Individual Time In Therapeutic Range Research Articles

Warfarin treatment quality and outcomes in patients with non-valvular atrial fibrillation and CKD G3-G5D

IntroductionWarfarin treatment quality is calculated as time in therapeutic range (TTR). TTR ≥ 70 % is considered reducing the risk of adverse events for patients with atrial fibrillation (AF). The association of TTR and adverse events in chronic kidney disease (CKD) is however poorly investigated. The aim is to explore this further. Materials and methodsSwedish cohort study based on national healthcare registers between 2009 and 2018, including Swedish Renal Registry, Swedish Stroke Register and AuriculA - the Swedish national quality register for AF and anticoagulation. Investigating the effect of individual TTR (iTTR) and iTTR ≥ 70 % versus <70 % on the risk of ischemic stroke, major bleeding and death for patients with CKD GFR category 3–5 (G3-G5) including patients on dialysis (G5D) and non-valvular AF (NVAF). ResultsOf 2379 included patients 21.9 % had G3, 47.5 % G4, 10.8 % G5 and 19.8 % G5D. TTR in G3 was 75.6 %, G4 72.2 %, G5 67.6 % and G5D 62.0 %. Increase by 10 percentage points iTTR conferred lower risk of major bleeding, ischemic stroke and death for all patients (hazard ratio 0.91 (95 % Confidence interval 0.87–0.94), 0.92 (0.85–0.99) and 0.88 (0.85–0.90)). iTTR≥ 70 % versus <70 % was associated with lower risk of bleeding and death in all patients (0.63 (0.51–0.77) and (0.51 (0.43–0.61)), and a non-significant tendency towards lower stroke risk (0.67 (0.43–1.06)). ConclusionsWarfarin treatment quality worsens with decreasing GFR. Higher iTTR confers lower risk of bleeding, ischemic stroke and death in patients with NVAF and G3-G5D. iTTR ≥ 70 % was associated with better safety profile. Close monitoring of patients with CKD on warfarin is recommended.

MO758: Warfarin Treatment Quality and Outcomes in Patients with Non-Valvular Atrial Fibrillation and Chronic Kidney Disease Including Patients on Dialysis

Abstract BACKGROUND AND AIMS Warfarin has traditionally been the drug of choice for patients with atrial fibrillation and GFR &amp;lt; 30 mL/min. Observational studies have shown a lower risk of ischemic stroke with warfarin compared with no treatment, but also an increased risk of bleeding [1]. For patients on dialysis, the role of warfarin is less clear due to high bleeding risk and diverging data on stroke protection [2, 3]. Warfarin treatment quality can be calculated as time in therapeutic range (TTR). TTR ≥ 70% is considered lowering the risk of adverse events [4]. The impact of a patient’s individual TTR (iTTR) on ischemic stroke and bleeding is poorly investigated for patients with eGFR &amp;lt; 60 mL/min/1.73 m2 including patients on dialysis, and the aim is to study this further. METHOD A Swedish retrospective national cohort study investigating the risk of ischemic stroke and major bleeding in patients with non-valvular atrial fibrillation (NVAF) during warfarin treatment depending on iTTR (individual time in therapeutic range). Patients included have warfarin treated NVAF, eGFR &amp;lt; 60 mL/min or on dialysis, kidney transplant recipients excluded, between 2009 and 2018. Data extracted from Swedish high quality national health-care registries including Swedish Renal Registry for GFR-category, The Stroke Register for stroke-related outcomes and Auricula—the Swedish national quality register for AF and anticoagulation for warfarin treatment periods and INR measurements. ITTR is calculated in a 90-day Window and updated at each new INR value. The impact of iTTR is tested with the Cox regression and time-dependent covariates regarding risk for ischemic stroke, major bleeding (intracranial, gastrointestinal and other) and all-cause mortality. RESULTS At enrolment of 2421 patients (29.1% female) 22.1% had G3 (eGFR 59–30 mL/min/1.73 m2) 47.4% G4 (eGFR 15–29), 10.9% G5 (eGFR &amp;lt; 15) and 19.7% G5D (on dialysis). Mean iTTR for all patients was 64% (G3 71%, G4 66%, G5 61% and G5D 55%). The number of events, time on warfarin and event rates are found in Table 1. Adjusted analysis shows that a 0.2 unit increase of iTTR lowers the risk of major bleeding for all patients, patients in G3–G5 and patients on dialysis (G5D) {hazard ratio 0.69 [95% confidence interval (95% CI) 0.61–0.78], 0.65 (0.55–0.77) and 0.78 (0.62–1.0)} (Fig. 1). Increased iTTR by 0.2 units does not seem to have a significant effect on the hazard of ischemic stroke for all patients, G3–G5 and G5D [HR 0.72 (95% CI 0.51–1.00), 0.77 (0.49–1.19) and 0.70 (0.36–1.37)]. An ITTR increase of 0.2 units lowers the risk of all-cause mortality for all patients, G3–G5 and G5D [0.62 (0.55–0.69), 0.56 (0.48–0.65) and 0.75 (0.62–0.9)]. ITTR &amp;gt; 70% compared with &amp;lt;70% lowers the risk of major bleeding and all-cause mortality in all patients [HR 0.63 (0.52, 0.76) and HR 0.52 (0.44, 0.61) but no significant effect on ischemic stroke (HR 0.61 (0.37, 1.01)]. CONCLUSION Warfarin treatment quality worsens with decreasing GFR. Higher iTTR confers a lower risk of major bleeding and death for patients with NVAF and CKD, eGFR &amp;lt; 60 including dialysis. Conclusions cannot be made regarding the effect of iTTR and ischemic stroke due to few events. Patients with NVAF and chronic kidney disease including patients on dialysis on warfarin should be closely monitored to lower the bleeding risk.

Evaluation of the anticoagulant effect of vitamin K antagonists in patients with non-valvular atrial fibrilation

Background/Aim. Despite the introduction of new oral anticoagulants (dabigatran, rivoroxaban, apixaban), vitamin K antagonists (VKA), such as warfarin and acenocoumarol are still the most widely used oral anticoagulants for the treatment of nonvalvular atrial fibrillation (NVAF). The time in therapeutic range (TTR) represents a measure of the quality of the anticoagulant effect of these drugs, and it is considered that the lower value of TTR is associated with the adverse effects of therapy. The aim of this study was to evaluate of the effectiveness of VKA therapy in patients with NVAF and to identify factors affecting the anticoagulation efficacy. Methods. A retrospective study was conducted on a population of 725 outpatients with NVAF, treated with VKA and followed in the Blood Transfusion Institute of Nis, Serbia, from January to December 2017. Laboratory control of the INR was done from capillary blood of patients on Thrombotrack Solo (Axis Shield, Norway) and Thrombostat (Behnk Elektronik, Germany). Targeted therapeutic INR was between 2.0 and 3.0. For each patient all available INR values were evaluated to calculate the individual TTR according to the Rosendaal method. Results. The study included a total of 725 patients with NVAF which had 6,105 INR measurements, what was 8.13 ? 2.47 INR measurements per patient. The mean value of TTR and was 60.15 ? 17.52%, but 49.72% of patients had TTR less than 60%. Patients were at high risk of thrombosis in 6.15% of time (INR &lt; 1.5) and high risk of bleeding in 2.2% of time (INR &gt; 4.5). The most significant independent factors affecting the quality of VKA therapy were gender, arterial hypertension, diabetes mellitus and the use of amiodarone and antiplatelet drugs (aspirin, clopidogrel). Conclusion. The TTR is undoubtedly useful indicator of the VKA treatment effectiveness. The most important predictors of poorer efficacy of VKA therapy are: arterial hypertension, diabetes mellitus, patients' gender and the use of amiodarone and antiplatelet drugs (aspirin, clopidogrel). To improve the quality of VKA therapy, education of patients and better collaboration with them, as well as a successful teamwork of clinicians are also imperative.

Predictors for INR-control in a well-managed warfarin treatment setting

Warfarin is well studied in patients with non-valvular atrial fibrillation (AF). It has low complication rates for patients achieving individual Time in Therapeutic Range (iTTR) > 70%. The risk scores SAMe-TT2R2 and PROSPER are designed to predict future TTR, but are derived from a heterogeneous population with generally low iTTR. The aim of this study was to evaluate predictors for high and low iTTR in an AF population in Sweden, where there is a generally good anticoagulation control. A retrospective register study based on Swedish warfarin dosing system AuriculA, including 28,011 AF patients starting treatment during 1 January 2006 to 31 December 2011. Complications and risk factors were analysed and related to iTTR. Mean age was 73.7 (SD ± 9.5) years, with 42.0% women. Mean CHA2DS2-VASc score (SD) was 3.6 (± 1.7). For patients with iTTR < 60% there were over three times higher prevalence of excessive alcohol consumption than for patients with iTTR > 70% (3.7% vs. 1.1%). Previous stroke were more prevalent for patients with high than low iTTR (17.1% vs. 20.3%). Concomitant comorbidities were associated with increased risk of poor iTTR. In Swedish AF patients, excessive alcohol use is clearly associated with iTTR below 60%. Patients with previous stroke are more likely to get iTTR above 70%, unlike those with concomitant disorders who more often have poor anticoagulation control. The SAMe-TT2R2-score cannot be applied in Sweden.

Bleeding complications and mortality in warfarin-treated VTE patients, dependence of INR variability and iTTR.

High quality of warfarin treatment is important to prevent recurrence of venous thromboembolism (VTE) without bleeding complications. The aim of this study was to examine the effect of individual time in therapeutic range (iTTR) and International Normalised Ratio (INR) variability on bleeding risk and mortality in a large cohort of well-managed patients with warfarin due to VTE. A cohort of 16612 patients corresponding to 19502 treatment periods with warfarin due to VTE between January 1, 2006 and December 31, 2011 was retrieved from the Swedish national quality register AuriculA and matched with the Swedish National Patient Register for bleeding complications and background characteristics and the Cause of death register for occurrence and date of death. The rate of bleeding was 1.79 (confidence interval (CI) 95 % 1.66-1.93) per 100 treatment years among all patients. Those with poor warfarin treatment quality had a higher rate of clinically relevant bleeding, both when measured as iTTR below 70 %, 2.91 (CI 95 % 2.61-3.21) or as INR variability over the mean value 0.85, 2.61 (CI 95 % 2.36-2.86). Among those with both high INR variability and low iTTR the risk of clinically relevant bleeding was clearly increased hazard ratio (HR) 3.47 (CI 95 % 2.89-4.17). A similar result was found for all-cause mortality with a HR of 3.67 (CI 95 % 3.02-4.47). Both a low iTTR and a high INR variability increase the risk of bleeding complications or mortality. When combining the two treatment quality indicators patients at particular high risk of bleeding or death can be identified.

Impact of Vitamin K Antagonists on Quality of Life in a Prospective Cohort of 807 Atrial Fibrillation Patients.

Vitamin K antagonists (VKA) use is challenging because of frequent blood monitoring and complex dosing. Therefore, many patients and physicians are reluctant to start VKA. However, it is unclear whether VKA use actually lowers quality of life. We aimed to determine the impact of VKA initiation on quality of life and to analyze the correlation between patient and treatment characteristics and VKA perception in atrial fibrillation patients. In a prospective cohort of 240 new and 567 long-term VKA users, general quality of life and VKA perception (satisfaction and convenience) were measured at inclusion and at 3 months by the validated Study Short-Form 36 and Perception of Anticoagulant Treatment Questionnaire. Scores were converted to a 0 to 100 scale. Higher scores are more favorable. In the new patients, Medical Outcomes Study Short-Form 36 scores improved during the initial 3 months to a level comparable with the general population. At 3 months, the median convenience score was 95 (Q1-Q3, 88-98) and was higher in older patients (regression coefficient, 0.47 per year; 95% confidence interval, 0.25-0.69) and lower after bleeding (regression coefficient, -12; 95% confidence interval, -20 to -4.7). The median satisfaction score was 64. For the long-term patients, VKA perception scores were highly comparable with the new patients. The convenience score mildly improved in patients with increased individual time in therapeutic range (regression coefficient, 0.03; 95% confidence interval, 0.01-0.05; r(2)=0.01), and satisfaction scores decreased in patients with new comedication (regression coefficient, -7.0; 95% confidence interval, -12 to -1.9; r(2)=0.02). VKA were well tolerated in real-life, and the influences of patient and treatment related factors on VKA perception were very limited.

The SAMe-TT2R2 Score Predicts Poor Anticoagulation Control in AF Patients: A Prospective ‘Real-world’ Inception Cohort Study

ObjectivesInternational guidelines recommend that an average individual time in therapeutic range should be >65% to 70% for optimal efficacy and safety outcomes while taking a vitamin K antagonist. The Sex, Age (<60 years); Medical history (at least 2 of the following: hypertension, diabetes, coronary artery disease/myocardial infarction, peripheral arterial disease, congestive heart failure, previous stroke, pulmonary disease, hepatic or renal disease); Treatment (interacting drugs, eg, amiodarone for rhythm control) [all 1 point]; and the current Tobacco use (2 points) and Race (non-Caucasian; 2 points) (SAMe-TT2R2) score would help decision making by identifying those patients with newly diagnosed atrial fibrillation who could do well on vitamin K antagonists. The study objective was to validate the predictive value of the SAMe-TT2R2 score for discriminating those who would achieve a high time in the therapeutic range (≥65%) in a prospective “real-world” cohort of patients with atrial fibrillation initiating oral anticoagulation therapy with vitamin K antagonists. MethodsWe studied an inception cohort of consecutive patients with nonvalvular atrial fibrillation who initiated oral anticoagulation in our outpatient anticoagulation clinic. The baseline SAMe-TT2R2 score was calculated. At 6 months, we calculated the time in therapeutic range using a linear method. ResultsWe included 459 patients, of whom 222 (47%) were male. Their median age was 76 years (interquartile range, 70-82 years), median Cardiac failure or dysfunction, Hypertension, Age over 75 years [Doubled], Diabetes, Stroke [Doubled] – Vascular disease, Age between 65-74 and Sex category [Female] (CHA2DS2-VASc) score was 4 (3-5), and median Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly (HAS-BLED) score was 3 (2-3). The median SAME-TT2R2 score was 2 (1-2). At 6 months, the mean ± standard deviation time in therapeutic range was 64% ± 17% overall, and 248 patients (54%) had a time in therapeutic range value >65%. Patients with a SAME-TT2R2 score 0 to 1 had a mean time in therapeutic range of 67% ± 18%, whereas patients with a SAME-TT2R2 score ≥2 had a mean time in therapeutic range of 61% ± 16% (P < .001). The odds ratio for having a low time in therapeutic range value was 2.10 (95% confidence interval, 1.44-3.06; P < .001) for those patients with a SAME-TT2R2 score ≥2. ConclusionsIn a prospective “real-world” inception cohort of patients with atrial fibrillation initiating oral anticoagulation with acenocoumarol, we have validated the clinical value of the SAME-TT2R2 score for the identification of patients who would have poor-quality anticoagulation. Thus, rather than imposing a “trial of vitamin K antagonists” for such patients (and exposing such patients to thromboembolic risks), we can a priori identify those patients who can (not cannot) do well on a vitamin K antagonists. Such patients would benefit from additional strategies for improving anticoagulation control with vitamin K antagonists or alternative oral anticoagulant drugs.

Independent predictors of poor vitamin K antagonist control in venous thromboembolism patients. Data from the EINSTEIN-DVT and PE studies.

Vitamin K antagonists (VKA) are used to prevent recurrent disease in patients with venous thromboembolism (VTE). Their efficacy and safety depend on individual time in therapeutic range (iTTR) and variability of International Normalised Ratios (INR). We aimed to identify independent predictors of poor VKA control > 28 days. In a prospective cohort of 3825 VTE patients, separate logistic regression analyses were performed to identify predictors of low iTTR (first quartile) and instability (iTTR <median and variability >median). Subsequently, the association between these predictors and clinical outcomes was investigated. Weight < 50 kg (odds ratio [OR]=1.89; 95 % confidence interval [CI] 1.03-3.49), active cancer at baseline (OR=1.52; CI1.05-2.19), secondary VTE (OR=1.42; CI1.20-1.68), and INR < 2.0 at stop of double therapy (OR=1.35; CI1.09-1.67) were independent predictors of low iTTR. The first two were also predictive for instability (OR=1.96; CI1.06-3.63 and OR=1.95; CI1.36-2.80, respectively). ORs of early (≤ 28 days) low iTTR and instability depended on VKA type. In acenocoumarol users, early low iTTR was an independent predictor of subsequent low iTTR (OR=1.92; CI1.31-2.80) and instability (OR=1.55; CI1.07-2.23). In warfarin users, early low iTTR (OR=1.36; CI1.09-1.69) and instability (OR=1.25; CI1.01-1.55) were additionally predictive for low iTTR, but only the latter was predictive for instability (OR=1.91; CI1.57-2.32). Many predictors of VKA control also predicted premature discontinuation, but only region was prognostic for clinical outcome. In conclusion, we identified several independent predictors of low iTTR and instability > 28 days, which showed some similarities but did not fully overlap. Early VKA control was of additional value for prediction of both, but had to be interpreted in the context of VKA type.

MY APPROACH to the use of NOACs for stroke prevention in patients with atrial fibrillation

Stroke prevention is central to the management of atrial fibrillation (AF). The approach is to initially identify patients at a low risk for stroke (CHA2DS2-VASc score of 0 [men] or 1 [women]), who do not need any antithrombotic therapy. Subsequent to this step, patients with Z additional stroke risk factors (thus, CHA2DS2-VASc score of Z2, as well as men with a score of 1) can be offered effective stroke prevention. Effective stroke prevention essentially means oral anticoagulation (OAC), whether given as a well-controlled, adjusteddose vitamin K antagonist (VKA; e.g., warfarin), or one of the non-VKA oral anticoagulants (NOACs; previously referred to as new, or novel, OACs) [1]. If VKAs are used, the challenge is to maintain patients within an international normalized ratio (INR) of 2.0–3.0. Guidelines recommend good-quality anticoagulation control, as reflected by an average individual time in therapeutic range (TTR) of Z70% [2,3]. The TTR correlates with the efficacy and safety of VKAs, whereby a high TTR is associated with low risks for thromboembolism and bleeding, but a low TTR (i.e., o60%) is associated with a high risk for thromboembolism or hemorrhage [3,4]. For newly diagnosed anticoagulation-naive patients with AF, use of the SAMe-TT2R2 score can help identify those patients (SAMe-TT2R2 score of 0–2) who are likely to do well with a VKA (with TTR Z 70%). On the other hand, patients with a

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Efficacy and Safety of Apixaban Compared With Warfarin at Different Levels of Predicted International Normalized Ratio Control for Stroke Prevention in Atrial Fibrillation

In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR). The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53-1.00) and 0.88 (95% CI, 0.57-1.35) (Pinteraction=0.078), for mortality were 0.91 (95% CI, 0.74-1.13) and 0.91 (95% CI, 0.71-1.16) (Pinteraction=0.34), and for major bleeding were 0.50 (95% CI, 0.36-0.70) and 0.75 (95% CI, 0.58-0.97) (Pinteraction=0.095), respectively. Similar results were seen for quartiles of individual TTR. The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers' and patients' predicted quality of international normalized ratio control.

A prospective study of an aggressive warfarin dosing algorithm to reach and maintain INR 2 to 3 after heart valve surgery

Good anticoagulation control in patients during the first months after heart valve surgery is important to prevent thrombotic complications. This is difficult to achieve, partly because the sensitivity to warfarin decreases progressively during approximately three months after valve surgery. A recently developed, simple but aggressive algorithm might improve anticoagulation control in this patient group. It was the objective of this study to evaluate the level of anticoagulation control when a specialised anticoagulation clinic changed from empirical dosing to the use of this new algorithm. In a before-and-after design, a cohort of consecutive patients managed with a new, aggressive dosing algorithm ('Algorithm cohort') was compared to a 'Retrospective cohort' of similar patients dosed empirically. Primary endpoint was individual time in therapeutic range (ITTR) during the first three months of warfarin therapy. Secondary endpoints included proportion of extreme International Normalised Ratio (INR) results, thrombotic and bleeding complications. Ninety-eight patients were included in the Algorithm cohort, 94 of whom were warfarin-naïve. Two hundred patients were included in the Retrospective cohort. Mean ITTR was 60.1% in the Algorithm cohort versus 48.7% in the Retrospective cohort (p <0.001). Patients in the Algorithm cohort spent 0.5% of time at an INR >5, versus 0.2 % in the Retrospective cohort. There was no major bleeding in either cohort; one patient in each cohort had a thrombotic complication. We demonstrate an improvement of the level of anticoagulation control with the use of a condition-specific, aggressive algorithm, as compared to standard dosing, in patients after heart valve surgery.