Warfarin Time In Therapeutic Range Research Articles

Comparison of oral anticoagulants for stroke prevention in atrial fibrillation using the UK clinical practice research Datalink Aurum: A reference trial (ARISTOTLE) emulation study.

Stroke prevention guidance for patients with atrial fibrillation (AF) uses evidence generated from randomised controlled trials (RCTs). However, applicability to patient groups excluded from trials remains unknown. Real-world patient data provide an opportunity to evaluate outcomes in a trial analogous population of direct oral anticoagulants (DOACs) users and in patients otherwise excluded from RCTs; however, there remains uncertainty on the validity of methods and suitability of the data. Successful reference trial emulation can support the generation of evidence around treatment effects in groups excluded or underrepresented in trials. We used linked United Kingdom primary care data to investigate whether we could emulate the pivotal ARISTOTLE trial (apixaban versus warfarin) and extend the analysis to investigate the impact of warfarin time in therapeutic range (TTR) on results. Patients with AF in the UK Clinical Practice Research Datalink (CPRD Aurum) prescribed apixaban or warfarin from 1 January 2013 to 31 July 2019 were selected. ARISTOTLE eligibility criteria were applied to this population and matched to the RCT apixaban arm on baseline characteristics creating a trial-analogous apixaban cohort; this was propensity-score matched to warfarin users in the CPRD Aurum. ARISTOTLE outcomes were assessed using Cox proportional hazards regression stratified by prior warfarin exposure status during 2.5 years of patient follow-up and results benchmarked against the trial results before treatment effectiveness was further evaluated based on (warfarin) TTR. The dataset comprised 8,734 apixaban users and propensity-score matched 8,734 warfarin users. Results [hazard ratio (95% confidence interval)] confirmed apixaban noninferiority for stroke or systemic embolism (SE) [CPRD 0.98 (0.82,1.19) versus trial 0.79 (0.66,0.95)] and death from any cause [CPRD 1.03 (0.93,1.14) versus trial 0.89 (0.80,0.998)] but did not indicate apixaban superiority. Absolute event rates for stroke/SE were similar for apixaban in CPRD Aurum and ARISTOTLE (1.27%/year), whereas a lower event rate was observed for warfarin (CPRD Aurum 1.29%/year, ARISTOTLE 1.60%/year). Analysis by TTR suggested similar effectiveness of apixaban compared with poorly controlled warfarin (TTR < 0.75) for stroke/SE [0.91 (0.73, 1.14)], all-cause death [0.94 (0.84, 1.06)], and superiority for major bleeding [0.74 (0.63, 0.86)]. However, when compared with well-controlled warfarin (TTR ≥ 0.75), apixaban was associated with an increased hazard for all-cause death [1.20 (1.04, 1.37)], and there was no significant benefit for major bleeding [1.08 (0.90, 1.30)]. The main limitation of the study's methodology are the risk of residual confounding, channelling bias and attrition bias in the warfarin arm, and selection bias and misclassification in the analysis by TTR. Analysis of noninterventional data generated results demonstrating noninferiority of apixaban versus warfarin consistent with prespecified benchmarking criteria. Unlike in ARISTOTLE, superiority of apixaban versus warfarin was not seen, possible due to the lower proportion of Asian patients and higher proportion of patients with well-controlled warfarin compared to ARISTOTLE. This methodological template can be used to investigate treatment effects of oral anticoagulants in patient groups excluded from or underrepresented in trials and provides a framework that can be adapted to investigate treatment effects for other conditions.

Abstract 13168: Benefits of Apixaban Over Warfarin are Preserved Independent of Warfarin Time in Therapeutic Range: Insights From the AUGUSTUS Trial

Introduction: In the AUGUSTUS trial, patients randomized to apixaban had lower rates of major or clinically relevant non-major (CRNM) bleeding, lower rates of death or hospitalization, and similar rates of death or ischemic events compared with warfarin. Patients randomized to aspirin (ASA) had higher rates of bleeding with similar rates of death or hospitalization, and death or ischemic event. The impact of warfarin time-in-therapeutic-range (TTR) on these outcomes is not known; however, it is plausible that sites achieving better TTR might have better outcomes with warfarin use. Methods: Using average site TTR, we assessed the hazard of bleeding, ischemic events, and death/hospitalization across quartiles of site-based TTR. These analyses were performed for both randomized strategies: apixaban vs warfarin and ASA vs placebo. Results: This analysis included data from 4420 patients at 399 sites. Site TTR was separated into quartiles of TTR (Q1: 0-49%, Q2: 42-55%, Q3: 56-69%, Q4: 70-100%). Sites with higher TTR tended to have fewer female patients (32.4% Q1 vs 25.4% Q4), more White patients (88.5% Q1 vs 97.1% Q4), and more patients previously prescribed oral anticoagulants (44.5% Q1 vs 52.5% Q4). There was no significant interaction between site TTR quartile and the hazard ratio (HR) for bleeding, death or hospitalization, or death or ischemic event with apixaban vs warfarin, or on the HR for bleeding, or death or hospitalization with ASA vs placebo (Figure). There was a borderline significant interaction (p&lt;0.047) between site TTR quartile and the HR for death or ischemic events with ASA vs placebo, such that patients at sites with higher TTR were more likely to derive a benefit from ASA compared with placebo. Conclusion: The benefits of apixaban over warfarin seen previously in AUGUSTUS are consistent across the spectrum of quartiles of site TTR. Patients at sites with higher average TTR may be more likely to derive a benefit from aspirin use to prevent death or ischemic events.

Virtual Education for Patient Self-Testing for Warfarin Therapy Is Effective During the COVID-19 Pandemic.

BackgroundPrior to the COVID-19 pandemic, warfarin users were required to complete in-person training in order to participate in approved international normalized ratio (INR) patient self-testing (PST) programs. To minimize in-person contact during the pandemic, a federal waiver of the in-person training requirement allowed new patients to begin PST after completing virtual training. However, it was uncertain whether such patients achieved comparable levels of INR control to patients receiving in-person training.MethodsINR results for patients receiving virtual training upon PST commencement between April 1, 2020, and December 31, 2020, were compared to those of patients initiating PST with in-person training between April 1, 2019, and December 31, 2019. The primary outcome was the difference in warfarin time in therapeutic range (TTR) between the groups, with secondary outcomes including differences in the percentages of INR values within individually prescribed INR range and of critical INR values.ResultsThe records of 33,683 patients were included in the analysis (13,568 in the “In-Person” sample; 20,115 in the “Virtual” sample). Patients in the Virtual sample achieved a TTR of 66.78%, compared to the In-Person sample (64.19%; absolute difference 2.59; 95% confidence interval [CI] = 2.50–2.68, p < 0.001). The TTR values were also statistically significantly higher in all subgroups evaluated across categories of patient age, gender, geography, and indication. Similarly favorable results were achieved for INR values in range and critical values.ConclusionVirtual education for PST for warfarin therapy is effective and should continue to be an option for patients and providers throughout the pandemic, and possibly beyond.

Improved Time in Therapeutic Range with International Normalized Ratio Remote Monitoring for Patients with Left Ventricular Assist Devices.

Despite advances in therapy, bleeding and thromboembolic events are frequent complications in patients with left ventricular assist device (LVAD) support. Maintaining warfarin in therapeutic range has been shown to be more challenging in this patient population compared to other indications. Patients with LVADs on warfarin typically are within goal international normalized ratio (INR) range 36-57% of the time, compared to about 65% for other indications. The goal of this study was to evaluate if an INR remote monitoring system along with the implementation of a standardized warfarin management protocol improves warfarin time in therapeutic range (TTR) for patients with LVADs. This single-center, retrospective, observational study included 78 patients with LVADs that were followed at our academic center from January 2015 to October 2017. In October 2016, we updated our warfarin management protocol and implemented a remote monitoring system with patients' weekly INR results monitored. The primary objective of the study was to determine the difference between TTRs in remote monitoring versus standard monitoring. We found that the average TTR was significantly higher in the remote monitoring group compared to the standard monitoring cohort (61.1% vs. 40.0%, p < 0.005). However, bleeding, thrombotic incidence, and hospital readmission rates were similar between the two patient cohorts. Remote monitoring improved warfarin TTR significantly in this study and may have the potential to improve anticoagulation-related outcomes in patients with LVADs.

Identification of environmental and genetic factors that influence warfarin time in therapeutic range.

Warfarin is an oral anticoagulant prescribed to prevent and treat thromboembolic disorders. It has a narrow therapeutic window and must have its effect controlled. Prothrombin test, expressed in INR value, is used for dose management. Time in therapeutic range (TTR) is an important outcome of quality control of anticoagulation therapy and is influenced by several factors. The aim of this study was to identify genetic, demographic, and clinical factors that can potentially influence TTR. In total,422 patients using warfarin were investigated. Glibenclamide co-medication and presence of CYP2C9*2 and/or *3 alleles were associated with higher TTR, while amiodarone, acetaminophen and verapamil co-medication were associated with lower TTR. Our data suggest that TTR is influenced by co-medication and genetic factors. Thus, individuals in use of glibenclamide may need a more careful monitoring and genetic testing (CYP2C9*2 and/or *3 alleles) may improve the anticoagulation management. In addition, in order to reach and maintain the INR in the target for a longer period, it is better to discuss dose adjustment in office instead of by telephone assessment. Other studies are needed to confirm these results and to find more variables that could contribute to this important parameter.

Fluoropyrimidine-based chemotherapy for gastrointestinal cancer in patients with direct oral anticoagulants or warfarin

Abstract Background The warfarin is known to enhance its activity by interaction with fluoropyrimidine. On the other hands, direct oral anticoagulants (DOACs) have several advantages compared with warfarin such as the unnecessity of dose monitoring and their few drug interactions. Therefore, the aim of this study is to assess the dose intensity and safety of fluoropyrimidine-based chemotherapy for gastrointestinal cancer in patients with DOACs or warfarin. Methods Between January 2006 to June 2018, a total of 1,413 patients with esophageal, gastric, colorectal, and pancreatic cancer received fluoropyrimidine-based chemotherapy at two institutions. Among all patients, 49 patients with anticoagulant therapy were enrolled in this study. They were further divided into the warfarin group (27 patients) and the DOACs group (22 patients). We retrospectively analyzed their Relative Dose Intensity (RDI) of fluoropyrimidine, Time in Therapeutic Range (TTR) of warfarin, and bleeding or thrombosis events. Results In the warfarin group, the median RDI of fluoropyrimidne and TTR of warfarin was 80.0% (0-100%) and 37.5% (0-100%), respectively. The proportion of patients with prolonged PT-NR values (cut off value of 3.00) was 51.9% (14/27). In the DOACs group, the median RDI was 72.9% (0-100%). There was no significant difference in RDI (p = 0.88), although TTR of warfarin was relatively low. The bleeding or thrombosis events occurred only in the warfarin group (3.7% and 7.4%, respectively). Conclusions This study showed the RDI of fluoropyrimidine in the DOACs group was sufficient compared with the warfarin group. However, major bleeding and thrombosis events, which seemed to be related with low TTR of warfarin, occurred only in the warfarin group. These data may suggest that DOACs are recommended as better anti-coagulation agents than warfarin during chemotherapies using fluoropyrimidine for gastrointestinal cancer.

Predictors of Warfarin Time in Therapeutic Range after Continuous‐Flow Left Ventricular Assist Device

Patients with a continuous-flow left ventricular assist device (CF-LVAD) require anticoagulation with a vitamin K antagonist to prevent thromboembolic events. Fluctuations in the international normalized ratio are associated with both increased thrombotic and bleeding episodes. To date, risk factors for low time in therapeutic range (TTR) among ambulatory patients with a CF-LVAD have not been explored. A retrospective single-center analysis of 121 patients implanted with a CF-LVAD was performed. International normalized ratios were systematically recorded from the initial postdischarge outpatient visit to 12months of time on the device. Risk factors for low TTR were evaluated using a multivariable linear regression analysis. Each of the 21 independent variables was entered into a stepwise regression designed to minimize the Akaike information criteria. In the multivariable analysis, the model output revealed that every 1-year increase in age was associated with a 0.4% increase in TTR (p=0.008), and every 1 mile further from clinic was associated with a 0.08% increase in TTR (p=0.03). Female sex was associated with a 10.1% decrease in TTR (p=0.04), type 2 diabetes was associated with an 11.5% decrease in TTR (p=0.006), and prior warfarin use was associated with an 8.3% decrease in TTR (p=0.03). In CF-LVAD recipients receiving warfarin, increasing age and distance from clinic are independent predictors of higher TTR. Female sex, type 2 diabetes, and prior warfarin use are independent predictors of lower TTR.

Long-Term Statin Administration Does Not Affect Warfarin Time in Therapeutic Range in Australia or Singapore.

Background: Warfarin requires ongoing monitoring of the International Normalised Ratio (INR). This is because numerous factors influence the response, including drug interactions with commonly-prescribed medications, such as statins. The administration of statins with warfarin may change INR; however, there is limited information regarding the effects on warfarin control as measured by time in therapeutic range (TTR). Statins may also alter bleeds with warfarin, but there are conflicting reports demonstrating both increased and decreased bleeds, and limited data on diverse ethnic populations. Therefore, the aim of this study was to determine the effect of statin administration on warfarin control and bleeds in patients in Australia and Singapore. Methods: Retrospective data were collected for patients on warfarin between January and June 2014 in Australia and Singapore. Patient data were used to calculate TTR and bleed events. Concurrent statin therapy was assessed and comparisons of TTR and bleed incidence were made across patient subgroups. Results: Warfarin control in Australia and Singapore was not significantly affected by statins, as measured by TTR (83% and 58%, respectively), frequency of testing, and warfarin doses. In Australia, statin use did not significantly affect bleeds, whilst in Singapore the bleed incidence was significantly lower for patients on statins. Conclusions: Chronic concurrent administration of statins with warfarin does not adversely affect warfarin TTR in Australia or Singapore. In Singapore, patients on statins, compared to no statins, had a lower bleed incidence and this requires further investigation, especially given the potential genetic influences of ethnicity on both statin and warfarin metabolism.

Outcomes associated with warfarin time in therapeutic range among US veterans with nonvalvular atrial fibrillation

Background: Poor quality of warfarin control (time in therapeutic range [TTR] < 65%) can lead to increased risk of adverse events. The objective of this study was to examine the overall quality of international normalized ratio (INR) control and the association of TTR with clinical outcomes including stroke, major bleeding, and all-cause mortality among US warfarin users.Methods and results: This retrospective observational cohort study utilized the US Veterans Affairs electronic medical records database (VA EMR). Patients with NVAF who newly initiated warfarin from 1 January 2005 to 31 December 2015 were grouped into two cohorts based on TTR <65% or ≥65%. TTR was computed from INR test results. Clinical outcomes assessed were stroke/systemic embolism (SE), hemorrhagic stroke, ischemic stroke, and major bleeding, defined based on hospitalization with those conditions as primary diagnosis, as well as all-cause mortality. Patients were followed from warfarin initiation to the first occurrence of an outcome or censoring. Propensity score weighted time-varying Cox regression was used to evaluate the risk of the clinical events. A total of 127,385 NVAF patients with mean TTR of 51% were included. TTR <65% was observed in 65% of patients. Mean CHA2DS2-VASC score (SD) was 2.9 (1.5) in the low TTR cohort and 2.7 (1.4) in the high TTR cohort. Patients with TTR <65% had a higher risk for any stroke/SE (HR: 1.57; 95% CI: 1.41–1.75), major bleeding (HR: 2.78; 95% CI: 2.55–3.03) and all-cause mortality (HR: 1.73; 95% CI: 1.67–1.79).Conclusions: The observed quality of warfarin control in VA EMR suggests room for improvement given the association with elevated risk of adverse clinical outcomes.

Net clinical benefit of dabigatran vs. warfarin in venous thromboembolism: analyses from RE-COVER\xae, RE-COVER\u2122 II, and RE-MEDY\u2122

The direct oral anticoagulants, e.g., dabigatran etexilate (DE), are effective and well tolerated treatments for venous thromboembolism (VTE). Net clinical benefit (NCB) is a useful concept in weighing potential benefits against potential harm of comparator drugs. The NCB of DE vs. warfarin in VTE treatment was compared. Post-hoc analyses were performed on pooled data from the 6-month RE-COVER® and RE-COVER™ II trials, and data from the RE-MEDY™ trial (up to 36 months), to compare the NCB of DE (150 mg twice daily) and warfarin [target international normalized ratio (INR) 2.0–3.0]. Patients (≥18 years old) had symptomatic proximal deep vein thrombosis and/or pulmonary embolism. NCB was the composite of cardiovascular endpoints (non-fatal events of recurrent VTE, myocardial infarction, stroke or systemic embolism), all-cause death, and bleeding outcomes, all weighted equally. A broad definition of NCB included major bleeding events (MBE) and clinically relevant non-major bleeding events as bleeding outcomes, while a narrow definition included just MBE. The pooled dataset totalled 5107 patients from RE-COVER/RE-COVER II and 2856 patients from RE-MEDY. When NCB was narrowly defined, NCB was similar between DE and warfarin. When broadly defined, NCB was superior with DE vs. warfarin [RE-COVER/RE-COVER II, hazard ratio (HR) 0.80; 95% confidence interval (CI), 0.68–0.95 and RE-MEDY, HR 0.73; 95% CI 0.59–0.91]. These findings were unaffected by warfarin time in therapeutic range. The NCB of DE was similar or superior to warfarin, depending on the NCB definition used, regardless of the quality of INR control.

Abstract 13411: Outcomes Associated With Warfarin Time in Therapeutic Range among Veterans With Nonvalvular Atrial Fibrillation in the US, 2005-2015

Introduction: This study evaluated the relationship between quality of warfarin control and clinical outcomes among US veterans with nonvalvular atrial fibrillation (NVAF). Hypothesis: Poor quality of warfarin control (time in therapeutic range (TTR) &lt;65%) is associated with reduced effectiveness and safety. Methods: Using the US Veterans Affairs electronic medical records database, patients with NVAF who newly initiated warfarin from 1/1/2005-12/31/2015 were grouped into two cohorts based on TTR &lt;65% or ≥65%. TTR was computed from international normalized ratio test results comprehensively recorded in the database. Clinical outcomes assessed in the study were stroke/systemic embolism (SE), hemorrhagic stroke, ischemic stroke, and major bleeding, defined based on hospitalization with those conditions as primary diagnosis, as well as all-cause mortality. Patients were followed from warfarin initiation to the first occurrence of an outcome or censoring. For each outcome, unadjusted and adjusted hazard ratios (HR and aHR) between two cohorts were estimated, with the latter from propensity score weighting-adjusted time-varying Cox proportional hazard regression stratified by CHA 2 DS 2 -VAS C score (≥2 or not), controlling for setting of warfarin initiation, baseline patient demographic and clinical characteristics, and use of co-medications. Results: A total of 127,385 patients with NVAF (mean age (SD): 71.3 (9.8) years, 99% male) with a median of 1.4 follow-up years (IQR: 3.3) were included. Mean TTR was 51%. TTR&lt;65% was observed in 65% of patients. Mean CHA 2 DS 2 -VAS C score (SD) was 2.9 (1.5) in low TTR cohort and 2.7 (1.4) in high TTR cohort. Low TTR cohort (with mean TTR as 38%) had significantly higher risk for assessed outcomes compared with high TTR cohort (with mean TTR as 77%) (Table). Conclusions: In the study, the observed quality of warfarin control among US veterans with NVAF was suboptimal and associated with elevated risk of adverse clinical outcomes.

The Use of Fish Oil with Warfarin Does Not Significantly Affect either the International Normalised Ratio or Incidence of Adverse Events in Patients with Atrial Fibrillation and Deep Vein Thrombosis: A Retrospective Study.

Background: Warfarin is a leading anticoagulant in the management of atrial fibrillation (AF) and deep vein thrombosis (DVT). Drug interactions influence the safety of warfarin use and while extensive literature exists regarding the effect on warfarin control and bleeding incidence with many medicines, there is little evidence on the influence of complementary medicines. The aim of this study was to assess the influence of fish and krill oil supplementation on warfarin control and bleeding incidence in AF and DVT patients. Methods: A retrospective analysis was conducted utilising patient information from a large private pathology clinic. AF and DVT patients receiving long-term warfarin therapy (>30 days) at the clinic and taking fish and krill oil supplements were eligible for study inclusion. Results: Of the 2081 patients assessed, a total of 573 warfarin users met the inclusion criteria with 145 patients in the fish and krill oil group (supplement group) and 428 patients in the control group. Overall, it was found that fish and krill oils did not significantly alter warfarin time in therapeutic range (TTR) or bleeding incidence, even when compared by gender. Conclusion: Omega-3 supplementation with fish and krill oil does not significantly affect long-term warfarin control and bleeding and thromboembolic events when consumed concurrently in patients managed at an anticoagulation clinic.

Warfarin time in therapeutic range and its impact on healthcare resource utilization and costs among patients with nonvalvular atrial fibrillation

Background:Warfarin is efficacious for reducing stroke risk among patients with nonvalvular atrial fibrillation (NVAF). However, the efficacy and safety of warfarin are influenced by its time in therapeutic range (TTR).Objective:To assess differences in healthcare resource utilization and costs among NVAF patients with low (<60%) and high (≥60%) warfarin TTRs in an integrated delivery network (IDN) setting.Methods:Patients with NVAF were identified from an electronic medical record database. Patients were required to have ≥6 international normalized prothrombin time ratio (INR) tests. NVAF patients were grouped into two cohorts: those with warfarin TTR <60% (low TTR) and those with warfarin TTR ≥60% (high TTR). Healthcare resource utilization and costs were evaluated during a 12 month follow-up period. Multivariable regressions were used to assess the impact of different warfarin TTRs on healthcare costs.Results:Among the study population, greater than half (54%, n = 1595) had a low TTR, and 46% (n = 1356) had a high TTR. Total all-cause healthcare resource utilization was higher among patients in the low TTR cohort vs. the high TTR cohort (number of encounters: 70.2 vs. 56.1, p < 0.001). After adjusting for patient characteristics, total all-cause healthcare costs and stroke-related healthcare costs were $2398 (p < 0.001) and $687 (p = 0.02) higher, respectively, for patients in the low TTR cohort vs. the high TTR cohort.Limitations:In this retrospective study, we were only able to evaluate the association and not the causality between healthcare resource utilization and costs with the different warfarin TTRs.Conclusion:Many warfarin-treated NVAF patients have a low warfarin TTR. NVAF patients with low vs. patients with high warfarin TTR used healthcare resources to a greater extent, which was reflected in higher healthcare costs.

Evaluation of the impact of warfarin time in therapeutic range on outcomes of patients with atrial fibrillation in Turkey: perspectives from the observational, prospective WATER Registry.

Warfarin is highly efficacious in reducing stroke risk in patients with atrial fibrillation (AF). However, its safety and efficacy in stroke prevention is markedly influenced by its time in therapeutic range (TTR). The quality of anticoagulant therapy varies considerably among countries. Representative data concerning the quality of anticoagulant therapy and its effects on clinical outcomes in Turkey are lacking. Warfarin in Therapeutic Range (WATER) registry is a prospective, observational study which followed 572 AF patients (mean age 67.3 ± 12 years; females 60%; 71% non-valvular AF) treated with warfarin. At a median of 22-month follow-up, the mean TTR value was 42.3 ± 18% (median: 40%) for the whole population and lower in non-valvular AF su group than valvular AF subgroup (40.3 ± 18 vs. 46.9 ± 19, respectively, p < 0.001). Death, cardiac hospital-ization and minor bleeding rates were higher in the group with TTR value < 40% than the group with > 40% (3.4% vs. 5.9%; 28.6% vs. 35.4%; 36.5% vs. 41.7%, respectively, all of them p < 0.001). A correlation analysis showed a negative correlation between age and TTR value (r = -0.178, p < 0.001). Mean CHA2DS2VASc score was 3.63 ± 1.5 and mean HASBLED score was 2.38 ± 1.01 in the non-valvular AF group. A negative correlation was observed between TTR levels and CHA2DS2VASc score. WATER provides insight into the anticoagulation control status of AF patients in Turkey. The quality of anticoagulation was poor. Strategies should be undertaken by clinicians and patients to improve TTR. New oral anticoagulant agents may be perfect alternatives for non-valvular AF patients.

Abstract 221: Outcomes Associated with Warfarin Time in Therapeutic Range Among Nonvalvular Atrial Fibrillation Patients Treated in an Integrated Healthcare Delivery System in the U.S.

Background: The efficacy of warfarin therapy for stroke risk reduction among nonvalvular atrial fibrillation (NVAF) patients is reduced when its time in therapeutic range (TTR) is not optimal. This study assessed differences in healthcare resource utilization and costs among NVAF patients with different warfarin TTRs in an integrated healthcare delivery system (IHDS) setting in the U.S. Methods: Patients with NVAF were identified from an electronic medical record database (1/1/2004-8/31/2013). Patients were required to have ≥6 international normalized prothrombin time ratio (INR) tests to ensure chronic warfarin therapy. The first INR test was defined as the index event with the corresponding date as the index date. The warfarin TTR of NVAF patients was determined by the modified Rosendaal method. NVAF patients were grouped into two cohorts, those with warfarin TTR &lt;60% (Low TTR) and those with warfarin TTR ≥60% (High TTR). Demographics, clinical characteristics, healthcare resource utilization and costs were evaluated during a 12-month follow-up period. Multivariable regressions were used to assess the impact of different levels of warfarin TTRs on healthcare costs. Results: NVAF patients in the high TTR cohort (n=1,595) had an average warfarin TTR of 73%, while patients in the low TTR cohort (n=1,356) had an average warfarin TTR of 45%. Total all-cause healthcare resource utilization was greater among patients in the low TTR cohort vs. the high TTR cohort (number of all-cause healthcare encounters: 70.2 vs. 56.1, p&lt;0.001). The mean number of all-cause inpatient admissions (0.64 vs. 0.33, p&lt;0.001), hospital length-of-stay (3.3 vs. 1.6 days, p&lt;0.001), and ICU length-of-stay (0.21 vs. 0.09, p=0.02) were significantly greater for the low TTR cohort in comparison to the high TTR cohort during the follow-up period. After adjusting for patient characteristics, total healthcare costs for all-cause and stroke-related healthcare costs were $2,398 (p&lt;0.001) and $687 (p=0.02) higher, respectively for patients in the low TTR cohort vs. the high TTR cohort (Table). Conclusions: NVAF patients with low warfarin TTR, in comparison to those with high warfarin TTR, used more healthcare resources resulting in higher healthcare costs.

OP-005 Assessment of Warfarin TTR (Time in Therapeutic Range ) Results in a tertiary Reference Center

OP-005 Assessment of Warfarin TTR (Time in Therapeutic Range ) Results in a tertiary Reference Center

Abstract 263: The Risk of Stroke or Systemic Embolism for Antithrombotic Treatment Episodes among Non-Valvular Atrial Fibrillation (NVAF) Patients

Background: The quality of antithrombotic therapy during routine medical care is often suboptimal.This study evaluated stroke or systemic embolism (SE) risk for real-world antithrombotic treatment patterns in NVAF patients within an integrated healthcare system. Methods: Patients aged ≥18 years and newly diagnosed with NVAF (index date) were identified between 01/01/2006-12/31/2011 within Kaiser Permanente Southern California, categorized by baseline CHADS 2 risks, and followed until 12/31/2012. Longitudinal analyses examined time-varying antithrombotic treatment episodes for each individual patient. The unadjusted and adjusted relative risk (RR) of stroke/SE was reported from generalized estimating equation models for 6 different treatment episodes: 1) warfarin time in therapeutic range (TTR) ≥55%, 2) warfarin TTR &lt;55%, 3) off warfarin, 4) on aspirin (ASA), 5) off ASA, and 6) never on antithrombotic therapy. Results: Among 23,297patients with CHADS 2 ≥1, 1,782 stroke/SE events occurred during 60,021 person-years of follow-up. The warfarin TTR ≥55% category had the lowest stroke/SE rate (Rate = 0.87 per 100 person-years, 3.23 TTR&lt;55%, 4.38 off warfarin, 3.11 ASA, 3.81 off ASA, and 3.76 never on therapy). Warfarin TTR ≥55% was associated with a 77% lower risk of stroke/SE, and ASA was associated with a 27% lower risk of stroke/SE compared to never on therapy (adjusted RR [95% CI] = 0.23 [0.19-0.29], 0.73 [0.65-0.82] respectively). Warfarin TTR &lt;55% was only marginally associated with the stroke/SE reduction compared to never on therapy (adjusted RR = 0.83 [0.70-0.99]). The stroke/SE risk for off warfarin and off ASA were not statistically different from never on therapy. Other significant factors associated with stroke/SE included older age, female, Black or Hispanic race, having diabetes, hypertension, previous stroke/TIA, peripheral vascular events, higher comorbidity score, and not having a major bleed. Conclusion: Warfarin TTR ≥55% was associated with the greatest reduction in stroke/SE among the antithrombotic treatment groups examine here. Future studies should examine modifiable factors to improve outcomes for patients with warfarin TTR &lt;55% or those who are off antithrombotic therapy.

Abstract 262: Aspirin vs. Warfarin Therapy Outcomes for Non-Valvular Atrial Fibrillation Patients with Moderate Stroke Risk

Background: The American College of Cardiology Foundation and American Heart Association guidelinerecommends aspirin 81-325 mg or warfarin use for Non-Valvular Atrial Fibrillation (NVAF) patients with one risk factor for stroke. This study evaluated outcomes associated with antithrombotic treatment among NVAF patients with CHADS 2 =1 in an integrated healthcare system. Methods: Patients age ≥18 years newly diagnosed with NVAF with a CHADS 2 score=1 at diagnosis were identified between 01/01/2006-12/31/2011 within Kaiser Permanente Southern California’s membership and followed until 12/31/2012. The rate of stroke or systemic embolism (SE) and major bleeding events per 100 person-years were evaluated for: 1) aspirin (ASA) only, 2) warfarin time in therapeutic range (TTR) ≥55%, 3) warfarin TTR &lt;55%, and 4) no antithrombotic therapy. The 55% threshold was selected as the lower bound of reported means from previous studies. Results: Among 7,899patients with CHADS 2 =1, 336 stroke and 34 SE events were observed during the 22,542 person-years of follow-up. ASA only therapy was associated with 2.3 times higher risk of stroke/SE (Rate Ratio [RR] = 2.34 [95% CI: 1.61-3.39]) compared to warfarin TTR ≥55%. ASA only events were similar to warfarin TTR &lt;55% but were 23% lower than no antithrombotic therapy. Major bleeding events were lower in ASA therapy compared to warfarin TTR ≥55% (RR = 1.50 [1.23-1.83]) or warfarin TTR &lt;55% (RR= 4.09 [1.23-1.83]). The higher bleeding rates in no therapy compared to warfarin TTR ≥55% or ASA only needs to be further investigated. Conclusion: ASA therapy was associated with a higher rate of stroke/SE but with a lower rate of bleed compared to TTR ≥55% warfarin in NVAF patients with CHADS 2 =1. These results suggest that treatment decisions should be carefully made based on the risk and benefit assessment in patients whose CHADS 2 =1.

Estimation of the impact of warfarin’s time-in-therapeutic range on stroke and major bleeding rates and its influence on the medical cost avoidance associated with novel oral anticoagulant use-learnings from ARISTOTLE, ROCKET-AF, and RE-LY trials

Warfarin's time-in-therapeutic range (TTR) is highly variable among patients with nonvalvular atrial fibrillation (NVAF). The objective of this study was to estimate the impact of variations in wafarin's TTR on rates of stroke/systemic embolism (SSE) and major bleedings among NVAF patients in the ARISTOTLE, ROCKET-AF, and RE-LY trials. Additionally, differences in medical costs for clinical endpoints when novel oral anticoagulants (NOACs) were used instead of warfarin at different TTR values were estimated. Quartile ranges of TTR values and corresponding event rates (%/patient - year = %/py) of SSE and major bleedings among NVAF patients treated with warfarin were estimated from published literature and FDA documents. The associations of SSE and major bleeding rates with TTR values were evaluated by regression analysis and then the calculated regression coefficients were used in analysis of medical cost differences associated with use of each NOAC versus warfarin (2010 costs; US payer perspective) at different TTRs. Each 10 % increase in warfarin's TTR correlated with a -0.32%/py decrease in SSE rate (R(2) = 0.61; p < 0.001). Although, the rate of major bleedings decreased as TTR increased, it was not significant (-0.035%/py, p = 0.63). As warfarin's TTR increased from 30 to 90% the estimated medical cost decreased from -$902 to -$83 for apixaban, from -$506 to +$314 for rivaroxaban, and from -$596 to +$223 for dabigatran. Among NVAF patients there is a significant negative correlation between warfarin's TTR and SSE rate, but not major bleedings. The variations in warfarin's TTR impacted the economic comparison of use of individual NOACs versus warfarin.