Stacy Voils

Comparative effectiveness of 3- versus 4-factor prothrombin complex concentrate for emergent warfarin reversal

INTRODUCTION Three- and 4-factor prothrombin complex concentrates (PCC) are routinely administered for emergent reversal of warfarin, but direct comparisons of clinical outcomes are lacking. The purpose of this study was to compare the safety and effectiveness of 3- and 4-PCC in patients requiring emergent warfarin reversal. MATERIALS AND METHODS This was a single-center retrospective study in adult patients requiring administration of either 3-PCC or 4-PCC for emergent reversal of warfarin. RESULTS One hundred sixty-five patients were included (3-PCC, n=109; 4-PCC, n=56). The most frequent indications for PCC were intracranial and gastrointestinal bleeding. Baseline median INR was 2.5 (2.0-3.2) and 2.4 (2.0-4.2) in the 3-PCC and 4-PCC groups. Thirty minutes after PCC administration, median INR decreased to 1.3 in both groups (p<0.001), and 87 (80%) versus 47 (84%) of patients had INR values≤1.5 (p=0.52) in the 3-PCC group versus the 4-PCC group. Thromboembolic events occurred in 7 patients (4%) and were similar between the 3-PCC (n=3, 3%) and 4-PCC (n=4, 7%) groups (p=0.23). Thirty-four (31%) patients in the 3-PCC group died compared to 5 patients (9%) in the 4-PCC group (p=0.001). INR>1.5 thirty minutes after PCC was associated with increased mortality (OR 4.3; 95% CI 1.8-10.4, p=0.001), and administration of a 4-PCC was associated with decreased mortality (OR 0.19; 95% CI 0.06-0.54, p=0.002). CONCLUSION Patients who received 4-PCC, and those with INR≤1.5 regardless of type of PCC received were more likely to survive. Thromboembolic events were low in both groups and similar to previous studies.

Trends in utilization of warfarin and direct oral anticoagulants in older adult patients with atrial fibrillation

PURPOSE Results of a study to determine trends in oral anticoagulant (OAC) use and OAC switching in patients with atrial fibrillation (AF) or atrial flutter are presented. METHODS Warfarin has been the most prescribed anticoagulant in patients with AF for decades. Since 2010, several direct OACs (DOACs) have gained U.S. marketing approval for stroke prevention in AF or atrial flutter. A cross-sectional longitudinal analysis was conducted using healthcare and prescription claims databases to characterize OAC use and rates of OAC and DOAC switching during the period 2008-14 in cohorts of Medicare beneficiaries 65 years of age or older with AF or atrial flutter. RESULTS Overall, 66% of patients with AF or atrial flutter were receiving OACs during the study period. The prevalence of warfarin use decreased from 69.8% in 2008 to 42.2% in 2014. This decrease in warfarin use was paralleled by an increase in dabigatran use, which rose from 1.3% in 2010 to 12.1% in 2011 and then declined to 7.6% in 2014. The prevalence of rivaroxaban use increased from 0.13% in 2011 to 13.87% in 2014. Among anticoagulated patients, an average of 6% annually were switched from one OAC to another. CONCLUSION Overall OAC utilization in patients with AF or atrial flutter remained steady over the study period. Beginning in 2010, a gradual decrease in use of warfarin was paralleled by an increase in use of DOACs.

Chemoprophylaxis Use and Risk of Venous Thromboembolism and Death in Adult Patients following Orthotopic Liver Transplantation

Background: Coagulation abnormalities in end-stage liver disease may preclude patients from receiving venous thromboembolism (VTE) prophylaxis immediately following orthotopic liver transplantation. Methods: To identify risk factors for VTE and death following liver transplantation, a retrospective chart review was conducted in adult liver transplant recipients from January 1, 2001, to October 1, 2011. Results: In 716 transplantations in 701 patients, the overall incidence of VTE was 2.1%. The incidence was 3.6% in patients who received chemoprophylaxis compared to 1.4% in those without chemoprophylaxis (P = .06). Most patients (69.5%) did not receive chemoprophylaxis postsurgery during their hospitalization. Multivariate logistic regression modeling revealed no association between the use of chemoprophylaxis (adjusted odds ratio [OR] 1.5 [0.45-4.7], P = .53) and VTE. A significant positive association was observed between the use of chemoprophylaxis (adjusted OR 3.2 [1.3-8.0], P = .01) and death. Conclusion: Use of chemoprophylaxis and increasing amounts of blood products following orthotopic liver transplant was associated with increased mortality. A significant positive association was observed between blood product administration and VTE, while chemoprophylaxis use was not significantly associated with VTE. Larger prospective studies are necessary to further examine the significance of this finding.

Adverse Neurologic Effects of Medications Commonly Used in the Intensive Care Unit

Adverse drug effects often complicate the care of critically ill patients. Therefore, each patients medical history, maintenance medication, and new therapies administered in the intensive care unit must be evaluated to prevent unwanted neurologic adverse effects. Optimization of pharmacotherapy in critically ill patients can be achieved by considering the need to reinitiate home medications, and avoiding drugs that can decrease the seizure threshold, increase sedation and cognitive deficits, induce delirium, increase intracranial pressure, or induce fever. Avoiding medication-induced neurologic adverse effects is essential in critically ill patients, especially those with neurologic injury.

Trends of Neonatal Abstinence Syndrome Epidemic and Maternal Risk Factors in Florida

This study aimed to examine secular trends of (i) maternal prescription opioid use in late pregnancy, (ii) neonatal abstinence syndrome (NAS) stratified by late maternal prescription opioid use, and (iii) maternal risk factors among NAS deliveries.

No difference in mechanical ventilation–free hours in critically ill patients who received intravenous, oral, or enteral phosphate replacement

Purpose: To determine the impact on duration of mechanical ventilation (MV) and the need for reintubation after changing from intravenous (IV) to oral phosphate formulations, in response to a national shortage of IV phosphate. Methods: A retrospective study was performed in adult patients who required MV for at least 48 hours. Results: A total of 136 patients were included, with 68 patients in both the restricted phosphate group and unrestricted phosphate groups. There was no difference in the cumulative phosphate supplementation received (IV and oral) between groups (P = .08). The overall mean serum phosphorus concentration in unrestricted vs restricted group was 3.0 vs 2.9 mg/dL, respectively (P = .24), and the phosphorus concentration was not significantly different between groups during the first 21 days of the study (P = .24). The median MV‐free hours in the unrestricted group was 462 hours compared with 507 hours in the restricted group (P = .16), and 9 (13.2%) of patients in each group required reintubation (P = .99). There was no significant difference in mortality, or hospital, or intensive care unit (ICU) length of stay. Conclusions: No difference in MV‐free hours or need for reintubation was observed after a national shortage requiring the restriction of IV phosphate supplementation. Oral phosphate replacement is a safe and an efficient alternative.

Association of Deep-Vein Thrombosis (DVT) With Missed Doses of Prophylactic Antithrombotic Medications in ICU Patients: A Case-Control Study

Background: Medications for prevention of venous thromboembolism (VTE) are routinely prescribed in critically ill patients. Objective: To identify any association between missed doses of VTE prophylaxis medications and acute, in-hospital deep-vein thrombosis (DVT). Methods: Case-control study in hospitalized adult patients at high risk for developing VTE, defined as an ICU length of stay (LOS) of at least 24 hours. Cases were defined as patients with acute DVT during hospitalization, and controls were patients with no documented DVT. Multivariate logistic regression was used to assess the odds of acute DVT in patients with any missed dose of prophylactic antithrombotic medication. Results: Of 920 patients, 59 (6.4%) experienced an acute, in-hospital DVT. Overall, 64% of patients missed at least 1 dose of VTE prophylaxis medication, and 33% missed more than 3 doses. In the univariate analysis, there was no significant association between any missed dose of prophylaxis medication and acute DVT (odds ratio [OR] = 0.96; CI = 0.56-1.7). Multivariate logistic regression modeling confirmed no association between missed doses of pharmacological VTE medications and acute DVT (OR = 0.69 [0.39-1.2]; P = 0.21). Prolonged hospital LOS was associated with increased odds of acute DVT (LOS = 4-6 days; OR = 0.75 [0.21-2.6]; LOS = 7-13 days; OR = 2.3 [0.9-5.9]; and LOS = ≥14 days; OR = 6.4 [2.6-15.9]). Conclusion: We found no evidence of a relationship between any missed dose of prophylactic antithrombotic medication and development of acute DVT. The odds of acute DVT increased in patients with prolonged hospital LOS.

Innovative Use of Novel Biomarkers to Improve the Safety of Renally Eliminated and Nephrotoxic Medications

Over the last decade, the discovery of novel renal biomarkers and research on their use to improve medication effectiveness and safety has expanded considerably. Pharmacists are uniquely positioned to leverage this new technology for renal assessment to improve medication dosing and monitoring. Serum cystatin C is a relatively new, inexpensive, functional renal biomarker that responds more quickly to changing renal function than creatinine and is not meaningfully affected by age, sex, skeletal muscle mass, dietary intake, or deconditioning. Cystatin C has been proposed as an adjunct or alternative to creatinine for glomerular filtration rate assessment and estimation of drug clearance. Tissue inhibitor of metalloproteinase‐2·insulin‐like growth factor‐binding protein 7 ([TIMP‐2]·[IGFBP7]) is a composite of two damage biomarkers released into the urine at a checkpoint in mitosis when renal cells undergo stress or sense a future risk of damage. Concentrations of [TIMP‐2]·[IGFBP7] increase before a rise in serum creatinine is evident, thus providing insightful information for evaluation in the context of other patient data to predict the risk for impending kidney injury. This article provides a brief overview of novel renal biomarkers being used as a mechanism to improve medication safety including a discussion of cystatin C, as part of drug‐dosing algorithms and specifically for vancomycin dosing, and the use of [TIMP‐2]·[IGFBP7] for risk prediction in acute kidney injury and drug‐induced kidney disease. Select cases of clinical experience with novel renal biomarkers are outlined, and lessons learned and future applications are described.

Early thrombin formation capacity in trauma patients and association with venous thromboembolism

Incidence of venous thromboembolism (VTE) in adult trauma patients is high despite mechanical and pharmacologic prophylaxis. We hypothesized that thrombin formation capacity as measured by calibrated automated thrombogram (CAT) is increased early in hospitalization and is associated with the development of VTE. METHODS We conducted a prospective study in adult, critically ill trauma patients. Plasma was generated from whole blood samples collected within the first 3days of hospital admission. CAT was used to determine lag time, thrombin peak, time to thrombin peak, endogenous thrombin potential (ETP), and velocity index in plasma samples from patients, and in control samples of platelet-poor, pooled normal plasma. RESULTS There were 35 trauma patients and 35 controls included in this pilot analysis. Patients were a mean (SD) age of 45 (19) years, and 23 (66%) were male. The most common mechanism of injury was motor vehicle crash followed by falls, and the median (IQR) injury severity score was 17 (12-27). Three patients (8.6%) had deep vein thrombosis (DVT) confirmed by Doppler ultrasound on median hospital day 7. Compared to control samples, patients had significantly longer lag times (3.1min vs. 2.7min, p=0.02) and significantly higher ETP (1136nM∗min vs. 1019nM∗min, p=0.007), peak thrombin generation (239nM vs. 176nM, p<0.001), and velocity index (108nM/min vs. 57nM/min, p<0.001) (Fig. 1). There was no difference in the time to peak thrombin generation between the two groups (5.5min vs. 5.7min, p=0.22). In the 3 patients with VTE compared to controls, lag times were shorter and velocity index was higher while ETP and peak thrombin generation were similar. There were no statistically significant differences in thrombin generation parameters in patients with or without VTE, but lag time was numerically shorter, and thrombin peak, time to peak and area-under-the-curve (ETP) were numerically lower in patients with DVT. CONCLUSIONS We observed a thrombin generation profile in critically ill trauma patients consistent with an early hypercoagulable state; however, thrombin generation parameters did not discriminate patients with VTE.

Metabolomic association between venous thromboembolism in critically ill trauma patients and kynurenine pathway of tryptophan metabolism

OBJECTIVE Incidence of venous thromboembolism (VTE) in critically ill patients remains unacceptably high despite widespread use of thromboprophylaxis. A systems biology approach may be useful in understanding disease pathology and predicting response to treatment. Metabolite profile under specific environmental conditions provides the closest link to phenotype, but the relationship between metabolomics and risk of VTE in critically ill patients is unknown. In this study, metabolomics signatures are compared in patients with and without VTE. DESIGN Multicenter case-control study using prospectively collected data from the Inflammation and Host Response to Injury program, with pathway and in silico gene expression analyses. SETTING Eight level 1 US trauma centers. PATIENTS Critically ill adults with blunt trauma who developed VTE within the first 28 days of hospitalization compared to patients without VTE (N-VTE). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Patients included in the study (n = 20 VTE, n = 20 N-VTE) were mean age of 34 years, injury severity score of 35, and VTE diagnosed a median of 10.5 days after admission. Global metabolomics revealed two kynurenine metabolites, N-formylkynurenine (AUC = 0.77; 95% CI: 0.59-0.89) and 5-hydroxy-N-formylkynurenine (AUC = 0.80; 95% CI:0.63-0.90) significantly discriminated VTE and N-VTE; ratio between N-formylkynurenine/5-hydroxy-N-formylkynurenine improved predictive power (AUC = 0.87; 95% CI: 0.74-0.95). In the pathway analysis, tryptophan was the only significant metabolic pathway including N-formylkynurenine and 5-hydroxy-N-formylkynurenine (p < 0.001), and 8 proteins directly or indirectly interacted with these metabolites in the interaction network analysis. Of the 8 genes tested in the in silico gene expression analyses, KYNU (p < 0.001), CCBL1 (p < 0.001), and CCBL2 (p = 0.001) were significantly different between VTE and N-VTE, controlling for age and sex. CONCLUSIONS Two novel kynurenine metabolites in the tryptophan pathway associated with hospital-acquired VTE, and 3 candidate genes were identified via pathway and interaction network analyses. Future studies are warranted to validate these findings in diverse populations using a multi-omics approach.