Multifaceted approach to reducing occurrence of severe hypoglycemia in a large healthcare system.

PURPOSE: Substantial reductions in inpatient episodes of severe hypoglycemia achieved by a large healthcare system through enhanced use of technology and sustained quality-improvement initiatives are described. SUMMARY: After internal data collection and analysis revealed that severe hypoglycemia accounted for 75% of all systematically monitored adverse drug events in its hospital network, St. Louis-based BJC HealthCare designed and executed a multifaceted approach to reducing hypoglycemia events. Initiated by a pharmacist-led task force, the project entailed (1) automated event detection and creation of dashboards for comparing hypoglycemia rates among at-risk patients at 11 BJC facilities, (2) implementation of evidence-based and internal best practices in use at BJC's top-performing hospitals, (3) development of an online "Hypoglycemic Event Analysis Tool" (HEAT) to support event investigation and collection of data on causative factors, and (4) the assembly of targeted interventions at a "Hypoglycemia Facility Strategy Tracking" (H-FaST) intranet site. As a result of the launch of the HEAT and H-FaST tools and associated provider education activities, the systemwide rate of hypoglycemia events in the specified at-risk patient population declined from 6.45 per 1000 patient-days during a preimplementation baseline period (July-December 2009) to 1.32 per 1000 patient-days during a designated postimplementation period (January-June 2014), an 80% overall reduction in hypoglycemia (p < 0.01); reductions in severe hypoglycemia events ranging from 70% to 100% were observed at all 11 hospitals. CONCLUSION: A multifaceted, evidence-based, data-driven approach enabled a large healthcare system to markedly reduce the frequency of severe hypoglycemia events.

Efficacy and safety of high-dose thromboprophylaxis in morbidly obese inpatients.

Obesity increases the risk for venous thromboembolism (VTE), but whether high-dose thromboprophylaxis is safe and effective in morbidly obese inpatients is unknown. It was the objective of this study to quantify the efficacy and safety of high-dose thromboprophylaxis with heparin or enoxaparin in inpatients with weight > 100 kilograms (kg) within the BJC HealthCare system. Ina retrospective cohort study, we analysed 9,241 inpatients with weight > 100 kg discharged from three hospitals in the BJC HealthCare system from 2010 through 2012. We compared the incidence of VTE in patients who received high-dose thromboprophylaxis (heparin 7,500 units three times daily or enoxaparin 40 mg twice daily) to those who received standard doses (heparin 5,000 units two or three times daily or enoxaparin 40 mg once daily). The primary efficacy outcome was hospital-acquired VTE identified by International Classification of Diseases (ICD)-9 diagnosis codes. The primary safety outcome was bleeding events identified by ICD-9 codes. Among the 3,928 morbidly obese inpatients (weight > 100 kg and body mass index [BMI] ≥ 40 kg/m²), high-dose thromboprophylaxis approximately halved the odds of symptomatic VTE (odds ratio [OR] 0.52, 95% confidence interval [CI] 0.27-1.00; p = 0.050). The rate of VTE was 1.48% (35/2,369) in these morbidly obese inpatients who received standard doses of thromboprophylaxis, compared to 0.77% (12/1,559) in those who received high doses. High-dose thromboprophylaxis did not increase bleeding (OR 0.84, 95% CI 0.66-1.07, p = 0.15). Independent predictors of VTE were surgery, male sex, cancer, and BMI. In conclusion, high-dose thromboprophylaxis nearly halves the rate of VTE in morbidly obese inpatients.

Risk factors for inpatient venous thromboembolism despite thromboprophylaxis.

INTRODUCTION: Venous thromboembolism (VTE) is the most common preventable cause of morbidity and mortality in the hospital. Adequate thromboprophylaxis has reduced the rate of hospital-acquired VTE substantially; however, some inpatients still develop VTE even when they are prescribed thromboprophylaxis. Predictors associated with thromboprophylaxis failure are unclear. In this study, we aimed to identify risk factors for inpatient VTE despite thromboprophylaxis. MATERIALS AND METHODS: We conducted a case-control study to identify independent predictors for inpatient VTE. Among patients discharged from the BJC HealthCare system between January 2010 and May 2011, we matched 94 cases who developed in-hospital VTE while taking thromboprophylaxis to 272 controls who did not develop VTE. Matching was done by hospital, patient age, month and year of discharge. We used multivariate conditional logistic regression to develop a VTE prediction model. RESULTS: We identified five independent risk factors for in-hospital VTE despite thromboprophylaxis: hospitalization for cranial surgery, intensive care unit admission, admission leukocyte count >13,000/mm(3), presence of an indwelling central venous catheter, and admission from a long-term care facility. CONCLUSIONS: We identified five risk factors associated with the development of VTE despite thromboprophylaxis in the hospital setting. By recognizing these high-risk patients, clinicians can prescribe aggressive VTE prophylaxis judiciously and remain vigilant for signs or symptoms of VTE.

Reducing medication prescribing errors in a teaching hospital.

BACKGROUND: Medication errors occur frequently, result in significant morbidity and mortality, and are often preventable. A multifaceted intervention was conducted to reduce prescribing errors in handwritten medication orders written by house staff. METHODS: A before-and-after design was used to evaluate the intervention--which included grand rounds, an interactive presentation for house staff, and reminders (a checklist, chart inserts, and requests for clarification)--and targeted 20 safe prescribing behaviors. RESULTS: At baseline, prescribing errors were more common among surgical house staff than medical house staff (1.08 errors/order versus 0.76 errors/order, p < .001). Only 1% of orders contained an overt error, but 49% were incomplete, 27% contained dangerous dose and frequency abbreviations, and 17% were illegible. Postintervention, the mean number of prescribing errors per order decreased for surgical house staff from 1.08 (standard deviation [SD], 0.23) to 0.85 (SD, 0.11; p < .001), with a more marked effect for house staff who attended the didactic portion of the intervention. In addition, the mean number of the more significant errors per order decreased from 0.65 (SD, 0.19) to 0.45 (SD, 0.13; p < .001), and significant decreases occurred in the proportion of orders that were incomplete, were illegible, and contained an overt error. However, prescribing errors per order increased in orders written by medical house staff from 0.76 (SD, 0.14) to 0.98 (SD, 0.11; p < .001). DISCUSSION: The intervention was associated with a modest improvement in the quality of medication orders written by surgical house staff. To reduce prescribing errors, multilevel interventions are needed, including training in safe prescribing for all physicians. Such training may need to be started in medical school and augmented and reinforced throughout residency.

Optimal initial dose adjustment of warfarin in orthopedic patients.

BACKGROUND: Warfarin sodium is commonly prescribed for the prophylaxis and treatment of venous thromboembolism. Dosing algorithms have not been widely adopted because they require a fixed initial warfarin dose (eg, 5 mg) and are not tailored to other factors that may affect the international normalized ratio (INR). OBJECTIVE: To develop an algorithm that could predict a therapeutic warfarin dose based on drug interactions, INR response after the initial warfarin doses, and other clinical factors. METHODS: We used stepwise regression to quantify the relationship between these factors in patients beginning prophylactic warfarin therapy immediately prior to joint replacement. In the derivation cohort (n = 271), we separately modeled the therapeutic dose after 2 and 3 initial doses. We prospectively validated these 2 models in an independent cohort (n = 105). RESULTS: About half of the therapeutic dose variability was predictable after 3 days of therapy: R2 was 53% in the derivation cohort and 42% in the validation cohort. INR response after 3 warfarin doses (INR3) inversely correlated with therapeutic dose (p < 0.001). Intraoperative blood loss transiently, but significantly, elevated the postoperative INR values. Other significant (p < 0.03) predictors were the first and second warfarin doses (+7% and +6%, respectively, per 1 mg), and statin use (-15.0%). The model derived after 2 warfarin doses explained 32% of the variability in therapeutic dose. CONCLUSIONS: We developed and validated algorithms that estimate therapeutic warfarin doses based on clinical factors and INR response available after 2-3 days of warfarin therapy. The algorithms are implemented online at www.WarfarinDosing.org.

Genetic-based dosing in orthopedic patients beginning warfarin therapy.

High variability in drug response and a narrow therapeutic index complicate warfarin therapy initiation. No existing algorithm provides recommendations on refining the initial warfarin dose based on genetic variables, clinical data, and international normalized ratio (INR) values. Our goal was to develop such an algorithm. We studied 92 patients undergoing primary or revision total hip or knee replacement. From each patient we collected a blood sample, clinical variables, current medications, and preoperative and postoperative laboratory values. We genotyped for polymorphisms in the cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase (VKORC1) genes. Using stepwise regression, we developed a model for refining the warfarin dose after the third warfarin dose. The algorithm explained four fifths of the variability in therapeutic dose (R(2)(adj) of 79%). Significant (P > .05) predictors were INR value after 3 doses (47% reduction per 0.25-unit rise), first warfarin dose (+7% per 1 mg), CYP2C9*3 and CYP2C9*2 genotype (-38% and -17% per allele), estimated blood loss (interacting with INR(3)), smoking status (+20% in current smokers), and VKORC1 (-11% per copy of haplotype A). If validated, this model should provide a safer, more effective process for initiating warfarin therapy.

Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF).

BACKGROUND: Although warfarin and other anticoagulants can prevent ischemic events, they can cause hemorrhage. Quantifying the rate of hemorrhage is crucial for determining the risks and net benefits of prescribing antithrombotic therapy. Our objective was to find a bleeding classification scheme that could quantify the risk of hemorrhage in elderly patients with atrial fibrillation. METHODS: We combined bleeding risk factors from existing classification schemes into a new scheme, HEMORR2HAGES, and validated all bleeding classification schemes. We scored HEMORR2HAGES by adding 2 points for a prior bleed and 1 point for each of the other risk factors: hepatic or renal disease, ethanol abuse, malignancy, older (age > 75 years), reduced platelet count or function, hypertension (uncontrolled), anemia, genetic factors, excessive fall risk, and stroke. We used data from quality improvement organizations representing 7 states to assemble a registry of 3791 Medicare beneficiaries with atrial fibrillation. RESULTS: There were 162 hospital admissions with an International Classification of Diseases, Ninth Revision, Clinical Modification code for hemorrhage. With each additional point, the rate of bleeding per 100 patient-years of warfarin increased: 1.9 for 0, 2.5 for 1, 5.3 for 2, 8.4 for 3, 10.4 for 4, and 12.3 for > or =5 points. In patients prescribed warfarin, HEMORR2HAGES had greater predictive accuracy (c statistic 0.67) than other bleed prediction schemes (P < .001). CONCLUSIONS: Adaptations of existing classification schemes, especially a new bleeding risk scheme, HEMORR2HAGES, can quantify the risk of hemorrhage and aid in the management of antithrombotic therapy.

Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype.

Cytochrome P-450 2C9 (CYP2C9) polymorphisms (CYP2C9*2 and CYP2C9*3) reduce the clearance of warfarin, increase the risk of bleeding, and prolong the time to stable dosing. Whether prospective use of a retrospectively developed algorithm that incorporates CYP2C9 genotype and nongenetic factors can ameliorate the propensity to bleeding and delay in achieving a stable warfarin dose is unknown. We initiated warfarin therapy in 48 orthopedic patients tailored to the following variables: CYP2C9 genotype, age, weight, height, gender, race, and use of simvastatin or amiodarone. By using pharmacogenetics-based dosing, patients with a CYP2C9 variant achieved a stable, therapeutic warfarin dose without excessive delay. However compared to those without a CYP2C9 variant, patients with a variant continued to be at increased risk (hazard ratio 3.6, 95% confidence interval 1.4-9.5, p = 0.01) for an adverse outcome (principally INR > 4), despite pharmacogenetics-based dosing. There was a linear relationship (R(2) = 0.42, p < 0.001) between the pharmacogenetics-predicted warfarin doses and the warfarin maintenance doses, prospectively validating the dosing algorithm. Prospective, perioperative pharmacogenetics-based dosing of warfarin is feasible; however, further evaluation in a randomized, controlled study is recommended.

Effect of warfarin nonadherence on control of the International Normalized Ratio.

OBJECTIVE: The frequency and causes of ab- errant International Normalized Ratios (INRs) in warfarin recipients and the percentage explainable by warfarin nonadherence were studied. METHODS: The medical records of patients whose warfarin therapy was monitored by a telephone-based anticoagulation service in a Midwestern urban hospital between March 2000 and March 2001 were reviewed for causes of out-of-range INRs, the percentage of out-of-range INRs attributable to warfarin nonadherence, and demographic and clinical variables predictive of nonadherence. RESULTS: Data from 347 patients were studied. The cohort yielded 4305 INRs, of which 1002 (23%) were out of range (lower than 1.8 or higher than 3.4). Thirty-six percent of the out-of-range INRs were due to warfarin or dietary nonadherence, 9% were due to medical systems problems (including drug interactions), 18% were due to a change in clinical status, and 38% were idiopathic. Age younger than 65 years, age greater than 80 years, and living closer to the laboratory were predictive of warfarin nonadherence. CONCLUSION: Warfarin nonadherence was the most common cause of explainable aberrant INRs in patients taking warfarin. Age younger than 65 years, age greater than 80 years, and living close to the laboratory were predictive of warfarin nonadherence.

Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin.

Knowledge of pharmacogenetics may help clinicians predict their patients' therapeutic dose of warfarin, thereby decreasing the risk of bleeding during warfarin initiation. Our goal was to use pharmacogenetics to develop an algorithm that uses genetic, clinical, and demographic factors to estimate the warfarin dose a priori. We collected a blood sample, demographic variables, laboratory values, smoking status, names of medications, and dietary history from 369 patients who were taking a maintenance dose of warfarin. Using polymerase chain reaction, we genotyped each participant for the presence of 8 polymorphisms in the cytochrome P450 2C9 system. Using multiple regression, we quantified the association between warfarin dose and all factors. Advanced age, lower body surface area (BSA), and the presence of cytochrome P450 2C9 *2 or *3 single nucleotide polymorphisms were strongly associated (P < 0.001) with lower warfarin dose: the maintenance dose decreased by 8% per decade of age, by 13% per standard deviation decrease in BSA, by 19% per 2C9*2 allele, and by 30% per 2C9*3 allele. Warfarin doses were 29% lower in patients who took amiodarone, 12% lower in patients who took simvastatin, 21% lower in patients whose target INR was 2.5 rather than 3.0, and 11% lower in white rather than African-American participants (P < 0.05 for these comparisons). An algorithm that included these factors and one of borderline significance (sex), explained 39% of the variance in the maintenance warfarin dose. Use of this pharmacogenetic model had potential to prevent patients from being overdosed when initiating warfarin: we estimate that only 24 (6.5%) patients would have been over- dosed by >2 mg/day with pharmacogenetic dosing compared to 59 (16%) patients who would have been overdosed if they had been prescribed the empirical dose of 5 mg/day (P < 0.001). In conclusion, the maintenance warfarin dose can be estimated from demographic, clinical, and pharmacogenetic factors that can be obtained at the time of warfarin initiation.

Warfarin dose reduction vs watchful waiting for mild elevations in the international normalized ratio.

BACKGROUND: Whether clinicians should decrease the warfarin dose in response to a mild, asymptomatic elevation in the international normalized ratio (INR) is unknown. OBJECTIVES: The study objectives were as follows: (1) to evaluate the safety of an anticoagulation service (ACS) policy advocating that the warfarin dose not be changed for isolated, asymptomatic INRs of < or = 3.4; (2) to compare the dosing strategies of an ACS and primary care providers (PCPs); and (3) to quantify the relationship between reduction of the warfarin dose and the subsequent fall in the INR. DESIGN AND SETTING: Randomized controlled study of health maintenance organization outpatients who were receiving warfarin. PATIENTS: We identified 231 patients with a target INR of 2.5 and an isolated, asymptomatic INR between 3.2 and 3.4. Our ACS monitored 103 of the patients; PCPs monitored the remaining 128 patients. MEASUREMENTS: From all 231 patients, we obtained INRs and warfarin dosing history. From the 103 ACS enrollees, we also recorded adverse events. RESULTS: One ACS patient had epistaxis in the 30 days after the elevated INR. Twenty-three percent of ACS enrollees and 47% of PCP patients reduced their warfarin dose (p < 0.001). The median follow-up INRs were similar in both cohorts: 2.7 in the ACS enrollees and 2.6 in the PCP patients. However, in a subgroup analysis of 190 patients who presented with an INR of 3.2 or 3.3, ACS enrollees were more likely to have a follow-up INR in the range of 2 to 3 (p = 0.03). The median follow-up INR was 2.7 in 148 patients who maintained their warfarin dose, 2.5 in 77 patients who decreased their dose by 1 to 20%, and 1.7 in 6 patients who decreased their dose by 21 to 43% (p < 0.001). CONCLUSIONS: These findings support maintaining the same warfarin dose in asymptomatic patients with an INR of < or = 3.3, and reducing the dose for patients who have a greater INR or an increased risk of hemorrhage. Warfarin dose reductions > 20% should be avoided for mildly elevated INRs.

Validation of automated event triggers using laboratory values related to two problem-prone drugs.

We used computerized alerts to identify patients with laboratory values that could be related to medication errors associated with digoxin and warfarin. Over a six-week period at two inpatient facilities, we generated 62 laboratory-based alerts for warfarin, and 66 for digoxin. The positive predictive value for these alerts representing a preventable event was 71% and 57% for warfarin and digoxin, respectively.

Substitution of generic warfarin for Coumadin in an HMO setting.

BACKGROUND: Substitution of generic warfarin for Coumadin presents safety concerns due to warfarin's narrow therapeutic index and because a prior generic formulation was removed from the US market after it was associated with adverse events. OBJECTIVE: To determine whether a health maintenance organization (HMO) can add generic warfarin to its formulary without adversely affecting warfarin management or increasing adverse events. DESIGN: In a prospective, observational study, an HMO that formerly dispensed only Coumadin added a generic warfarin preparation (Barr Laboratories, Pomona, NY) to its formulary. SETTING: An anticoagulation service (ACS) affiliated with an HMO that was based in St. Louis, MO. PARTICIPANTS: The cohort consisted of 182 enrollees in the ACS as of May 1, 1999. At the start of the study, these participants were taking Coumadin; by October 31, 2000, all had switched to Barr warfarin. MEASUREMENTS AND MAIN RESULTS: We collected data 8 months prior to and 10 months after the introduction of generic warfarin for the following endpoints: international normalized ratio (INR) control, frequency of INR monitoring, number of dose changes, and rate of thrombotic and hemorrhagic events. Statistical process control charts were used to differentiate between random variation in the endpoints and changes due to different warfarin formulations, and we used the Wilcoxon signed-rank test to look for a change in any endpoint after patients changed to generic warfarin. No significant differences were found in any endpoint. CONCLUSIONS: Substitution of Barr warfarin for Coumadin did not significantly affect INR control, warfarin management, or adverse events. Our findings suggest that HMOs can safely substitute at least 1 generic formulation of warfarin without extra monitoring.

Risk factors for bleeding in patients taking coumarins.

Coumarins (e.g., warfarin) are used for the treatment and prophylaxis of venous and arterial thromboembolism. Unfortunately, their use is limited by bleeding. In deciding whether to initiate coumarin therapy, the therapeutic benefits must be weighed against the potential risk of bleeding for each individual patient. The major determinants of coumarin-related bleeding are the intensity of anticoagulant effect as measured by the International Normalized Ratio, patient characteristics, concomitant use of other drugs, and the length of anticoagulant therapy. At the initiation of coumarin therapy, the risk factors for bleeding can be identified by the COUMARINS acronym and by one of the bleeding prediction models. During ongoing therapy with coumarins, the risks and benefits of therapy should be reassessed periodically. This article reviews the current evidence for the prediction and prevention of coumarin-related bleeding.