A Systemwide Approach for Navigating the Dilemma of Oral Factor Xa Inhibitor Interference With Unfractionated Heparin Anti-Factor Xa Concentrations.

BACKGROUND: Oral factor Xa inhibitors are known to significantly increase heparin anti-Xa concentrations, which leads to inaccuracies when monitoring intravenous unfractionated heparin (IV UFH). Guidance for managing this laboratory interference is lacking, creating substantial uncertainty in clinical practice. OBJECTIVE: To describe a strategy used by a large academic institution for managing the controversy of laboratory interference in the setting of oral factor Xa inhibitor use and provide effectiveness and safety data for this approach. METHODS: In December 2016, a new Heparin IV Direct Oral Anticoagulant (DOAC) Interference PowerPlan (a comprehensive order set) was made available in the electronic health record (Cerner, North Kansas City, MO) throughout the health system. We retrospectively examined 169 patients with events reported in the error reporting system, RISKMASTER, and evaluated reports with and without the use of the PowerPlan. Effectiveness was determined through evaluation of thrombosis. The Naranjo criteria for causality were applied to assess thrombotic events. RESULTS: Of 56 events that were reported with apixaban when the PowerPlan was not ordered, 4 (7%) thrombotic events occurred within 7 days of UFH initiation. One out of the 4 events (25%) that occurred when the PowerPlan was not appropriately initiated was considered probable using the Naranjo Scale. Three additional events (75%) were possible using the Naranjo Scale. CONCLUSION AND RELEVANCE: The Heparin IV DOAC Interference PowerPlan appears to be conducive to positive patient outcomes when evaluating voluntary reported events and may assist clinicians with managing the therapeutic dilemma of this laboratory interference.

Comparison of three pharmacovigilance algorithms in the ICU setting: a retrospective and prospective evaluation of ADRs.

BACKGROUND: Pharmacovigilance algorithms are used to assess the likelihood of adverse drug reaction (ADR) occurrence. The preferred instrument for use in the intensive care unit (ICU) is not established. OBJECTIVE: The primary objective of this study was to compare the agreement between the Kramer algorithm, Naranjo criteria and Jones algorithm for the evaluation of ADRs in the ICU. A secondary objective was to compare the agreement between the same pharmacovigilance algorithms for ADR determination when applied in a retrospective versus concurrent fashion in the ICU. STUDY DESIGN: There were two phases in this study. Phase I was the retrospective evaluation (i.e. after the patient was discharged from the hospital) conducted in patients admitted during July 2005 to June 2006. Phase II was the concurrent phase (i.e. while the patient was in the hospital) conducted over 6 weeks in 2008. Both phases were conducted at the University of Pittsburgh Medical Center and included adult patients admitted to the medical ICU. INTERVENTION: In phase I, a random sample of 261 medication signals were evaluated individually for potential ADRs using the Kramer algorithm, Naranjo criteria and Jones algorithm. In phase II, an active medication monitoring system was used to detect five abnormal laboratory values, resulting in a random sample of 253 signals that were evaluated using the same three algorithms. MAIN OUTCOME MEASURE: Percentage agreement among the algorithms for all levels of causality was estimated using a kappa statistic for both phases of the study. RESULTS: For phase I, the kappa values were all >0.7 ranging from 0.721 to 0.855 between instruments, with Naranjo versus Kramer having the highest kappa, which is considered excellent agreement. The kappa statistic between individual instruments for phase II are <0.7 ranging from 0.423 to 0.635, which is considered moderate agreement, with Naranjo versus Jones displaying the lowest kappa while still exhibiting moderate agreement. For phase II, the Kramer algorithm had better agreement with both the Naranjo criteria and the Jones algorithm. CONCLUSIONS: These instruments demonstrated similar results for evaluating ADRs in the ICU retrospectively, suggesting that instrument selection with any of the three instruments is reasonable. For concurrent ADR evaluations, there is greater variability in the level of causality obtained among pharmacovigilance algorithms and Kramer displayed better agreement with its comparators. A suggestion for a more definitive concurrent ADR assessment is to use more than one algorithm. This may be challenging in daily clinical practice; however, it is a reasonable expectation for research.

Analysis of risk factors for adverse drug events in critically ill patients*.

OBJECTIVES: An evaluation of risk factors for adverse drug events in critically ill patients has not been previously studied. The purpose of this original study was to determine risk factors for adverse drug events in critically ill adult patients. DESIGN: This retrospective case-control study includes patients who were admitted to the intensive care unit during a 7.5-yr period. SETTING: Academic medical center with 647 beds that contains approximately 120 intensive care unit beds. PATIENTS: Patients in the case group experienced an adverse drug event as documented in the hospital's database. The control group comprised the next two patients admitted to the same intensive care unit by the same admitting service. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-nine suspected risk factors identified from the literature were evaluated, including patient characteristics, drug characteristics, and laboratory values using a multiple logistic regression. A sample of 1101 cases and controls (54% male), with a mean age of 59.4 ± 17.5 yrs, were identified. In 367 cases, there was a total of 499 documented adverse drug events. Patients with kidney injury, thrombocytopenia, and those admitted emergently were 16-times, 3-times, and 2-times more likely to have an adverse drug event, respectively. Patients who were administered intravenous medications had a 3% higher risk of having an adverse drug event for each drug dispensed. Overall, the case group received more drugs per intensive care unit day and more drugs per intensive care unit stay. CONCLUSIONS: Several patient and drug-related characteristics contribute to the risk of adverse drug events in critically ill patients. Diligent monitoring of factors that can influence the pharmacokinetic properties for existing drug therapies is necessary. Drug regimens should be evaluated daily for minimization. Based on previous studies, pharmacists as part of the interdisciplinary team could help to manage these risks.

Effect of drug information request templates on pharmacy student compliance with the modified systematic approach to answering drug information questions.

BACKGROUND: The modified systematic approach to answering drug information questions is a technique used in drug information practice and in teaching pharmacy students to effectively provide drug information. Drug information request templates were developed to prompt students and other trainees to ask appropriate background questions and perform an effective search. OBJECTIVE: An evaluation was conducted to determine whether use of drug information templates by fourth-year pharmacy students during their drug information experiential rotation improved compliance with the modified systematic approach. METHODS: Fifty documented drug information requests, including 25 prior to template implementation (August 2005-August 2006) and 25 after template implementation (August 2007-August 2008), were randomly selected for evaluation. Each question was evaluated for completeness of background information obtained, categorization and identification of the ultimate question, completeness of references searched, and formulation of a concise response and an evidence-based recommendation. RESULTS: Background information was complete in 16% of pre-template questions and 92% of post-template questions (p < 0.001). Eighty-four percent of pre-template questions and 96% of post-template questions were appropriately categorized (p = 0.349). The requestor's ultimate question was clearly identified in 68% of pretemplate questions and 92% of post-template questions (p = 0.074). All necessary references were searched in 36% of pre-template questions and 88% of post-template questions (p < 0.001). A concise response was documented in 80% of pretemplate questions and 92% of post-template questions (p = 0.417). In questions determined to require a specific recommendation among the pre-template (n = 20) and post-template groups (n = 14), a clear and evidence-based recommendation was described in 40% (p = 0.038) and 79% (p = 0.038), respectively. CONCLUSIONS: Use of drug information request templates improves students' compliance with the modified systematic approach, most notably in obtaining background information and searching necessary references including primary literature.

Evaluating the positive predictive values of antidote signals to detect potential adverse drug reactions (ADRs) in the medical intensive care unit (ICU).

PURPOSE: Signals are used to alert clinicians of potential ADRs. Positive predictive values (PPVs) of antidote signals in ICUs are unknown. The primary purpose was to determine PPVs of six signals. The secondary objective was to determine the sensitivity of various ADR detection strategies including manual chart review, administrative data review, and voluntary reporting at identifying the same ADRs discovered using antidotes as a signal. METHODS: Adult patients admitted to a medical ICU from July 1, 2005 to June 30, 2006 who were prescribed select signals were eligible. Evaluated antidote signals included injectable diphenhydramine, protamine, phytonadione, dextrose 50%, injectable methylprednisolone, and sodium polystyrene. For each signal, a random sample of 50 patients was evaluated for the presence of an ADR. ADR occurrences were determined using two objective causality instruments through retrospective chart review. Agreement between the instruments was required for ADR consideration. PPVs were determined for each signal. RESULTS: Two hundred and twenty three patients (52% male) were evaluated, with a mean +/- SD age of 60 +/- 17 years, and a median simplified acute physiology score (SAPSII) of 48. PPVs were 0.64, 0.50, 0.38, 0.26, 0.24, and 0.02 for protamine, sodium polystyrene, dextrose 50%, diphenhydramine, phytonadione, and methylprednisolone, respectively. Sensitivity of other detection strategies from highest to lowest was chart review for explicit documentation, administrative database review, and voluntary reporting. CONCLUSIONS: Protamine and sodium polystyrene performed the best by detecting ADRs in at least one out of two evaluations. Detection strategies other than signals were not as sensitive at identifying the same ADRs as antidote signals.

Coronary vasospasm and atrial fibrillation associated with ondansetron therapy.

OBJECTIVE: To provide further evidence of cardiovascular adverse effects of ondansetron, including new-onset atrial fibrillation, ST segment elevation, and chest pain subsequent to ondansetron administration, and to review cardiovascular adverse events related to several 5-hydroxytryptamine type 3 (5-HT(3)) receptor antagonists. CASE SUMMARY: A 51-year-old male with an uncomplicated past medical history was admitted for an elective inguinal hernia repair and septoplasty. His maintenance medications were discontinued prior to surgery. After a second 4-mg dose of intravenous ondansetron was administered, he developed nausea and diaphoresis. His electrocardiograph revealed new-onset atrial fibrillation and inferolateral ST segment elevation with ST segment alternans. During emergent cardiac catheterization, no obstructive coronary artery disease was evident. The patient's heart rhythm was electrically converted to normal sinus rhythm. During 3 years of follow-up, he has had no return of chest pain or hypotension. DISCUSSION: Although considered a safe class of medications by many clinicians, several of the 5-HT(3) receptor antagonists have been associated with serious cardiovascular effects. Three case reports described cardiac dysrhythmias and 9 documented coronary vasospasm and chest pain, possibly resulting from ondansetron. This is the first reported case of a combination of hypotension, atrial fibrillation, ST segment elevation, and chest pain following ondansetron administration after elective surgery in a healthy adult male with a nonconfounding medication profile. The Naranjo probability scale indicated that ondansetron was the probable cause of these cardiovascular events. CONCLUSIONS: This case report supports the concern regarding cardiovascular adverse effects of ondansetron. Clinicians should be aware of cardiovascular adverse reactions that may be associated with intravenous ondansetron and monitor for electrocardiographic changes as indicated. Further investigation is needed to delineate the actual incidence of cardiovascular effects associated with ondansetron and whether the intravenous rate of administration is a contributing factor.

Adverse-drug-event rates for high-cost and high-use drugs in the intensive care unit.

PURPOSE: The rates of adverse drug events (ADEs) associated with high-cost and high-use drugs in the intensive care unit (ICU) were studied. METHODS: This retrospective analysis was conducted from October 1997 through June 2001 in a 647-bed academic medical center with over 120 ICU beds. Adult patients with a documented ADE occurring in the ICU were included in the analysis. ADE information, including suspected medication, causality, preventability, and severity, was extracted from the institutional ADE database. Published definitions of ADEs and published scales for causality and severity assessments were used. High-cost medications were those in the top 50% of cumulative ICU medication costs, and high-use medications accounted for the upper 50% of all medications used in the ICU. Between-group comparisons of ADE rates, preventability, and severity associated with high-cost and high-use medications were conducted. RESULTS: Of the 17 medications that were considered high cost, 9 (53%) were associated with ADEs. Of the 15 medications that met the criteria for high-use drugs, 12 (80%) were associated with ADEs. The rates of ADEs associated with high-cost and high-use drugs did not significantly differ (43% versus 75%, respectively; p = 0.098). ADEs associated with high-cost and high-use medications were categorized as mild (15% versus 10%, respectively), moderate (52% versus 50%, respectively), and severe (33% versus 40%, respectively) (p > 0.05). CONCLUSION: The frequency, severity, and preventability of ADEs in the ICU were not associated with a drug's cost or frequency of use. Monitoring priorities of the critical care pharmacist should not be dictated by cost alone but should include frequency of use and the potential for causing an ADE.

Promethazine adverse events after implementation of a medication shortage interchange.

BACKGROUND: Prochlorperazine and droperidol were commonly used antiemetics at the University of Pittsburgh Medical Center-Presbyterian Hospital until a shortage of prochlorperazine occurred and a black box warning was added to droperidol prescribing information. Subsequently, promethazine was selected as the approved intravenous antiemetic for therapeutic interchange in December 2001. Promethazine use and adverse drug events (ADEs) were investigated following review of a serious ADE that identified promethazine use as a probable contributing factor. OBJECTIVE: To illustrate ADEs associated with promethazine and characterize high-risk patients. METHODS: An ADE database analysis identified promethazine ADEs reported from 2000 to 2003. Promethazine utilization and ADEs were compared with those of other antiemetics during the pre- and post-interchange periods. RESULTS: Promethazine utilization increased significantly during the post-interchange period compared with all other antiemetics (p < 0.001). Promethazine ADEs increased from one event during the pre-interchange period to 13 events during the post-interchange period. Causality assessment using the Naranjo algorithm ranged from possible to probable. The promethazine ADE rate per 10 000 doses was significantly higher than the combined ADE rate for all other antiemetics (p < 0.001; incident rate ratio [IRR] 4.32). Elderly patients (aged > or =65 y) experienced more promethazine ADEs than younger patients (p = 0.005; IRR 4.68). Concurrent use of opioids and/or sedating drugs contributed to promethazine ADEs in 11 of 14 (78.6%) patients. CONCLUSIONS: Geriatric status is a significant risk factor for promethazine ADEs. Concomitant use of sedating drugs may further increase the risk for ADEs. Therapeutic interchange programs should be monitored for both ADEs and utilization.

Adverse Drug Events Involving COX-2 Inhibitors.

OBJECTIVE: To describe the types and severity of adverse drug-related events (ADEs) observed in patients receiving cyclooxygenase-2 (COX-2) inhibitors and to increase the awareness of risk factors that predispose patients to ADEs associated with COX-2 inhibitors. METHODS: A review of ADEs reported at the University of Pittsburgh Medical Center Presbyterian Hospital (UPMC-P) revealed significant events related to use of celecoxib or rofecoxib. A query of the internal ADE database was performed to identify ADEs involving COX-2 inhibitors from January 1999 to June 2002. A similar query was performed to identify ADEs involving nonselective nonsteroidal antiinflammatory drugs (NSAIDs) reported during this same time period. Utilization data were also collected. RESULTS: Forty-eight ADEs involving 24 patients receiving COX-2 inhibitors were reported and validated via the UPMC-P ADE review process compared with 38 events in 33 patients receiving nonselective NSAIDs. The types of ADEs reported as related to COX-2 inhibitors were similar to those reported in association with nonselective NSAIDs. Forty-two percent of ADEs (n = 20) involving COX-2 inhibitors and 45% of events (n = 17) involving nonselective NSAIDs were classified as severe. All patients receiving COX-2 inhibitors and 91% of patients receiving nonselective NSAIDs exhibited risk factors that increased their risk to experience an ADE; all but 1 of these patients were receiving outpatient COX-2 inhibitor therapy. CONCLUSIONS: The observed ADEs involving COX-2 inhibitors were similar to those associated with nonselective NSAIDs. Most events may have been preventable, highlighting the need for education regarding the appropriate use of COX-2 inhibitors.