Comparing Treatment Response Between Older and Younger Patients with Chronic Hepatitis C Virus Infection on Direct-acting Antiviral Agents.

OBJECTIVE: To compare sustained virologic response 12 weeks post-treatment completion (SVR12) and patient characteristics for older versus younger patients with chronic hepatitis C virus infection (HCV) receiving direct-acting antiviral (DAA) agent therapy. METHODS: This retrospective cohort study included patients with chronic HCV who received DAA therapy, between 2015 and 2018, in the largest health system in Rhode Island (N=154). Patient characteristics, comorbid diagnoses, and SVR12 status were compared between older (aged ≥60 years) and younger (<60 years) adults using chi-squared tests. RESULTS: Overall, 94.1% (95% CI: 90.4-97.8) achieved SVR12; response rates were 91.8% (95% CI: 84.9-98.6) for older adults and 95.6% (95% CI: 91.5-99.8) for younger adults (p=0.51). CONCLUSIONS: Our findings refute the historical notion that older adults were a "difficult-to-treat" subpopulation for whom clinicians should expect less treatment success. This is no longer the case with DAA therapy.

Pharmacokinetics of flucytosine in a critically ill patient on continuous venovenous hemodiafiltration.

PURPOSE: To describe the pharmacokinetics of flucytosine in a critically ill patient undergoing continuous venovenous hemodiafiltration (CVVHDF) treated for cryptococcal meningitis. SUMMARY: A 20-year-old female weighing 93.4 kg with a body mass index of 34.3 kg/m2 with a past medical history of systemic lupus erythematous with diffuse proliferative lupus nephritis (class IV) was admitted to the hospital after several months of worsening dyspnea, fatigue, myalgia, vomiting, and diarrhea. The patient developed worsening renal function and volume overload requiring CVVHDF on hospital day 7. She was diagnosed with cryptococcal meningitis on hospital day 8, and flucytosine 2,500 mg enterally every 12 hours and liposomal amphotericin B 500 mg intravenously every 24 hours were initiated. Flucytosine serum concentrations were collected on day 4 of therapy, and pharmacokinetics were performed on 2 sequential levels. Pharmacokinetic calculations displayed an elimination rate constant of 0.0338 h-1, a volume of distribution between 0.42 and 0.43 L/kg, a half-life of 20.5 hours, and a total drug clearance between 1.32 and 1.36 L/h while on CVVHDF. The nonsequential levels displayed good correlation, and no further monitoring or dosage adjustment was required. The patient completed therapy, with clinical resolution of her infection, and no toxicities due to flucytosine were noted. CONCLUSION: Flucytosine dosed at 25 mg/kg of actual body weight every 12 hours during CVVHDF conferred therapeutic levels with no appreciable toxicities. Because of its narrow therapeutic index and risk of toxicity, additional pharmacokinetic studies are needed to determine optimal drug dosing of this medication in patients requiring renal replacement therapy.

Effect of Best Practice Advisories on Sedation Protocol Compliance and Drug-Related Hazardous Condition Mitigation Among Critical Care Patients.

OBJECTIVES: To determine whether best practice advisories improved sedation protocol compliance and could mitigate potential propofol-related hazardous conditions. DESIGN: Retrospective observational cohort study. SETTING: Two adult ICUs at two academic medical centers that share the same sedation protocol. PATIENTS: Adults 18 years old or older admitted to the ICU between January 1, 2016, and January 31, 2018, who received a continuous infusion of propofol. INTERVENTIONS: Two concurrent best practice advisories built in the electronic health record as a clinical decision support tool to enforce protocol compliance with triglyceride and lipase level monitoring and mitigate propofol-related hazardous conditions. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were baseline and day 3 compliance with triglyceride and lipase laboratory monitoring per protocol and time to discontinuation of propofol in the setting of triglyceride and/or lipase levels exceeding protocol cutoffs. A total of 1,394 patients were included in the study cohort (n = 700 in the pre-best practice advisory group; n = 694 in the post-best practice advisory group). In inverse probability weighted regression analyses, implementing the best practice advisory was associated with a 56.6% (95% CI, 52.6-60.9) absolute increase and a 173% relative increase (risk ratio, 2.73; 95% CI, 2.45-3.04) in baseline laboratory monitoring. The best practice advisory was associated with a 34.0% (95% CI, 20.9-47.1) absolute increase and a 74% (95% CI, 1.39-2.19) relative increase in day 3 laboratory monitoring after inverse probability weighted analyses. Among patients with laboratory values exceeding protocol cutoffs, implementation of the best practice advisory resulted in providers discontinuing propofol an average of 16.6 hours (95% CI, 4.8-28.3) sooner than pre-best practice advisory. Findings from alternate analyses using interrupted time series were consistent with the inverse probability weighted analyses. CONCLUSIONS: Best practice advisories can be effectively used in ICUs to improve sedation protocol compliance and may mitigate potential propofol-related hazardous conditions. Best practice advisories should undergo continuous quality assurance and optimizations to maximize clinical utility and minimize alert fatigue.

Pertuzumab-associated diarrhea in HER2/neu-positive breast cancer patients: A comparison of trials to actual practice.

BACKGROUND: Although landmark trials in the metastatic (CLEOPATRA) and neo-adjuvant (NeoSphere; TRYPHAENA) settings identified all-grade diarrhea as a pertuzumab-associated adverse event, it was not classified as dose-limiting. In actual practice, diarrhea is often a reason for treatment modifications. OBJECTIVES: To compare the risk of pertuzumab-associated diarrhea in actual practice to the risks in randomized controlled trials. METHODS: We conducted a retrospective cohort study of HER2/neu-positive breast cancer patients who received a pertuzumab-containing regimen between January 2012 and August 2015. We calculated the risk of diarrhea with 95% confidence limits (CLs), and then used two-sample t-tests to compare the risk between trials and actual practice. RESULTS: A total of 27 patients in the study cohort received a pertuzumab-containing treatment regimen for HER2/neu-positive breast cancer. The overall risk of all-grade and severe diarrhea in actual practice was 70% (95% CLs 55-90%) and 37% (95% CLs 20-66%), respectively. No severe diarrhea was observed in the metastatic setting, and the risk of all-grade diarrhea (44%, 95% CLs 21-92%) was similar to the CLEOPATRA study (67%). The risk of all-grade diarrhea in the neo-adjuvant setting was 83% (95% CLs 68-100%), compared to 46% in the NeoSphere trial (p = 0.03). The risk of severe diarrhea (Grade 3-4) in the neo-adjuvant setting was 47% (95% CLs 27-80%) versus 6% in the NeoSphere (p < 0.0001) and 12% in the TRYPHAENA (p < 0.01) trials. CONCLUSIONS: The risk of all-grade and severe diarrhea associated with neoadjuvant pertuzumab use for HER2/neu-positive breast cancer was greater in actual practice than in trials.

Exogenous supplementation of antithrombin III in adult and pediatric patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Antithrombin III deficiency can occur with heparin anticoagulation during extracorporeal membrane oxygenation leading to heparin resistance. Antithrombin III supplementation has been shown to improve anticoagulation; however, there is no consensus on appropriate administration. We described the effect of antithrombin III supplementation on coagulation parameters in adult and pediatric extracorporeal membrane oxygenation patients. METHODS: We conducted a retrospective cohort study using electronic medical records of patients who received ⩾1 dose of antithrombin III during extracorporeal membrane oxygenation while on continuous heparin. Endpoints included the change in anti-Xa levels and antithrombin III activity at -6 versus 6 h relative to antithrombin III supplementation, and heparin infusion rates at 6 versus 12 h after antithrombin III supplementation. RESULTS: Eighteen patients receiving 36 antithrombin III administrations were analyzed. Mean (standard deviation) anti-Xa values at -6 versus 6 h were 0.15 (0.07) versus 0.24 (0.15) IU/mL (p-value: 0.250) for pediatrics and 0.19 (0.22) versus 0.31 (0.27) IU/mL (p-value: 0.052) for adults. Mean (standard deviation) plasma antithrombin III activity at the same intervals were 32% (14.2%) versus 66.8% (25.1%; p-value: 0.062) for pediatrics and 30.3% (14%) versus 52.8% (8.1%; p-value: 0.094) for adults. Mean (standard deviation) heparin rates at 6 versus 12 h after antithrombin III for pediatrics were 23.6 (6) versus 23.5 (6.5) units/kg/h (p-value: 0.728), and 15.3 (6.6) versus 13.5 (8) units/kg/h (p-value: 0.188) for adults. CONCLUSION: Administration of antithrombin III improved anti-Xa levels in both populations, however, did not significantly reduce heparin rates. Our findings suggest that the use of antithrombin III restores heparin responsiveness in patients with low antithrombin III activity and low anti-Xa activity.

Controlled substance diversion in health systems: A failure modes and effects analysis for prevention.

PURPOSE: The purpose of this study was to demonstrate the utility of failure modes and effects analysis (FMEA) for systematically identifying potential sources of controlled substance diversion and developing solutions in an academic health system. METHODS: The FMEA was conducted by an 18-member cross-functional team from the department of pharmacy. The team developed scoring criteria specifically for controlled substance diversion, outlined the controlled substance processes from procurement to administration or disposal, and identified ways in which each step of the medication supply process might fail (failure modes) and result in diversion of controlled substances. Failure modes with a vulnerability score of 48 or 64 were considered highest risk and were immediately intervened on by the FMEA team. RESULTS: The FMEA outlined a total of 10 major steps and 30 substeps in the controlled substance supply process. From this, 103 potential failure modes were identified, with 24 modes (23%) receiving a vulnerability score of 48 or 64. Development of specific reports addressed 15 failure modes, while 9 involved pharmacy workflow alterations. Notable reports included controlled substance activity under temporary patients and discrepancy trends by user, medication, and patient care area. Notable workflow alterations included expanded use of cameras in high-risk areas and additional verification checks. CONCLUSION: FMEA allowed for systematic identification of controlled substance diversion opportunities, prioritization by level of vulnerability, and the development of targeted strategies to reduce risk of diversion.

Association Between Secondary Prevention Medication Use and Outcomes in Frail Older Adults After Acute Myocardial Infarction.

Background Secondary prevention medications are often not prescribed to frail, older adults following acute myocardial infarction, potentially because of the absence of data to support use, perceived lack of benefit, and concern over possible harms. We examined the effect of using more guideline-recommended medications after myocardial infarction on mortality, rehospitalization, and functional decline in the frailest and oldest segment of the US population-long-stay nursing home residents. Methods and Results We conducted a retrospective cohort study of nursing home residents aged ≥65 years using 2007 to 2010 national US Minimum Data Set clinical assessment data and Medicare claims. Exposure was the number of secondary prevention medications (antiplatelets, ß-blockers, statins, and renin-angiotensin-aldosterone system inhibitors) initiated after myocardial infarction. Outcomes were 90-day death, rehospitalization, and functional decline. We compared outcomes for new users of 2 versus 1 and 3 or 4 versus 1 medications using the inverse probability of treatment-weighted odds ratios with 95% CI. The cohort comprised 4787 residents, with a total of 509 death, 820 functional decline, and 1226 rehospitalization events. Compared with individuals who initiated 1 medication, mortality odds ratios were 0.98 (95% CI, 0.79-1.22) and 0.74 (95% CI, 0.57-0.97) for users of 2 and 3 or 4 medications, respectively. Rehospitalization odds ratios were 1.00 (95% CI, 0.85-1.17) for 2 and 0.97 (95% CI, 0.8-1.17) for 3 or 4 medications. Functional decline odds ratios were 1.04 (95% CI, 0.85-1.28) for 2 and 1.12 (95% CI, 0.89-1.40) for 3 or 4 medications. In a stability analysis excluding antiplatelet drugs from the exposure definition, more medication use was associated with functional decline. Conclusions Use of more guideline-recommended medications after myocardial infarction was associated with decreased mortality in older, predominantly frail adults, but no difference in rehospitalization. Results for functional decline from the main and stability analyses were discordant and did not rule out an increased risk associated with more medication use.

Comparative effectiveness of pharmacist care delivery models for hepatitis C clinics.

PURPOSE: The optimal health care delivery models for providing services to patients with infections caused by hepatitis C virus (HCV) remain unknown. Pharmacist involvement may be a key component of optimal HCV care delivery. We examined the comparative effectiveness of a pharmacist-managed HCV clinic versus a pharmacist-assisted HCV clinic. METHODS: This retrospective cohort study used electronic health record data on patients ≥18 years old initiating HCV treatment at a pharmacist-managed clinic or a pharmacist-assisted clinic within a single health-system between January 2015 and June 2017. Outcomes included treatment completion, sustained virologic response 12 weeks following treatment completion (SVR-12), and dispensation of direct-acting antiviral agents at the institution-based specialty pharmacy. Inverse probability of treatment-weighted (IPTW) logistic regression models were used to compare outcomes between the 2 clinic models. RESULTS: A total of 127 patients initiated HCV treatment therapy: 64 patients from the pharmacist-managed clinic and 63 patients from the pharmacist-assisted clinic. The cohort had a mean age of 55 years, was 51% male, and 68% white. In IPTW analyses, there was no difference in treatment completion (odds ratio [OR], 1.1; 95% confidence interval [CI], 0.1-13.8; p = 0.93), achievement of sustained virologic response at 12 months (SVR-12) (OR, 1.0; 95% CI, 0.2-4.5; p = 0.62), or use of institution-based specialty pharmacy (OR, 0.6; 95% CI, 0.2-1.7; p = 0.33) between pharmacist-managed and pharmacist-assisted clinics. CONCLUSION: There were no significant differences in outcomes between patients receiving care at the pharmacist-managed HCV clinic and the pharmacist-assisted clinic. Given the frequency of SVR-12 achieved in both groups, both pharmacist-managed and pharmacist-assisted clinic models may be reasonable alternatives for providing outpatient HCV care.

Overuse and underuse of pegfilgrastim for primary prophylaxis of febrile neutropenia.

INTRODUCTION: Guidelines recommend pegfilgrastim for primary prophylaxis of febrile neutropenia after highly myelosuppressive chemotherapy. While deviations from guidelines could result in overuse and increased costs, underuse is also a concern and could compromise quality of care. Our objectives were to evaluate guideline adherence and quantify the extent to which physician heterogeneity may influence pegfilgrastim use. METHODS: We randomly sampled 550 patients from a retrospective cohort of those who received infusions at an academic cancer center between 1 September 2013 and 1 September 2014. Electronic medical and drug dispensing records provided information on patient characteristics, chemotherapy characteristics, prescribing physician, and pegfilgrastim administration. RESULTS: We included 154 patients treated by 25 physicians. About half of patients were male and mean age was 61.3 years. Forty (26.1%) patients had no febrile neutropenia risk factors, 62 (40.5%) had one, and 51 (33.3%) had two or more. Thirty patients (19.5%) received pegfilgrastim, of which 12 (40%) received palliative chemotherapy. Nine (60%) of 15 patients on a regimen with a febrile neutropenia risk ≥ 20% received pegfilgrastim. Pegfilgrastim use significantly varied by cancer type (p < 0.01), chemotherapy regimen (p < 0.001), and regimen febrile neutropenia risk (p < 0.001). Multivariable analysis reaffirmed the association between chemotherapy regimen febrile neutropenia risk ≥ 20% and pegfilgrastim use (odds ratio (OR) = 10.1, 95% confidence interval (CI): 1.6-62.7) and suggested that 31% (95% CI: 8%-71%) of the variation in use was attributable to physician characteristics. CONCLUSION: Pegfilgrastim was potentially overused for palliative chemotherapy and underused for chemotherapy regimens with febrile neutropenia risk ≥ 20%. Successful interventions to modify prescribing practices likely require an understanding of the relationship between specific physician characteristics and pegfilgrastim use.

Outcomes of "diabetes-friendly" vs "diabetes-unfriendly" ß-blockers in older nursing home residents with diabetes after acute myocardial infarction.

AIMS: To assess whether nursing home (NH) residents with type 2 diabetes mellitus (T2D) preferentially received "T2D-friendly" (vs "T2D-unfriendly") ß-blockers after acute myocardial infarction (AMI), and to evaluate the comparative effects of the two groups of ß-blockers. MATERIALS AND METHODS: This new-user retrospective cohort study of NH residents with AMI from May 2007 to March 2010 used national data from the Minimum Data Set and Medicare system. T2D-friendly ß-blockers were those hypothesized to increase peripheral glucose uptake through vasodilation: carvedilol, nebivolol and labetalol. Primary outcomes were hospitalizations for hypoglycaemia and hyperglycaemia in the 90 days after AMI. Secondary outcomes were functional decline, death, all-cause re-hospitalization and fracture hospitalization. We compared outcomes using binomial and multinomial logistic regression models after propensity score matching. RESULTS: Of 2855 NH residents with T2D, 29% initiated a T2D-friendly ß-blocker vs 24% of 6098 without T2D (P < 0.001). For primary outcomes among residents with T2D, T2D-friendly vs T2D-unfriendly ß-blockers were associated with a reduction in hospitalized hyperglycaemia (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.21-0.97), but unassociated with hypoglycaemia (OR 2.05, 95% CI 0.82-5.10). For secondary outcomes, T2D-friendly ß-blockers were associated with a greater rate of re-hospitalization (OR 1.26, 95% CI 1.01-1.57), but not death (OR 1.06, 95% CI 0.85-1.32), functional decline (OR 0.91, 95% CI 0.70-1.19), or fracture (OR 1.69, 95% CI 0.40-7.08). CONCLUSIONS: In older NH residents with T2D, T2D-friendly ß-blocker use was associated with a lower rate of hospitalization for hyperglycaemia, but a higher rate of all-cause re-hospitalization.

Development and validation of a transitions-of-care pharmacist tool to predict potentially avoidable 30-day readmissions.

PURPOSE: A practical tool for predicting the risk of 30-day readmissions using data readily available to pharmacists before hospital discharge is described. METHODS: A retrospective cohort study to identify predictors of potentially avoidable 30-day readmissions was conducted using transitions-of-care pharmacy notes and electronic medical record data from a large health system. Through univariate and multivariable logistic regression analyses of factors associated with unplanned readmissions in the study cohort (n = 690) over a 22-month period, a risk prediction tool was developed. The tool's discriminative ability was assessed using the C statistic; its calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: Three factors predictive of readmission risk were identified; these variables-medication count, comobidity count, and health insurance status at discharge-form the 3-predictor MEDCOINS score. Among patients identified as being at high risk for readmission using the MEDCOINS tool, the estimated readmission risk was 22.5%, as compared with an observed readmission rate of 21.9%. The discriminatory performance of MEDCOINS scoring was fair (C statistic = 0.65 [95% confidence interval, 0.60-0.70]), with good calibration (Hosmer-Lemeshow p = 0.99). CONCLUSION: Among a cohort of patients who were seen by a transitions-of-care pharmacist during an inpatient hospitalization, comorbidity burden, number of medications, and health insurance coverage were most predictive of 30-day readmission. The MEDCOINS tool was found to have fair discriminative ability and good calibration.

Concordance between Activated Partial Thromboplastin Time and Antifactor Xa Assay for Monitoring Unfractionated Heparin in Hospitalized Hyperbilirubinemic Patients.

BACKGROUND: Activated partial thromboplastin time (aPTT) and antifactor Xa (anti-Xa) monitoring methods for unfractionated heparin (UFH) often disagree. The extent of discordance for those with elevated bilirubin remains unclear. Our objective was to evaluate concordance between activated aPTT and anti-Xa methods for hyperbilirubinemic patients on UFH. METHODS: This was a retrospective cohort study of 26 patients hospitalized at Rhode Island Hospital between August 2014 and September 2014. Patients had at least one bilirubin measurement >5 mg/dL. After categorizing lab values, percent agreement and kappa were used to examine concordance between aPTT and anti-Xa. RESULTS: Overall percent agreement between aPTT and anti-Xa was 50%. A nontherapeutic aPTT and therapeutic anti-Xa accounted for 98% of all disagreement. Specifically, 76.7% of disagreement was due to a subtherapeutic aPTT and a therapeutic anti-Xa. Unweighted kappa was 0.141 (95%CI: 0.048-0.235). CONCLUSION: Concordance between aPTT and anti-Xa values was poor in hyperbilirubinemic patients.

Effects of an integrated clinical information system on medication safety in a multi-hospital setting.

PURPOSE: The implementation of vendor-based integrated clinical information technology was studied, and its effect on medication errors throughout the medication-use process in a health care system was evaluated. METHODS: The integrated systems selected for implementation included computerized physician order entry, pharmacy and laboratory information systems, clinical decision-support systems (CDSSs), electronic drug dispensing systems (EDDSs), and a bar-code point-of-care medication administration system. The primary endpoint was the reduction in related medication errors. Secondary endpoints included the reductions in medication order turnaround time and EDDS override transactions. RESULTS: Integrated clinical information system technology was implemented in a multihospital health care system with a phased-in approach. A positive effect of this integration on medication errors throughout the medication-use process was demonstrated. Most prescribing errors decreased significantly in the selected categories monitored, specifically drug allergy detection, excessive dosing, and incomplete or unclear orders. Pharmacists were also twice as likely to identify dosages requiring adjustment for renal insufficiency when the integrated technology was in place and more than six times as likely for drug levels outside of the therapeutic range. A positive effect on medication administration safety was also demonstrated: 73 administration-related errors were intercepted through electronic bar-code scanning for every 100,000 doses charted. CONCLUSION: Integration of clinical information system technology decreased selected types of medication errors throughout the medication-use process in a health care system and improved therapeutic drug monitoring in patients with renal insufficiency and in patients receiving drugs with narrow therapeutic ranges through the use of CDSS alerts.