Medication use evaluation of tocilizumab implementation in COVID-19 treatment guidelines: A causal inference approach.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Introduction of new medications to health-system formularies is often not accompanied by assessments of their clinical impact on the local patient population. The growing availability of electronic health record (EHR) data and advancements in pharmacoepidemiology methods offer institutions the opportunity to monitor the medication implementation process and assess clinical effectiveness in the local clinical context. In this study, we applied novel causal inference methods to evaluate the effects of a formulary policy introducing tocilizumab therapy for critically ill patients with coronavirus disease 2019 (COVID-19). METHODS: We conducted a medication use evaluation utilizing EHR data from patients admitted to a large medical center during the 6 months before and after implementation of a formulary policy endorsing the use of tocilizumab for treatment of COVID-19. The impact of tocilizumab on 28-day all-cause mortality was assessed using a difference-in-differences analysis, with ineligible patients serving as a nonequivalent control group, and a matched analysis guided by a target trial emulation framework. Safety endpoints assessed included the incidence of secondary infections and liver enzyme elevations. Our findings were benchmarked against clinical trials, an observational study, and a meta-analysis. RESULTS: Following guideline modification, tocilizumab was administered to 69% of eligible patients. This implementation was associated with a 3.1% absolute risk reduction in 28-day mortality (odds ratio, 0.86; number needed to treat to prevent one death, 32) attributable to the inclusion of tocilizumab in the guidelines and an additional 8.6% absolute risk reduction (odds ratio, 0.65; number needed to treat to prevent one death, 12) linked to its administration. These findings were consistent with estimates from published literature, although the effect estimates from the difference-in-differences analysis exhibited imprecision. CONCLUSION: Evaluating formulary management decisions through novel causal inference approaches offers valuable estimates of clinical effectiveness and the potential to optimize the impact of new medications on population outcomes.

Pharmacy-driven performance improvement initiative to increase compliance with intravenous smart pump drug error reduction systems at a large urban academic medical center.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Smart pump dose error reduction systems (DERS) reduce errors for intravenous (IV) administration medications by warning users of order, calculation, and programming errors. The purpose of this performance improvement initiative was to increase IV smart pump DERS usage from 77% to 95% at a large, urban academic medical center. METHODS: A pharmacy-led team with nurses, physicians, and quality improvement specialists executed interventions from July 2020 through April 2022 to increase DERS compliance. A discovery phase (phase I) was followed by 6 Plan-Do-Study-Act (PDSA) cycles created to address barriers to DERS utilization. Phase I revealed that problems involving the DERS library and bedside nurse training were the major drivers of noncompliance. Phase II consisted of 3 system-level PDSA cycles, and phase III included 3 focused group PDSA cycles. Data were collected monthly from the smart pump reporting software by the informatics pharmacist and analyzed by the team to assess compliance rates in response to the corresponding interventions. RESULTS: The median DERS compliance increased from 77% to 83% over the 2-year period, which correlates with approximately 109,000 additional infusions run on DERS each year within our institution. The implementation of a DERS problem reporting tool accessed through the medication administration record resulted in the most pronounced improvement. CONCLUSION: DERS compliance improved following system-level sustainable interventions, although further PDSA cycles are needed to meet the goal DERS utilization rate of 95%. The results of this study may help other institutions attempting to improve DERS utilization create targeted interventions.

Comparison of bleeding and ischemic events with apixaban vs. rivaroxaban in triple antithrombotic therapy regimens.

OBJECTIVE: To compare the risk of readmissions for major bleeding within one year between apixaban and rivaroxaban as a component of triple antithrombotic therapy. METHODS: This study was a multicenter, retrospective cohort study conducted at two academic medical centers in the Western New York and New York City region between July 1, 2011 and September 25, 2019. Adult patients were included if they were diagnosed with atrial fibrillation or venous thromboembolism and discharged on new triple antithrombotic therapy. The primary outcome compared the rates of 1-year readmission for major bleeding between apixaban and rivaroxaban groups. Secondary outcomes included rate of ischemic outcomes. Time to event analysis was determined with a Kaplan-Meier plot and Cox proportional hazard ratios (HR). RESULTS: A total of 378 patients were included in the study, 212 in the apixaban group and 166 in the rivaroxaban group. Within 1 year, readmission for major bleeding events occurred in six (2.8%) patients in the apixaban group and four (2.4%) patients in the rivaroxaban group ( P  = 1.000). After adjustment, the major bleeding event rate was not statistically significantly different between apixaban and rivaroxaban [adjusted hazard ratio (aHR) 0.68, 95% confidence interval (CI) 0.12-3.77; P  = 0.6624]. Higher albumin levels were identified to be protective against major bleeding related readmission events (aHR 0.18, 95% CI 0.05-0.63; P  = 0.0072). The ischemic outcome occurred in seven (3.3%) patients in the apixaban group and three (1.8%) in the rivaroxaban group ( P  = 0.7368). CONCLUSION: Use of apixaban or rivaroxaban in a triple antithrombotic regimen was not associated with bleeding or ischemic outcomes.

Comparison of the effects of sugammadex versus neostigmine for reversal of neuromuscular block on hospital costs of care.

BACKGROUND: Sugammadex reversal of neuromuscular block facilitates recovery of neuromuscular function after surgery, but the drug is expensive. We evaluated the effects of sugammadex on hospital costs of care. METHODS: We analysed 79 474 adult surgical patients who received neuromuscular blocking agents and reversal from two academic healthcare networks between 2016 and 2021 to calculate differences in direct costs. We matched our data with data from the Healthcare Cost and Utilization Project-National Inpatient Sample (HCUP-NIS) to calculate differences in total costs in US dollars. Perioperative risk profiles were defined based on ASA physical status and admission status (ambulatory surgery vs hospitalisation). RESULTS: Based on our registry data analysis, administration of sugammadex vs neostigmine was associated with lower direct costs (-1.3% lower costs; 95% confidence interval [CI], -0.5 to -2.2%; P=0.002). In the HCUP-NIS matched cohort, sugammadex use was associated with US$232 lower total costs (95% CI, -US$376 to -US$88; P=0.002). Subgroup analysis revealed that sugammadex was associated with US$1042 lower total costs (95% CI, -US$1198 to -US$884; P<0.001) in patients with lower risk. In contrast, sugammadex was associated with US$620 higher total costs (95% CI, US$377 to US$865; P<0.001) in patients with a higher risk (American Society of Anesthesiologists physical status ≥3 and preoperative hospitalisation). CONCLUSIONS: The effects of using sugammadex on costs of care depend on patient risk, defined based on comorbidities and admission status. We observed lower costs of care in patients with lower risk and higher costs of care in hospitalised surgical patients with severe comorbidities.

Evaluating Pharmacist-Led Heart Failure Transitions of Care Clinic: Impact of Analytic Approach on Readmission Rate Endpoints.

Studies evaluating pharmacist-led transitions of care (TOC) services for heart failure patients reported profound decreases in hospital readmissions. Most studies restricted their analysis to clinic attendees (as-treated analysis), which can introduce selection and immortal time bias. In this study, we evaluated the impact of including only clinic attendees vs all clinic referrals in assessing the effectiveness of a pharmacist-led heart failure transitions of care (PharmD HF TOC) clinic program on 30-day readmissions. This is a retrospective, observational study of patients discharged from a heart failure hospitalization at a large urban academic medical center from August 2016 to December 2018. Primary exposure was the provision of a PharmD HF TOC clinic appointment in the intent-to-treat analysis and the attendance of the clinic in the as-treated analysis. Primary outcome was all-cause readmissions within 30 days of discharge. There were 766 and 1015 patients included in the as-treated and intent-to-treat analyses, respectively. In the as-treated analysis, 30-day all-cause readmissions were significantly lower in the intervention group compared to the control group (12.4% vs 19.6%, P = 0.018). In contrast, the intent-to-treat analysis did not reveal a significant difference in 30-day all-cause readmissions between the intervention group and the control group (18.2% vs 19.6%, P = 0.643). Pharmacist-led heart failure TOC program is associated with a reduction in 30-day all-cause readmissions only when restricting the analysis to clinic attendees. Future studies evaluating the effectiveness of post-discharge TOC services need to carefully consider the biases inherent in the evaluation methods employed.

Effectiveness of Bariatric Surgery Targeting Opioid Prescriptions (BSTOP) protocol on postoperative pain control.

BACKGROUND: Surgical pain management is a critical component in the success of bariatric procedures. With the opioid epidemic, there have been increased efforts to decrease opioid use. In 2019, the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program developed the BSTOP protocol, a multimodal perioperative pain management regimen to minimize opioid use. The objective of this study is to evaluate the effectiveness of the BSTOP protocol on patients' need for opioid medications during their perioperative care. METHODS: This is a single-institution prospective cohort study on patients who underwent bariatric surgery from 10/2019 to 5/2021. Data was collected on morphine equivalent dose of opioids during different stages of inpatient and outpatient care. BSTOP was implemented on 7/2020. Primary outcomes were total inpatient and outpatient opioid use as well as hospital length of hospital stay (LOS). Gabapentin was removed from the protocol between 10/20/2020 and 12/31/2020 due to side effects; it was re-implemented on 1/1/2021 due to observed spikes in opioid use during its absence. RESULTS: 1264 patients who had bariatric surgery between 10/2019 and 5/2021 were included in the study, with 409 patients before (pre-BSTOP) and 855 patients after BSTOP implementation. There was a 36% reduction in total inpatient opiate use and a 57% reduction in total outpatient opiate use. LOS also significantly decreased, from 1.53 to 1.28 days. 179 patients received BSTOP without gabapentin. These patients used more opioids in the post-anesthesia care unit and on the inpatient floors compared to pre-BSTOP and BSTOP with gabapentin patients. With total inpatient and outpatient opioid use, patients on BSTOP without gabapentin used fewer opioids than those pre-BSTOP. However, those on BSTOP without gabapentin used more opioids than those with gabapentin. CONCLUSION: The BSTOP protocol significantly reduced inpatient and outpatient opioid use as well as LOS. Gabapentin is a crucial component of the BSTOP protocol.

Acute Kidney Injury Risk and Contrast Volume in Intact Versus Ruptured Endovascular Aneurysm Repair in the Vascular Quality Initiative.

OBJECTIVE: Renal impairment after repair of ruptured abdominal aortic aneurysm has been associated with post-operative mortality. Acute kidney injury (AKI) risk specifically related to contrast administration in endovascular aneurysm repair (EVAR) for intact vs ruptured aneurysms has not been previously described. It was our objective to evaluate the risk of AKI and the association with contrast administration in EVAR for ruptured (rEVAR) and intact (iEVAR) aneurysm repair in the Vascular Quality Initiative (VQI). METHODS: Adult patients less than 90 years old undergoing EVAR in the VQI without prior abdominal aortic surgery or who were not actively on dialysis preoperatively were included. Patients immediately converted to an open repair were excluded. Patients were grouped by repair urgency, and patient and operative characteristics and outcomes compared. Univariable and multivariable analyses were performed to identify factors associated with the primary outcome of AKI. Survival was evaluated by Kaplan-Meier analysis. RESULTS: Of 38,775 EVAR patients identified, 86.5% underwent elective surgery for an intact aneurysm, 8.4% had urgent surgery for a symptomatic, intact aneurysm, and 5.1% had emergent repair for a ruptured aneurysm. Significant risk factors for AKI included contrast volume, a preoperative eGFR <30 mL/min, procedure urgency, COPD, congestive heart failure (CHF), and total procedure time. The factor most associated with AKI was aneurysm rupture prior to repair (OR 8.6, CI 7.2-10.3, P <.01). The association of contrast volume with the outcome was the least strong with a 4% increase in risk per 25 mL of contrast (OR 1.04, 95% CI 1.01-1.07). With the development of AKI, postoperative survival was reduced regardless of indication. CONCLUSIONS: Of all factors assessed, aneurysm rupture was the most and contrast volume the least associated with AKI after EVAR. Further studies should evaluate methods of preventing post-EVAR AKI.

Assessment of Patiromer Monotherapy for Hyperkalemia in an Acute Care Setting.

Importance: Hyperkalemia is a common electrolyte disorder in hospitalized patients; however, the clinical usefulness of administering patiromer for reduction of serum potassium levels in this setting is unknown. Objective: To evaluate the outcomes associated with patiromer as monotherapy in patients with acute hyperkalemia in an acute care setting. Design, Setting, and Participants: This cohort study used electronic health record data from adult patients treated with patiromer for acute hyperkalemia in emergency departments, inpatient units, and intensive care units at an urban, academic medical center in the Bronx, New York, between January 30, 2018, and December 30, 2019. Data analysis was conducted between June 2020 and February 2021. Exposures: A single dose of oral patiromer (8.4 g, 16.8 g, or 25.2 g). Main Outcomes and Measure: The primary outcome was the mean absolute reduction in serum potassium level from baseline at 3 distinct time intervals after patiromer administration: 0 to 6 hours, greater than 6 to 12 hours, and greater than 12 to 24 hours. Key secondary outcomes were the incidence of hypokalemia and potassium reduction stratified by baseline potassium level and care setting. Results: Among 881 encounters of patiromer treatment, the mean (SD) age of patients was 67.4 (14.4) years; 463 encounters (52.6%) were for male patients, and most (338 [38.4%]) were for patients who identified as non-Hispanic Black. The mean (SD) baseline serum potassium level was 5.60 (0.35) mEq/L (to convert to mmol/L, multiply by 1.0), and within the first 6 hours after patiromer administration, the mean (SD) potassium reduction was 0.50 (0.56) mEq/L (P < .001). Both absolute and relative potassium reduction from baseline varied across baseline hyperkalemia severity but not by care setting. The lowest dose of patiromer (8.4 g) was used in 721 encounters (81.8%), and in 725 encounters (82.3%), no further doses of a potassium binder were required. Hypokalemia was noted in 2 encounters (0.2%) at 24 hours after patiromer administration. Conclusions and Relevance: In this cohort study of patients with acute, non-life-threatening hyperkalemia, a single dose of patiromer was associated with a significant decrease in serum potassium levels and a low incidence of hypokalemia. These findings suggest that patiromer monotherapy may be useful in an institutional setting for managing elevated potassium levels and minimizing the risk of hypokalemia associated with other potassium control measures.

Incidence of Complications Associated with Parenteral Nutrition in Preterm Infants < 32 Weeks with a Mixed Oil Lipid Emulsion vs a Soybean Oil Lipid Emulsion in a Level IV Neonatal Intensive Care Unit.

BACKGROUND: Parenteral nutrition (PN) is crucial for the improvement of long-term outcomes in very low birth weight (VLBW) neonates. Lipid injectable emulsions are a key component of PN, as they contain essential fatty acids and provide energy critical for brain growth. Prolonged administration increases risk of intestinal failure-associated liver disease, including cholestasis, and other complications. METHODS: This is a retrospective, quasi-experimental cohort study of 215 VLBW neonates. The primary outcome was a change in direct bilirubin concentration. Secondary outcomes included change in total bilirubin concentration and incidences of cholestasis and other disease states associated with PN and prematurity. Cholestasis was defined as direct bilirubin ≥ 1.0 mg/dL with total bilirubin < 5.0 mg/dL or direct bilirubin > 20% of total bilirubin with total bilirubin > 5.0 mg/dL. RESULTS: Change in direct bilirubin concentration was not different between groups. Incidence of cholestasis was not different between groups per charted diagnosis or per study definition. Non-stage-0 retinopathy of prematurity, bronchopulmonary dysplasia, sepsis, and necrotizing enterocolitis were all lower in the mixed oil lipid emulsion group, which remained significant after adjustment for differences in gestational age, birth weight, and PN duration. CONCLUSIONS: Although mixed oil lipid emulsion was not found to be associated with a lower risk of cholestasis, it may decrease risks of other disease states associated with PN therapy.

Safety of High-Dose Unfractionated Heparin for Prophylaxis of Venous Thromboembolism in Hospitalized Obese Patients.

BACKGROUND: Optimal dosing of unfractionated heparin (UFH) for thromboprophylaxis in the obese patient population is uncertain because of their high-risk, prothrombotic state and a complexity of pharmacokinetic considerations. Literature on the appropriateness of the use of a higher dose UFH regimen remains unclear and inconsistent. OBJECTIVE: To evaluate the safety of the use of 7500 units every 8 hours (high-dose) of subcutaneous UFH compared with the use of 5000 units every 8 hours (standard-dose) of subcutaneous UFH for thromboprophylaxis in obese patients (defined as BMI ≥30 kg/m2). METHODS: In a retrospective cohort study, 326 adult patients were included, with a BMI ≥30 kg/m2, who were admitted to a large, urban academic medical center between September 1, 2015, and September 1, 2018. Patients received either high-dose or standard-dose UFH for at least 48 hours. The primary end point was the incidence rate of bleeding events, defined as a ≥2-g/dL fall in hemoglobin level or receipt of transfusion of 2 or more units of packed red blood cells (pRBCs) from the start of the UFH order. RESULTS: The incidence rate of bleeding was significantly higher in those who received high-dose UFH (43%) compared with those who received standard-dose UFH (29%; P = 0.008). No significant difference was found between venous thromboembolism event rates. CONCLUSION AND RELEVANCE: High-dose UFH was associated with an increased bleeding event rate compared with standard-dose UFH in patients with a BMI ≥30 kg/m2. This raises safety concerns about the appropriateness of utilizing this regimen in this population.

Clinical Pharmacists: An Invaluable Part of the Coronavirus Disease 2019 Frontline Response.

Although coronavirus disease 2019 was first identified in December 2019, it rapidly spread and became a global pandemic. The number of patients infected with the novel coronavirus (severe acute respiratory syndrome coronavirus 2) rose rapidly in New York State, placing great stress on healthcare systems. The traditional roles and practices of healthcare providers were dramatically redefined to meet the demand to care for the large number of ill patients. While literature reports on the experiences of many frontline staff, there is a scarcity of reports on the role of clinical pharmacists during this crisis. We report the role of critical care clinical pharmacists at a large academic medical center in New York City during this pandemic. Effective crisis management required clinical pharmacists to employ a wide array of skills and knowledge. Areas included clinical expertise, education, data analysis, health informatics infrastructure, and inventory management in times of surging medication use and manufacturer shortages. Clinical pharmacists fulfilled an essential service during the coronavirus pandemic by working to ensure the best possible outcomes for the patients they served on the frontline.

Safety of direct oral anticoagulants vs warfarin in patients with chronic liver disease and atrial fibrillation.

BACKGROUND: A complication of chronic liver disease (CLD) is the abnormality of coagulation. In clinical practice, this increased risk of bleeding has not been identified as a protective factor against stroke or systemic embolism associated with atrial fibrillation (AF). The objective of this study was to assess the safety of direct oral anticoagulant (DOAC) agents vs warfarin in CLD patients with AF. METHODS: This was a retrospective cohort study of patients with CLD and AF initiated on oral anticoagulants. Rates of all-cause bleeding were compared between warfarin and DOAC agents. Secondary endpoints included rates of major bleeding and other risk factors for bleeding on anticoagulant therapy. RESULTS: The all-cause bleeding rates were similar between the groups, with 8.4% per year in the DOAC (n = 75) group and 8.8% in warfarin (n = 158) group (HR 0.9, 95% CI 0.4-1.8). No significant difference was noted in the rate of major bleeding. In the multivariable model, higher MELD-XI score and previous bleed were risk factors associated with increased bleeding. CONCLUSION: No significant differences in bleeding rates were noted in patients treated with warfarin and DOAC agents. Further studies evaluating DOAC agents are needed to better understand the optimal anticoagulation strategy in setting of CLD.

Antibiotic Use in Hospitalized Children With Respiratory Viruses Detected by Multiplex Polymerase Chain Reaction.

BACKGROUND: Multiplex polymerase chain reaction-based methods are increasingly used to detect respiratory pathogens in children. While rapid identification of viruses has been shown to reduce antibiotic use, the impact of detecting specific viruses on antibiotic utilization has not been ascertained. This study compared antibiotic utilization among hospitalized children who tested positive for different respiratory viruses at admission. METHODS: A single-center study of hospitalized children under 21 years of age who tested positive at admission for at least 1 respiratory virus by multiplex polymerase chain reaction from October 1, 2012 to October 1, 2015 was performed. Multivariable logistic regression was used to determine the association of testing positive for specific viruses with the use of antibiotics for ≥ 2 days, adjusted for demographic and clinical characteristics. RESULTS: The study included 1416 patients with a median age of 2.1 years (interquartile range: 0.6-6.2 years). Patients positive for influenza (odds ratio: 2.0, 95% confidence interval: 1.1-3.4) and human metapneumovirus (odds ratio: 2.0, 95% confidence interval: 1.1-3.7) were more likely to receive ≥ 2 days of treatment compared with patients positive for respiratory syncytial virus (RSV). Other variables affecting prolonged use of antibiotics included respiratory support, primary nonrespiratory diagnosis, complex comorbid conditions and admission to the intensive care unit. CONCLUSIONS: Providers are more likely to use antibiotics in non-RSV-infected patients compared with RSV. These trends likely represent concern about bacterial superinfection and may reflect lack of familiarity with these pathogens.

The Use of Idarucizumab for Dabigatran Reversal in Clinical Practice: A Case Series.

PURPOSE: To describe the use of idarucizumab (Praxbind, Boehringer Ingelheim) in routine clinical practice at a large urban academic medical center. SUMMARY: Seven total doses of idarucizumab were administered to six unique patients from October 31, 2015, to October 31, 2016. The reversal agent was used in conjunction with local bleeding control measures, blood product transfusions, and acid-suppressive therapy. In 86% of cases, idarucizumab administration resulted in a successful cessation of bleeding by clinical assessment. Two patients expired due to coexisting conditions. Idarucizumab was administered to patients with normal baseline coagulation tests in 43% of cases. No adverse reactions related to idarucizumab were reported. CONCLUSIONS: Idarucizumab administration resulted in successful resolution of bleeding by clinical assessment. The therapy for acute bleeding with use of dabigatran (Pradaxa, Boehringer Ingelheim) remains supportive care, in addition to idarucizumab in cases of severe or uncontrolled bleeding. Development of institution-specific protocols and better guidance for using baseline coagulation tests are needed.

What Is the Appropriate Duration of High-Dose Atorvastatin Therapy Post-Acute Coronary Syndrome?

PURPOSE: To determine the optimal duration of high-intensity atorvastatin therapy post-acute coronary syndrome (ACS). SUMMARY: A literature review was conducted using the MEDLINE database (1966-October 2013) and employing the search terms "atorvastatin OR statins AND myocardial infarction OR acute coronary syndromes." Clinical trials in the English language with available abstracts were used to identify potential data sources. Four major trials evaluating atorvastatin 80 mg daily after an ACS were identified. The duration of follow-up ranged from 16 weeks to a median of 4.9 years. High-dose atorvastatin regimens were associated with a reduction in coronary events but also with higher rates of drug discontinuation due to adverse reactions. The benefit of high-dose atorvastatin has been sustained for at least 5 years. CONCLUSION: After an ACS, high-dose atorvastatin should be continued for at least 5 years. High-dose atorvastatin demonstrated a reduction in coronary events but dose reductions and higher discontinuation rates were also noted.