Proportion Of International Normalized Ratio Research Articles

Quality of anticoagulant therapy and the incidence of in‐stent thrombosis after venous stenting

BackgroundIn patients with a venous outflow obstruction following iliofemoral deep vein thrombosis stenting of the venous tract to prevent or alleviate postthrombotic syndrome is applied with increasing frequency. The impact of the quality of anticoagulant therapy with vitamin K antagonists (VKAs) on the development of in‐stent thrombosis is currently unknown. ObjectivesTo determine the association between the quality of postinterventional VKA treatment and the occurrence of in‐stent thrombosis. MethodsSeventy‐nine patients with iliofemoral and/or caval venous stent placement for obstruction of the venous outflow were included in this study. All patients received postinterventional VKA. The quality of VKA anticoagulant therapy was expressed as the time within therapeutic range (TTR) calculated using the linear interpolation method and as the proportion of International Normalized Ratio (INR) values < 2.0. In‐stent thrombosis was assessed by the use of duplex ultrasound. Survival analysis (Kaplan‐Meier curves, Cox regression) was used to analyze the data. ResultsIn‐stent thrombosis developed in 16 patients (20.3%). The total population had a mean TTR of 64.0% (±19.0) and a mean proportion of INR values < 2.0 of 11.6% (±12.0). Overall, a TTR < 49.9% was associated with an increased risk of in‐stent thrombosis. The multivariable adjusted analysis showed a hazard ratio (HR) of 0.96 (95% confidence interval [CI], 0.92‐0.99; P = .02) per 1% increase in TTR. The proportion of INR values < 2.0 had no significant association with the occurrence of in‐stent thrombosis: HR 0.98 (95% CI, 0.91‐1.06; P = .66). ConclusionsWe conclude that the quality of anticoagulant treatment reflected in the TTR following a venous stenting procedure is an important independent determinant for the risk of in‐stent thrombosis. The role of anticoagulant treatment for the prevention of in‐stent thrombosis following stenting procedures therefore merits further research.

Meta-Analysis to Assess the Quality of International Normalized Ratio Control and Associated Outcomes in Venous Thromboembolism Patients

IntroductionPatients with venous thromboembolism (VTE) frequently require vitamin K antagonists (VKAs) to prevent recurrent events, but their use increases hemorrhage risk. We performed a meta-analysis to assess the quality of international normalized ratio (INR) control, identify study-level predictors of poor control and to examine the relationship between INR control and adverse outcomes in VTE patients. Materials and MethodsWe searched bibliographic databases (1990-June 2013) for studies of VTE patients receiving adjusted-dose VKAs that reported time in range (2.0-3.0) or proportion of INRs in range and/or reported INR measurements coinciding with thromboembolic or hemorrhagic events. Meta-analysis and meta-regression analysis was performed. ResultsUpon meta-analysis, studies found 59% (95%CI: 54-64%) of INRs measured and 61% (95%CI: 59-63%) of the time patients were treated were spent outside the target range of 2.0-3.0; with a tendency for under- versus over-anticoagulation. Moreover, this poor INR control resulted in a greater chance of recurrent VTE (beta-coefficient=-0.46, p=0.01) and major bleeding (beta-coefficient=-0.30, p=0.02). Patients with an INR<2.0 made up 58% (95%CI: 39-77%) of VTE cases, while those with an INR>3.0 made up 48% (95%CI: 34-61%) of major hemorrhage cases. Upon meta-regression, being VKA-naïve (-14%, p=0.04) and treated in the community (-7%, p<0.001) were associated with less time in range, while being treated in Europe/United Kingdom (compared to North America) was associated with (11%, p=0.003) greater time. ConclusionsStrategies to improve INR control or alternative anticoagulants, including the newer oral agents, should be widely implemented in VTE patients to reduce the rate of recurrent events and bleeding.

Genetics-Based Pediatric Warfarin Dosage Regimen Derived Using Pharmacometric Bridging

Warfarin dosage regimens using CYP2C9 and VKORC1 polymorphisms have been extensively studied in adults and is included in US Food and Drug Administration-approved warfarin labeling. However, no dosage algorithm is available for pediatric patients. To derive a genetics-based pediatric dosge regimen for warfarin, including starting dose and titration scheme. A model-based approach was developed based on a previously validated warfarin dosage model in adults, with subsequent comparison to pediatric data from pediatric warfarin dose, genotyping, and international normalized ratio (INR) results. The adult model was based on a previously established model from the CROWN (CReating an Optimal Warfarin dosing Nomogram) trial. Pediatric warfarin data were obtained from a study conducted at the Children's Hospital of Los Angeles with 26 subjects. Variant alleles of CYP2C9 (rs1799853 or *2, and rs1057910 or *3) and the VKORC1 single nucleotide polymorphism (SNP) rs9923231 (-1639 G>A) were assessed, where the rs numbers are reference SNP identification tags assigned by the National Center for Biotechnology Information. A pediatric warfarin model was derived using the previously validated model and clinical pharmacology considerations. The model was validated, and clinical trial simulation and stochastic modeling were used to optimize pediatric dosage and titration. The final dosage regimen was optimized based on simulations targeting a high (≥60%) proportion of INRs within the therapeutic range by week 2 of warfarin therapy while minimizing INRs >3.5 or <2. The proposed pediatric warfarin dosage scheme based on individual CYP2C9 (alleles *1,*2,*3) and VKORC1 rs9923231 (-1639 G>A) genotypes may offer improved dosage compared to current treatment strategies, especially in patients with variant CYP2C9 and VKORC1 alleles. This pilot study provides the foundation for a larger prospective evaluation of genetics-based warfarin dosage in pediatric patients.

Systematic Review to Identify Validated Manual Warfarin Maintenance Dosing Tools.

AbstractAbstract 3800 Rationale:Vitamin K antagonists, of which warfarin is the most widely used in North America, are some of the most difficult medications to control and require careful monitoring to keep the international normalized ratio (INR) in the therapeutic range. Anticoagulation clinics and computer-assisted decision support systems have been associated with an improved time patients spend in the therapeutic INR range, but these systems can be expensive. Also, patient self-management delivers the best INR control, but is only useful for patients who are capable to perform self testing and management. Simple, inexpensive and easy to use dosing algorithms have the potential to overcome some of these logistical barriers and offer a tool that could be used without the infrastructure of a formal anticoagulation clinic. We performed a systematic review to identify validated manual warfarin maintenance dosing algorithms that do not require computer support. Methods:MEDLINE was searched, without language restriction, by two independent reviewers for observational and experimental reports of warfarin dosing algorithms, nomograms or formulas. Studies that reported efficacy of anticoagulation clinics, patient self management and computer assisted warfarin dosing were reviewed for references for an underlying dosing process. Inclusion criteria for studies for this review were: 1) the tool needed to provide advice on maintenance dose adjustment and next INR testing, 2) the manual dosing tool needed to be compared to a control group, 3) time in therapeutic range or patient outcomes were reported, 4) the effect of the dosing method could be separated from other interventional aspects of warfarin management. Inter-rater agreement for inclusion of candidate studies was measured with the kappa statistic and disagreement was resolved by consensus. Results:Twenty-five studies were identified and 23 either did not report a manually useful tool (computer-based algorithm or complex formula), did not have a control comparator, did not report the time in therapeutic range or patient outcomes, or the effect of the tool could not be separated from other interventional aspects of anticoagulation clinics, computer systems or self-management. Only 2 studies fulfilled all of the inclusion criteria and there was 100% agreement between the two independent reviewers for their selection. Both studies were single center studies and used practice performance before implementation of the dosing tool as the comparator. One study (n=72) showed an improvement in the proportion of INRs in the therapeutic range from 32% to 46% (p < 0.05). The other study (n=1961) showed an improvement in the time in therapeutic range in patients with a target INR range of 2–3 from 67% to 73% (p < 0.001) and in patients with a range of 2.5–3.5, form 50% to 64% (p < 0.001). Data of the two studies were not pooled due to differences in the dosing tool, quality level of care and calculation of the primary outcome, and the negligible effect of the smaller study. Conclusion:We identified only 2 manually useful VKA maintenance dosing tools that have been compared with a control group. Both studies showed an improvement in the quality of INR control with a simple dosing algorithm, but the studies were limited by their pre/post interventional design. Our results stress the need for a randomized trial to validate the usefulness of a manual dosing algorithm which could yield a simple and inexpensive evidence-based method for many physicians managing patients taking a vitamin K antagonist. Disclosures:No relevant conflicts of interest to declare.

Evaluation of INR Monitoring Frequency and Time in Therapeutic Range

Background: Although anticoagulant therapy has been used for more than 50 years, the optimal interval between international normalized ratio (INR) measurements in patients who demonstrate a stable dose response remains unsettled. Based on the results of observational studies, the American College of Chest Physicians currently recommends that patients receiving a stable dose of warfarin undergo INR testing at least once every 4 weeks.1 Objective: To determine whether an increased frequency of INR monitoring impacts time in therapeutic range (TTR) among patients receiving maintenance warfarin therapy managed by an anticoagulation clinic. Methods: A total of 2,222 INR results belonging to more than 700 adults who were followed by the anticoagulation service at the University of Pittsburgh Medical Center and who were receiving maintenance warfarin therapy between April 1, 2006, and September 30, 2006, were retrospectively reviewed. INR measurements were categorized as having been determined fewer than 21 days or 21 or more days after the previous measurement, and the percentage of INRs within the therapeutic range was calculated for each interval. Results: During the evaluation period, INRs measured within 21 days of the preceding test were within the therapeutic range 75.1% of the time, whereas INRs obtained at least 21 days after the antecedent INR test were within the therapeutic range 79.9% of the time (p &lt; 0.001). Additionally, the proportion of INRs below 1.5 or above 5.0 was not significantly different between the 2 groups, representing only 0.04% of all results at either interval (p &gt; 0.05). Conclusions: Our evaluation suggests that more frequent INR monitoring among patients receiving maintenance warfarin does not impact TTR to a clinically meaningful extent. Moreover, these findings support the reevaluation of the anticoagulation service management algorithm to reduce the frequency of INR measurements among patients within the maintenance phase of therapy.

Comparison of a daily fixed 2.5-mg warfarin dose with a 5-mg, international normalized ratio adjusted, warfarin dose initially following heart valve replacement

Patients starting oral anticoagulant therapy after heart valve replacement initially require a lower target international normalized ratio (INR) (2.0, range 1.5 to 2.6) because of a higher risk of bleeding until pericardial wires are removed. In a previous retrospective analysis, we observed a higher sensitivity to warfarin in these patients compared with nonsurgical patients. In a randomized clinical trial, we compared a fixed, lower dose of warfarin (2.5 mg) with the standard treatment consisting of a 5-mg loading dose, then adjusted to the target INR during the first 5 days of anticoagulation. INRs were measured daily, but the fixed dose was only modified on day 3 if the INR was <1.5 or >3.0. One hundred ninety-seven patients were considered eligible for the study. The 2 groups were well matched according to age, gender, body mass index, concomitant treatments, and type of valves implanted. The proportion of INRs >2.6 during the study period was 42.5% in the 5-mg group and 26.2% in the 2.5-mg group (p <0.05), and the proportion of INRs >3.0 on day 3 was 23.9% and 9.5% (p <0.05), respectively. In the 2.5-mg group, 35.7% of patients had an INR <1.5 on day 3 and had the dose increased (vs 3.5%, p <0.001); however, in the 5-mg group, 95.6% had the initial dose reduced, 49.6% had the dose withheld for at least 1 day, and the mean dose during the 5 days of study was 3.08 mg. Average time to achieve therapeutic range was higher in the 2.5-mg group (2.72 vs 1.98 days, p <0.0001), but the approach to the targeted INR was more regular, and the gap between target and mean INR on day 5 was smaller. There were no bleeding or thromboembolic complications in either group. Thus, a lower loading dose of warfarin in patients after heart valve replacement reduces excessive anticoagulation and offers a more regular achievement of the therapeutic target by reducing the number of dose adjustments. Daily monitoring of the INR is still recommended.