T. Beasley

Influence of CYP2C9 Genotype on warfarin dose among African American and European Americans

BACKGROUND: Cytochrome P4502C9 (CYP2C9) plays a vital role in drug metabolism. There has been an increased effort to identify polymorphisms within the gene and determine their clinical consequences. However, most of these efforts have focused on populations of European descent. Herein we report the influence of CYP2C9 genotype on warfarin dose among European American and African American patients. We also identify two new mutations; one in the coding region and one in the non-coding region of the CYP2C9 gene. METHODS: Patients (≥20 years of age) are enrolled after obtaining medical, lifestyle and concomitant medication history. Changes in International Normalized Ratio (INR), warfarin dose, co-medications, diet, physical activity and the occurrence of complications are documented. CYP2C9 genotype was determined using PCR-RFLP and pyrosequencing. Differences in genotype frequencies and HWE assumptions were assessed using χ(2) statistics and exact tests. The genotype dose association was evaluated using multivariable linear regression. RESULTS: This report includes 490 patients (mean age 60.6 ± 15.6, 51.3% men). African American patients comprise 48.9% of the cohort with mean follow-up of 13.5 (±10.6) months. Both the CYP2C9 *2 and *3 allele were more frequent in European Americans (11.24%, 5.1%) compared to African Americans (1.1% and 1.8%). CYP2C9 *5 (0.9%), *6 (0.4%), and *11 (1.1%) variants were only observed in African Americans. The variant genotype is more frequent among European Americans compared to African Americans (29.8% vs. 9.73%, p<0.0001). Warfarin dose was significantly related to CYP2C9 genotype (p<0.0001) both in univariate and multivariate analyses. Multivariable race-specific analyses highlight the contribution of CYP2C9 genotype among European American but not among African American patients. CONCLUSION: The variant CYP2C9 genotype is more frequent among European Americans compared to African Americans. Among African Americans the variant genotype frequency is higher than previously reported. CYP2C9 genotype predicts warfarin dose in European Americans, but not in African Americans.

Loperamide Versus Psyllium Fiber for Treatment of Fecal Incontinence: The Fecal Incontinence Prescription (Rx) Management (FIRM) Randomized Clinical Trial

BACKGROUND: Fecal incontinence is a devastating condition with few US Food and Drug Administration–approved pharmacologic treatment options. Loperamide and psyllium, both first-line treatments, have different mechanisms of action without any comparative data. OBJECTIVE: The purpose of this study was to examine the effectiveness and tolerability of loperamide compared with psyllium for reducing fecal incontinence. We hypothesized that psyllium fiber supplementation would be more effective than loperamide for reducing fecal incontinence episodes and have fewer adverse effects. DESIGN: We conducted a randomized, double-blind, placebo-controlled crossover trial comparing loperamide (followed by psyllium) with psyllium (followed by loperamide). SETTINGS: Our sites included outpatient clinics within a Veterans Affairs medical center and university affiliate. PATIENTS: Participants included community-dwelling adults (n = 80) with at least 1 fecal incontinent episode on a 7-day bowel diary. INTERVENTION: Participants received either daily loperamide (plus placebo psyllium powder) or psyllium powder (plus loperamide placebo) for 4 weeks. After a 2-week washout, participants crossed over to 4 weeks of alternate treatment. MAIN OUTCOME MEASURES: The primary outcome was the number of fecal incontinence episodes from 7-day bowel diaries. Secondary outcomes included symptom severity, quality of life, and tolerability. RESULTS: Mean age was 60.7 ± 10.1 years; 68% were men. After determining nonsignificant carryover effects, combined analyses showed no differences between the loperamide and psyllium groups for reducing fecal incontinent episodes, symptom severity, or quality of life. Within each group, both loperamide and psyllium reduced fecal incontinent episodes and improved symptom severity and quality of life. Constipation occurred in 29% of participants for loperamide vs 10% for psyllium. LIMITATIONS: Limitations include the washout period length and dropout rate after crossing over to the second intervention. CONCLUSIONS: Both loperamide and psyllium improve fecal incontinence. Loperamide was associated with more adverse effects, especially constipation.

Infections Present on Admission Compared with Hospital-Acquired Infections in Acute Ischemic Stroke Patients

BACKGROUND To date, few studies have assessed the influence of infections present on admission (POA) compared with hospital-acquired infections (HAIs) on neurologic deterioration (ND) and other outcome measures in acute ischemic stroke (AIS). METHODS Patients admitted with AIS to our stroke center (July 2010 to December 2010) were retrospectively assessed. The following infections were assessed: urinary tract infection, pneumonia, and bacteremia. Additional chart review was performed to determine whether the infection was POA or HAI. We assessed the relationship between infections in ischemic stroke patients and several outcome measures including ND and poor functional outcome. A mediation analysis was performed to assess the indirect effects of HAI, ND, and poor functional outcome. RESULTS Of the 334 patients included in this study, 77 had any type of infection (23 POA). After adjusting for age, National Institutes of Health Stroke Scale at baseline, glucose on admission, and intravenous tissue plasminogen activator, HAI remained a significant predictor of ND (odds ratio [OR]=8.8, 95% confidence interval [CI]: 4.2-18.7, P<.0001) and poor functional outcome (OR=41.7, 95% CI: 5.2-337.9, P=.005), whereas infections POA were no longer associated with ND or poor functional outcome. In an adjusted analysis, we found that 57% of the effect from HAI infections on poor functional outcome is because of mediation through ND (P<.0001). CONCLUSIONS Our data suggests that HAI in AIS patients increases the odds of experiencing ND and subsequently increases the odds of being discharged with significant disability. This mediated effect suggests a preventable cause of ND that can thereby decrease the odds of poor functional outcomes after an AIS.

Short-term Bleeding Events Observed with Clopidogrel Loading in Acute Ischemic Stroke Patients

INTRODUCTION The Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence trial raised concern that loading doses of clopidogrel may increase hemorrhagic complications. We investigated if similar rates of hemorrhage occur in patients with acute ischemic stroke (AIS) of varying severity. METHODS Patients meeting inclusion criteria were divided into 2 groups: the LOAD group and non-LOAD group. The LOAD group was defined as patients who were administered a loading dose of 300 mg or more of clopidogrel with or without aspirin within 24 hours of admission. The non-LOAD group was devised using propensity score (PS): 55 patients who received a loading dose of clopidogrel of 300 mg or more were matched on PS to 55 patients who did not receive loading doses. These patients were taken from a pool of 341 consecutive ischemic patients ineligible for intravenous or intra-arterial fibrinolysis, 162 of whom received a clopidogrel loading dose and the remainder of whom did not. The frequency of hemorrhage was compared between the 2 groups using Student t test and chi-square. Logistic regression was used to assess the relationship between loading dose and serious bleeding events (symptomatic intracerebral hemorrhage [sICH] or transfusion for systemic bleeding). RESULTS AIS patients (N = 596) were screened during the 31-month period of this retrospective study. Of this sample, 170 patients were excluded: 149 patients were excluded because they were treated with intravenous tissue plasminogen activator (IV t-PA) alone, 11 were excluded because they were treated with IV t-PA combined with intra-arterial therapy (IAT), and 10 were excluded for treatment with IAT alone. An additional 85 patients were excluded because they were not admitted to the stroke service or because they had an in-hospital stroke. Baseline characteristics of the groups were well matched. There were no significant differences in the rates of sICH, transfusion, hemorrhagic transformation, or systemic bleeding. Clopidogrel loading was not associated with increased odds of serious bleeding events in the crude model (odds ratio [OR] .92, 95% confidence interval [CI] .27-3.13) or after adjusting for covariates and confounders of interest (OR 1.06, 95% CI .28-4.04). DISCUSSION Contrary to our original hypothesis, patients with AIS receiving clopidogrel loading doses within 24 hours of symptom onset did not appear to experience a higher rate of new serious bleeding events during acute hospitalization when compared with patients who did not receive loading doses. The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke trial is expected to provide insight into the safety of clopidogrel loading as an acute intervention after cerebral ischemia.

A Simple Prediction Score for Developing a Hospital-Acquired Infection after Acute Ischemic Stroke

BACKGROUND Hospital-acquired infections (HAIs) are a major cause of morbidity and mortality in acute ischemic stroke patients. Although prior scoring systems have been developed to predict pneumonia in ischemic stroke patients, these scores were not designed to predict other infections. We sought to develop a simple scoring system for any HAI. METHODS Patients admitted to our stroke center (July 2008-June 2012) were retrospectively assessed. Patients were excluded if they had an in-hospital stroke, unknown time from symptom onset, or delay from symptom onset to hospital arrival greater than 48 hours. Infections were diagnosed via clinical, laboratory, and imaging modalities using standard definitions. A scoring system was created to predict infections based on baseline patient characteristics. RESULTS Of 568 patients, 84 (14.8%) developed an infection during their stays. Patients who developed infection were older (73 versus 64, P < .0001), more frequently diabetic (43.9% versus 29.1%, P = .0077), and had more severe strokes on admission (National Institutes of Health Stroke Scale [NIHSS] score 12 versus 5, P < .0001). Ranging from 0 to 7, the overall infection score consists of age 70 years or more (1 point), history of diabetes (1 point), and NIHSS score (0-4 conferred 0 points, 5-15 conferred 3 points, >15 conferred 5 points). Patients with an infection score of 4 or more were at 5 times greater odds of developing an infection (odds ratio, 5.67; 95% confidence interval, 3.28-9.81; P < .0001). CONCLUSION In our sample, clinical, laboratory, and imaging information available at admission identified patients at risk for infections during their acute hospitalizations. If validated in other populations, this score could assist providers in predicting infections after ischemic stroke.

Trimming the fat in acute ischemic stroke: an assessment of 24-h CT scans in tPA patients

Background International management of acute ischemic stroke patients treated with intravenous tissue plasminogen activator frequently includes 24-h head imaging. These recommendations stem from the National Institute of Neurological Disorders and Stroke (NINDS) clinical trial protocol regarding the risk of intracerebral hemorrhage post-tissue plasminogen activator administration. Follow-up computed tomography scans on select patients, however, may not effect clinical management, resulting in unnecessary radiation exposure and healthcare costs. Aims Our study questions the utility of routine 24-h computed tomography imaging and looks at the National Institute of Health Stroke Scale as a possible clinical screen for selecting candidates for 24-h imaging. Such a tool would result in decreased radiation exposure to the patient and decreased cost to the hospital. Methods Consecutive patients with acute ischemic stroke given intravenous tissue plasminogen activator between June 2008 and December 2011 were retrospectively identified and dichotomized based on change in 24-h National Institute of Health Stroke Scale from baseline. Initial analysis compared patients with National Institute of Health Stroke Scale worsening to those without worsening. Subsequent analysis was limited to patients with a baseline National Institute of Health Stroke Scale ⩽10. Baseline demographics and medical history, baseline and 24-h computed tomography findings, medical and/or surgical orders within six-hours of imaging, and antithrombotic administration within 24–48-h postintravenous tissue plasminogen activator were compared between the two groups. Results Two-hundred patients met inclusion criteria: No 24-h National Institute of Health Stroke Scale worsening (n = 167) vs. 24-h National Institute of Health Stroke Scale worsening (n = 33). No baseline demographic or admission data differed significantly between the two groups. Patients without 24-h National Institute of Health Stroke Scale worsening had significantly lower incidence of hemorrhagic infarction (10·8% vs. 31·3%, P = 0·0014) on follow-up imaging. Less than 2% of all patients without 24-h National Institute of Health Stroke Scale worsening had a parenchymal hematoma. No patient with baseline National Institute of Health Stroke Scale ⩽10 and without 24-h National Institute of Health Stroke Scale worsening had parenchymal hematoma. Patients with 24-h worsening were significantly less likely to receive timely antithrombotic therapy (60·6% vs. 77·8%, odds ratio 0·44, 95% confidence interval 0·20–0·96). Conclusions Our results demonstrate that routine 24-h computed tomography scan in patients without 24-h National Institute of Health Stroke Scale worsening (especially those with baseline National Institute of Health Stroke Scale ⩽10) is less likely to yield information that results in a deviation from standard acute stroke care. No patient without worsening and baseline National Institute of Health Stroke Scale ⩽10 had parenchymal hematoma on 24-h computed tomography. Application of the National Institute of Health Stroke Scale to distinguish patients who should have 24-h follow-up imaging from those who will not benefit is a potential avenue for improving utilization of resources and warrants further study.

Influence of Regular Physical Activity on Warfarin Dose and Risk of Hemorrhagic Complications

To determine the influence of regular physical activity on stable warfarin dose and risk of major hemorrhage in patients on chronic anticoagulation therapy.

Dynamic contrast-enhanced MRI evaluates the early response of human head and neck tumor xenografts following anti-EMMPRIN therapy with cisplatin or irradiation

To assess the early therapeutic effects of anti‐EMMPRIN (extracellular matrix metalloprotease inducer) antibody with/without cisplatin or X‐ray radiation in head and neck cancer mouse models using dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI).

Influence of Age on Warfarin Dose, Anticoagulation Control, and Risk of Hemorrhage

We assessed the influence of age on warfarin dose, percentage time in target range (PTTR), and risk of major hemorrhage.

Vitamin K Intake, Body Mass Index and Warfarin Maintenance Dose

Background: Warfarin inhibits vitamin K-dependent coagulation factors. Being fat-soluble, the availability of vitamin K may vary according to body fat. We hypothesized that body mass index (BMI), a proxy of body fat, may interact with vitamin K intake in determining a warfarin maintenance (WM) dose. Methods: Patients with data on vitamin K intake, potential confounders and WM dose (n = 172) were included in linear regression models to test whether BMI modifies the relation between vitamin K intake and WM dose. Results: Warfarin loading dose correlated with the maintenance dose (r = 0.36, p < 0.0001) but was not significantly associated with WM dose in analyses adjusted for vitamin K epoxide reductase (VKORC1) and cytochrome P450 2C9 (CYP2C9) genotypes. In fully adjusted models, BMI was associated (p = 0.001) with WM dose but vitamin K was only marginally positively associated (p = 0.06) with WM dose. We found no interaction (p > 0.05) between BMI and vitamin K intake with regard to WM dose. Inclusion of vitamin K intake in the model only slightly improved the amount of variance (1.1%) explained by age, gender, BMI, race, physical activity, energy intake and VKORC1 and CYP2C9 genotypes. Conclusion: Our data suggest that body fat does not affect the relation between vitamin K intake and WM dose.