Natalie Oake

Anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: a systematic review and meta-analysis

Background: Patients taking oral anticoagulant therapy balance the risks of hemorrhage and thromboembolism. We sought to determine the association between anticoagulation intensity and the risk of hemorrhagic and thromboembolic events. We also sought to determine how under-or overanticoagulation would influence patient outcomes. Methods: We reviewed the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and CINAHL databases to identify studies involving patients taking anticoagulants that reported person-years of observation and the number of hemorrhages or thromboemboli in 3 or more discrete ranges of international normalized ratios. We estimated the overall relative and absolute risks of events specific to anticoagulation intensity. Results: We included 19 studies. The risk of hemorrhage increased significantly at high international normalized ratios. Compared with the therapeutic ratio of 2–3, the relative risk (RR) of hemorrhage (and 95% confidence intervals [CIs]) were 2.7 (1.8–3.9; p < 0.01) at a ratio of 3–5 and 21.8 (12.1–39.4; p < 0.01) at a ratio greater than 5. The risk of thromboemboli increased significantly at ratios less than 2, with a relative risk of 3.5 (95% CI 2.8–4.4; p < 0.01). The risk of hemorrhagic or thromboembolic events was lower at ratios of 3–5 (RR 1.8, 95% CI 1.2–2.6) than at ratios of less than 2 (RR 2.4, 95% CI 1.9–3.1; p = 0.10). We found that a ratio of 2–3 had the lowest absolute risk (AR) of events (AR 4.3%/yr, 95% CI 3.0%–6.3%). Conclusions: The risks of hemorrhage and thromboemboli are minimized at international normalized ratios of 2–3. Ratios that are moderately higher than this therapeutic range appear safe and more effective than subtherapeutic ratios.

Frequency of adverse events in patients with poor anticoagulation: a meta-analysis

Background: Patients taking anticoagulants orally over the long term have international normalized ratios (INRs) outside the individual therapeutic range more than one-third of the time. Improved anticoagulation control will reduce hemorrhagic and thromboembolic event rates. To gauge the potential effect of improved anticoagulation control, we undertook to determine the proportion of anticoagulant-associated events that occur when INRs are outside the therapeutic range. Methods: We conducted a meta-analysis of all studies that assigned hemorrhagic and thromboembolic events in patients taking anticoagulants to discrete INR ranges. We identified studies using the MEDLINE (1966–2006) and EMBASE (1980–2006) databases. We included studies reported in English if the majority of patients taking oral anticoagulants had an INR range with a lower limit between 1.8 and 2 and an upper limit between 3 and 3.5, and their INR at the time of the hemorrhagic or thromboembolic event was recorded. Results: The final analysis included results from 45 studies (23 that reported both hemorrhages and thromboemboli; 14 that reported hemorrhages only; and 8, thromboemboli only) involving a median of 208 patients (limits of interquartile range [25th–75th percentile] 131–523 subjects; total n = 71 065). Of these studies, 64% were conducted at community practices; the remainder, at anticoagulation clinics. About 69% of the studies were classed as having moderate or high quality. Overall, 44% (95% confidence interval [CI] 39%–49%) of hemorrhages occurred when INRs were above the therapeutic range, and 48% (95% CI 41%–55%) of thromboemboli took place when below it. The mean proportion of events that occurred while the patients INR was outside the therapeutic range was greater for studies with a short mean follow-up (< 1 yr). Between-study heterogeneity was significant (p < 0.001). Interpretation: Improved anticoagulation control could decrease the likelihood of almost half of all anticoagulant-associated adverse events.

The effect of hospital-acquired infection with Clostridium difficile on length of stay in hospital

Background: The effect of hospital-acquired infection with Clostridium difficile on length of stay in hospital is not yet fully understood. We determined the independent impact of hospital-acquired infection with C. difficile on length of stay in hospital. Methods: We conducted a retrospective observational cohort study of admissions to hospital between July 1, 2002, and Mar. 31, 2009, at a single academic hospital. We measured the association between infection with hospital-acquired C. difficile and time to discharge from hospital using Kaplan–Meier methods and a Cox multivariable proportional hazards regression model. We controlled for baseline risk of death and accounted for C. difficile as a time-varying effect. Results: Hospital-acquired infection with C. difficile was identified in 1393 of 136 877 admissions to hospital (overall risk 1.02%, 95% confidence interval [CI] 0.97%–1.06%). The crude median length of stay in hospital was greater for patients with hospital-acquired C. difficile (34 d) than for those without C. difficile (8 d). Survival analysis showed that hospital-acquired infection with C. difficile increased the median length of stay in hospital by six days. In adjusted analyses, hospital-acquired C. difficile was significantly associated with time to discharge, modified by baseline risk of death and time to acquisition of C. difficile. The hazard ratio for discharge by day 7 among patients with hospital-acquired C. difficile was 0.55 (95% CI 0.39–0.70) for patients in the lowest decile of baseline risk of death and 0.45 (95% CI 0.32–0.58) for those in the highest decile; for discharge by day 28, the corresponding hazard ratios were 0.74 (95% CI 0.60–0.87) and 0.61 (95% CI 0.53–0.68). Interpretation: Hospital-acquired infection with C. difficile significantly prolonged length of stay in hospital independent of baseline risk of death.

The Effect of Hospital-Acquired Clostridium difficile Infection on In-Hospital Mortality

BACKGROUND The effects of hospital-acquired Clostridium difficile infection (CDI) on patient outcomes are incompletely understood. We conducted this study to determine the independent impact of hospital-acquired CDI on in-hospital mortality after adjusting for the time-varying nature of CDI and baseline mortality risk at hospital admission. METHODS This retrospective observational study used data from the Ottawa Hospital (Ottawa, Ontario, Canada) data warehouse. Inpatient admissions with a start date after July 1, 2002, and a discharge date before March 31, 2009, were included. Stratified analyses and a Cox multivariate proportional hazards regression model were used to determine if hospital-acquired CDI was associated with time to in-hospital death. RESULTS A total of 136 877 admissions were included. Hospital-acquired CDI was identified in 1393 admissions (overall risk per admission, 1.02%; 95% confidence interval [CI], 0.97%-1.06%). The risk of hospital-acquired CDI significantly increased as the baseline mortality risk increased: from 0.2% to 2.6% in the lowest to highest deciles of baseline risk. Hospital-acquired CDI significantly increased the absolute risk of in-hospital death across all deciles of baseline risk (pooled absolute increase, 11%; 95% CI, 9%-13%). Cox regression analysis revealed an average 3-fold increase in the hazard of death associated with hospital-acquired CDI (95% CI, 2.4-3.7); this hazard ratio decreased with increasing baseline mortality risk. CONCLUSIONS Hospital-acquired CDI was independently associated with an increased risk of in-hospital death. Across all baseline risk strata, for every 10 patients acquiring the infection, 1 person died.

Effect of an interactive voice response system on oral anticoagulant management

Background: Monitoring oral anticoagulants is logistically challenging for both patients and medical staff. We evaluated the effect of adding an interactive voice response system to computerized decision support for oral anticoagulant management. Methods: We developed an interactive voice response system to communicate to patients the results of international normalized ratio testing and their dosage schedules for anticoagulation therapy. The system also reminded patients of upcoming and missed appointments for blood tests. We recruited patients whose anticoagulation control was stable after at least 3 months of warfarin therapy. We prospectively examined clinical data and outcomes for these patients for an intervention period of at least 3 months. We also collected retrospective data for each patient for the 3 months before study enrolment. Results: We recruited 226 patients between Nov. 23, 2006, and Aug. 1, 2007. The mean duration of the intervention period (prospective data collection) was 4.2 months. Anticoagulation control was similar for the periods during and preceding the intervention (mean time within the therapeutic range 80.3%, 95% confidence interval [CI] 77.5% to 83.1% v. 79.9%, 95% CI 77.3% to 82.6%). The interactive voice response system delivered 1211 (77.8%) of 1557 scheduled dosage messages, with no further input required from clinic staff. The most common reason for clinic staff having to deliver the remaining messages (accounting for 143 [9.2%] of all messages) was an international normalized ratio that was excessively high or low, (i.e., 0.5 or more outside the therapeutic range). When given the option, 76.6% of patients (164/214) chose to continue with the interactive voice response system for management of their anticoagulation after the study was completed. The system reduced staff workload for monitoring anticoagulation therapy by 48 min/wk, a 33% reduction from the baseline of 2.4 hours. Interpretation: Interactive voice response systems have a potential role in improving the monitoring of patients taking oral anticoagulants. Further work is required to determine the generalizability and cost-effectiveness of these results.

Changes in surrogate outcomes can be translated into clinical outcomes using a Monte Carlo model

OBJECTIVE To meaningfully interpret trials using surrogate outcomes, one must translate changes in the surrogate outcome to changes in the clinical outcome. Formulae to do this are uncommon because they require primary data from multiple randomized trials that measure both the surrogate and clinical outcome. STUDY DESIGN AND SETTING We developed a model to translate changes in anticoagulation control (the surrogate outcome) into hemorrhagic and thromboembolic event rates (the clinical outcome). The model used Monte Carlo simulation and association measures between the surrogate and the clinical outcome from a meta-analysis. In randomized trials having interventions that improved anticoagulation control, we used the model to predict and statistically compare event rates between the study groups. RESULTS Seven randomized trials found significantly improved anticoagulation control (mean increase in proportion of time in therapeutic range: 8.4%; range: 1.8-18%). These improvements in anticoagulation control translated to small decreases in hemorrhagic and thromboembolic events (mean: 0.66%/yr; range: 0.13-1.42%). These changes were never statistically significant. CONCLUSION Monte Carlo modeling can be used to translate surrogate outcomes into clinical outcomes. Statistically significant changes in anticoagulation control did not translate to significant differences in clinical outcomes. This methodology could be applied to other areas in medicine to assess surrogate outcomes.

Risk Factors for Methicillin-Resistant Staphylococcus aureus (MRSA) Colonization Among Patients Admitted to Obstetrical Units: A Nested Case-Control Study

OBJECTIVE Methicillin-resistant Staphylococcus aureus (MRSA) among obstetrical patients can increase birth complications for both mothers and infants, but little is known about the risk factors for MRSA in this population. The objective of this study was to determine the prevalence of MRSA among obstetrical patients and identify risk factors associated with MRSA colonization. METHODS This nested case-control study used obstetrical patients with MRSA colonization identified through a universal screening program at The Ottawa Hospital (February 2008-January 2010). Cases and three matched controls were compared using chi-square tests for categorical variables, median and interquartile range (IQR), and Wilcoxon rank-sum tests for continuous variables. Conditional logistic regression using ORs and 95% CIs was used to identify risk factors. Standard microbiologic techniques and pulsed-field gel electrophoresis of the MRSA isolates from case patients were performed. RESULTS Out of 11 478 obstetrical patients, 39 (0.34%) were MRSA colonized; 117 patients were selected as matched controls. The median age was 30 (IQR 27.5-35.00) and median length of stay was 2.55 days (IQR 1.95-3.24). Only MRSA cases had a previous MRSA infection (4 vs. 0). MRSA cases had significantly higher parity (median 3; IQR 2-5) compared with controls (median 2; IQR 1-3) (OR 1.52; 95% CI 1.22-1.90) CONCLUSION: This study identified a low prevalence of MRSA among obstetrical patients. Risk factors associated with MRSA colonization were previous MRSA infection and multiparity. Obstetrical patients who previously tested positive for MRSA should be placed on contact precautions at the time of hospital admission because this is a risk factor for future colonization.