suggesting that hospital policies, institutional structure and cross-functional departmental commitment to reducing opioid use may play a large role in the implementation of OFA.