International Normalized Ratio Variability Research Articles

Association between gene polymorphisms and initial warfarin therapy in patients after heart valve surgery.

Warfarin is widely used for the prevention and treatment of thrombotic events. This study aimed to examine the influence of gene polymorphisms on the early stage of warfarin therapy in patients following heart valve surgery. Nine single nucleotide polymorphisms were genotyped using microarray chips, categorizing patients into three groups: normal responders (Group I), sensitive responders (Group II), and highly sensitive responders (Group III). The primary clinical outcomes examined were time in therapeutic range (TTR) and international normalized ratio (INR) variability. To investigate potential influencing factors, a generalized linear regression model was employed. Among 734 patients, the prevalence of CYP2C9*3-1075A > C, CYP2C19*3-636G > A, and CYP2C19*17-806C > T variants were 11.2%, 9.9%, and 1.9% of patients, respectively. VKORC1-1639G > A or the linked -1173C > T variant was observed in 99.0% of the patients. Generalized linear model analysis revealed an impact of sensitivity grouping on INR variability. Compared to Group I, Group II showed higher TTR values (p = 0.023), while INR variability was poorer in Group II (p < 0.001) and Group III (p < 0.001). Individual gene analysis identified significant associations between CYP2C9*3-1075A > C (p < 0.001), VKORC1-1639G > A or the linked -1173 C > T (p = 0.009) and GGCX-3261G > A (p = 0.019) with INR variability. The genotypes of CYP2C9, VKORC1, and GGCX were found to have a significant impact on INR variability during the initial phase of warfarin therapy. However, no significant association was observed between TTR and gene polymorphisms. These findings suggest that focusing on INR variability is crucial in clinical practice, and preoperative detection of gene polymorphisms should be considered to assist in the initiation of warfarin therapy.

Effect of previous INR control during VKA therapy on subsequent DOAC adherence and persistence, in patients switched from VKA to DOAC.

Introduction Current guideline suggests a switch from vitamin K antagonist (VKA) to direct oral anticoagulant (DOAC) in patients with low time in therapeutic range (TTR<70%). Poor INR control may be the result of poor compliance, and might therefore be associated with subsequent DOAC intake. Therefore, this study evaluates the effect of previous TTR and other measures of INR control on DOAC non-adherence and non-persistence, in patients who switched from VKA to DOAC. Methods 437 patients who switched from VKA to DOAC between 2012 and 2019 were included using data from Certe Thrombosis Service, IADB.nl pharmacy community database University Groningen and Statistics Netherlands. DOAC prescriptions were used to determine non-adherence and non-persistence. INR control (i.e. TTR, time under therapeutic range (TUR) and INR variability) was assessed during the last 180 days of VKA use. Multivariable regression models were applied to determine the association between INR control and DOAC non-persistence / non-adherence. Results On VKA, 67.7% of the patients had a TTR below 70%. DOAC non-persistence was 39.8% (95% CI 33.4-45.5%) during a median follow-up of 34.4 months [IQR 19.1-49.2]. Approximately 80% of persistent patients were DOAC-adherent. Low TTR was not associated with DOAC non-persistence (HR 1.14, 95% CI 0.69-1.87) and DOAC non-adherence (OR 1.38, 95% CI 0.67-2.84), nor were TUR and INR variability. Conclusion Previous INR control during VKA therapy is not associated with subsequent DOAC non-adherence and non-persistence. This study suggests that INR control on VKA cannot, and therefore should not be used for predicting DOAC adherence or persistence.

Quantitative determination of plasma free and total concentrations of antivitamin K drugs using a new sensitive and rapid LC-MS/MS method: Application in hemodialysis patients

Background and aimsVitamin K antagonists (VKAs) are the first-line anticoagulants used in end stage renal disease. This population experiences a significant variability in their International Normalized Ratio (INR) over time. There is a need for methods allowing the study of the pharmacokinetics of free and total concentrations of VKAs to explain INR variability. Materials and methodsWe developed and validated a high-performance liquid chromatography-tandem mass spectrometry method allowing the quantification of warfarin and fluindione free and total plasma concentrations. Chromatographic separation was achieved in a raptor biphenyl column and the spectrometry acquisition was set in multiple reaction monitoring mode after negative electrospray ionization. We then applied it in describing the plasma free and total concentrations of VKAs in samples from 50 hemodialysis patients. ResultsThe developed method is rapid, sensitive and specific. Our cohort results showed a correlation between free and total VKA concentrations. The free VKA concentrations tended to be higher in patients with higher INR. Although VKAs are highly albumin-bound drugs, albumin concentration did not totally explain the high inter-individual total VKA concentrations variability. ConclusionThis opens the door to further studies to understand the factors involved in their variability.

Effect of INR on Outcomes of Endovascular Treatment for Acute Vertebrobasilar Artery Occlusion.

Endovascular treatment (EVT) has been proven to be the standard treatment for acute vertebrobasilar artery occlusion (VBAO). This study aimed to analyze the effects of international normalized ratio (INR) indicators on outcomes in patients with acute VBAO treated with EVT. Dynamic data on INR in patients with VBAO who received endovascular treatment (EVT) at 65 stroke centers in China were retrospectively enrolled. Outcome measures included the modified Rankin Scale (mRS) score at 90days and 1year and symptomatic intracranial hemorrhage (sICH). The associations between elevated INR (INR > 1.1), INR variability (time-weighted variance of INR changes), and various clinical outcomes were analyzed in all patients and subgroups stratified by oral anticoagulation (OAC) by mixed logistic regression analysis. A total of 1825 patients met the study criteria, of which 1384 had normal INR and 441 had elevated INR. Multivariate analysis showed that elevated INR was significantly associated with poor functional outcomes (mRS 4-6) at 90days (odds ratio [OR] 1.36, 95% confidence interval [CI] 1.08-1.72) and 1year (OR 1.32, 95% CI 1.05-1.66), but was not associated with an increased risk of sICH (OR 1.00, 95% CI 0.83-1.20). Similar associations exist between INR variability and poor functional outcomes at 90days (OR 2.17, 95% CI 1.09-4.30), 1year (OR 2.28, 95% CI 1.16-4.46), and sICH (OR 1.11, 95% CI 0.93-1.33). Subgroup analyses further revealed that elevated INR and INR variability remained associated with poor functional outcomes in patients not receiving oral anticoagulation (OAC) therapy, while no significant associations were observed in OAC-treated patients, regardless of whether they were on warfarin or direct oral anticoagulants. Elevated INR and INR variability in VBAO patients treated with EVT were associated with poor functional outcomes. The mechanism underlying the association between elevated INR and poor functional outcomes might be attributed to the fact that elevated INR indirectly reflects the burden of comorbidities, which could independently worsen outcomes. These findings underscore the importance of a comprehensive and dynamic evaluation of INR levels in the management of VBAO patients receiving EVT, providing valuable insights for optimizing patient outcomes.

Best quality indicator of vitamin K antagonist therapy to predict mortality and bleeding in haemodialysis patients with atrial fibrillation.

There is a high prevalence of atrial fibrillation (AF) in patients undergoing haemodialysis. Oral anticoagulant therapy with vitamin K antagonists (VKAs) is the only accepted treatment for the prevention of thromboembolism in haemodialysis patients with AF. However, in this population, the risk of bleeding is greatly increased. The aim of the study was to evaluate the ability of treatment quality indicators of VKA therapy to predict mortality and bleedings in a population of haemodialysis patients with AF. A total of 129 patients were included in this cohort study. Deaths and bleeding events were recorded during a follow-up of 4 years. In all patients, International Normalized Ratio (INR) values were assessed at least once a month. Time in therapeutic range (TTR) and INR variability, as measured by the standard deviation of INR, were updated at each INR measurement. A Cox model with time-dependent co-variates and sandwich variance was applied. During follow-up, 71 patients died and 55 bleeding episodes occurred in 31 patients. INR variability was the only indicator associated with both mortality (hazard ratio [HR]=1.67, 95% confidence interval [CI] 1.12; 2.49, p=0.012) and bleeding (HR=2.85, 95% CI: 1.71; 4.75, p=0.0001). HR of mortality was higher in patients with INR >3 (HR=2.06, 95% CI: 1.09; 3.88, p=0.0259) than in subjects in therapeutic range 2<INR≤3. TTR was inversely associated with the risk of recurrent haemorrhagic events (HR=0.88, 95% CI: 0.80; 0.95, p=0.0023), but not with a first episode of bleeding. Results were consistent after censoring patients at VKA withdrawal. Our study suggests that, in haemodialysis patients with AF taking VKAs, INR variability is the quality indicator that best predicts clinical outcomes. In this population, if more treatment quality indicators are considered together, it may become easier to identify patients at particularly high risk of bleeding and death.

Effect of switching from acenocoumarol to phenprocoumon on time in therapeutic range and INR variability: A cohort study.

BackgroundTreatment with vitamin K antagonists (VKA) requires a high proportion of time in the therapeutic range (TTR) and a low international normalised ratio (INR) variability to be maximally safe and effective. Switching from short-acting acenocoumarol to long-acting phenprocoumon could improve VKA control.AimsWe assessed whether switching from acenocoumarol to phenprocoumon improves the time in the therapeutic range (TTR) and INR variability.Methods and resultsIn a retrospective cohort with data on 236,957 patients-years of VKA management from two first-line anticoagulation clinics in the Netherlands, we identified 124 patients in target range 2–3, 269 patients in target range 2–3.5 and 98 patients in target range 2.5–3.5 who switched from acenocoumarol to phenprocoumon. They were matched in a 1:2 ratio to non-switching controls using propensity score matching. Over the first 180 days after a switch, switchers’ TTR declined 5 (95% CI 1 to 10), 10 (95% CI 7 to 13) and 5 (95% CI 0 to 11) percentage points relative to non-switchers, in target ranges 2–3, 2–3.5 and 2.5–3.5. Anticoagulation was more often supra-therapeutic in switchers, and switchers had a higher INR variability. In the following 180 days, TTR in switchers became 1 (95% CI -4 to 6), 4 (95% CI 0 to 7) and 6 (95% CI 1 to 12) percentage points better than in non-switchers. Switchers’ INRs were much more stable than non-switchers’.ConclusionEventually, a switch from acenocoumarol to phenprocoumon leads to a higher TTR and a lower INR variability. However, this is preceded by a transition period with opposite effects. An improved conversion algorithm could possibly shorten the transition period. Until then, physicians and patients should decide whether switching is worth the increased risk during the transition phase.

LRP1 and APOA1 Polymorphisms: Impact on Warfarin International Normalized Ratio-Related Phenotypes.

Warfarin international normalized ratio (INR)-related phenotypes such as the percentage of INR time in the therapeutic range (PTTR) and INR variability are associated with warfarin adverse reactions. However, INR-related phenotypes greatly vary among patients, and the underlying mechanism remains unclear. As a key cofactor for coagulation proteins, vitamin K can affect warfarin INR values. The aim of this study was to address the influence of vitamin K-related single-nucleotide polymorphisms (SNPs) on warfarin INR-related phenotypes. A total of 262 patients who were new recipients of warfarin therapy and followed up for 3 months were enrolled. Twenty-nine SNPs were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass array. Sixteen warfarin INR-related phenotypes were observed. After association analysis, 11 SNPs were significantly associated with at least one INR-related phenotype, and 6 SNPs were associated with at least 2 INR-related phenotypes (P < 0.05). In these SNPs, rs1800139, rs1800154, rs1800141, and rs486020 were the most representative. rs1800139, rs1800154, and rs1800141 locate in LRP1 and were found to be correlated with 1-month and 2-month INR variability (P < 0.05). Besides, the APOA1 rs486020 was significantly associated with the first month PTTR (P = 0.009), and patients with C-allele had higher PTTR than those with G-alleles almost during the entire monitoring period. In conclusion, the study revealed that the polymorphisms of LRP1 and APOA1 gene may play important roles in the variation of warfarin INR-related phenotypes. Our results provide new information for improving warfarin anticoagulation management.

Impact of CYP2C9-Interacting Drugs on Warfarin Pharmacogenomics.

Precise dosing of warfarin is important to achieve therapeutic benefit without adverse effects. Pharmacogenomics explains some interindividual variability in warfarin response, but less attention has been paid to drug‐drug interactions in the context of genetic factors. We investigated retrospectively the combined effects of cytochrome P450 (CYP)2C9 and vitamin K epoxide reductase complex (VKORC)1 genotypes and concurrent exposure to CYP2C9‐interacting drugs on long‐term measures of warfarin anticoagulation. Study participants predicted to be sensitive responders to warfarin based on CYP2C9 and VKORC1 genotypes, had significantly greater international normalized ratio (INR) variability over time. Participants who were concurrently taking CYP2C9‐interacting drugs were found to have greater INR variability and lesser time in therapeutic range. The associations of INR variability with genotype were driven by the subgroup not exposed to interacting drugs, whereas the effect of interacting drug exposure was driven by the subgroup categorized as normal responders. Our findings emphasize the importance of considering drug interactions in pharmacogenomic studies.

P4765Men who live alone have poor anticoagulation control: results from Danish registries

Abstract Background Efficacy and safety of vitamin K antagonists (VKAs) depend on quality of anticoagulation control, usually measured as time in therapeutic range (TTR). Factors that predict low TTR on VKAs could be used to identify patients who might benefit from interventions, or who would be better treated with a non-VKA oral anticoagulant (NOAC). Patients living alone may have difficulties in taking their medications, managing their diets, or coming to clinic for monitoring. Purpose To assess influence of cohabitation status on TTR with VKA among men and women. Methods We identified all Danish patients with atrial fibrillation (AF) who initiated VKA between 1997 and 2012, and studied patients who had 6 months of continuous VKA use and international normalized ratio (INR) monitoring. Patients were divided according to sex and whether they lived alone or with others. We calculated TTR using the Rosendaal method, and INR variability using Fihns method. We used a linear regression model to test for associations between TTR and covariates, and adjusted for age, income, medications and comorbidities. Results We identified 4,772 AF patients with 6 months of continuous VKA use and INR monitoring. 713 (15%) were men living alone, 1,073 (23%) were women living alone, 2,164 (45%) were men not living alone and 822 (17%) were women not living alone. INR was measured a median of 11 (interquartile range 8–15) times during the 180 days of VKA use, but men who lived alone had 0.6 (95% confidence interval (CI): 0.2 to 1.2) fewer INR measurements during the period. Median TTR was lowest among men living alone (57.2%), followed by women living alone (58.8%), women not living alone (61.0%) and men not living alone (62.5%). After multivariable adjustment, men who lived alone had a 3.6% (CI −5.6 to −1.6) lower TTR compared with men not living alone, but women who lived alone did not have significantly lower TTR (P=0.80) compared with women not living alone. Living alone had significantly greater effect on TTR among men than among women (interaction P=0.02). Men living alone also had higher adjusted INR variability (0.2, CI 0.0 to 0.4) compared with men not living alone. Conclusion Living alone was significantly related to low quality of anticoagulation control among men, but not among women. Acknowledgement/Funding this study was funded by an unrestricted grant from the Capital Region of Denmark, Foundation for Health Research

P3474Relationship between international normalized ratio variability, quality of anticoagulation control and outcomes in patients with atrial fibrillation: an AFFIRM post-hoc analysis

Abstract Introduction Quality of anticoagulation control is essential to ensure better clinical outcomes in patients with atrial fibrillation (AF). Time in therapeutic range (TTR) is recommended as a measure of the quality of anticoagulation control. The International normalized ratio (INR) variability has been suggested as an alternative index, even though large independent validations for this index are still lacking. Purpose To provide validation of clinical usefulness of INR variability as a measure of the quality of anticoagulation control in a large cohort of AF patients. Methods Data from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial were analysed. INR variability was defined as the standard deviation (SD) of mean INR values [INR-SD] recorded throughout the follow-up observation for each patient. All patients with available INR values were included in the analysis. Stroke, major bleeding, cardiovascular (CV) death and all-cause death were study outcomes. Results Among the original 4060 patients, a total of 3185 (78.4%) were available for analysis. Mean (SD) INR-SD was 0.58 (0.25). According to INR-SD patients were categorized into four quartiles. Mean (SD) CHA2DS2-VASc score was increased (p=0.040), with no difference in proportions of CHA2DS2-VASc ≥2 (p=0.582) between the subgroups. A significant inverse correlation was found between INR-SD and TTR (Spearman's Rho: −0.536, p&lt;0.001). Continuous INR-SD, after multiple adjustments, was inversely associated with TTR (standardized beta: −0.451, p&lt;0.001) and directly associated with SAMe-TT2R2score (standardized beta: 0.084, p&lt;0.001). A fully adjusted Cox multivariate regression analysis found that INR-SD was directly associated with increased risk of stroke, major bleeding and all-cause death (Table). An INR-SD ≥0.85 was directly associated with all the study outcomes, on multivariate analysis (Table). Cox Regression Analysis INR-SD INR-SD ≥0.85 HR (95% CI) HR (95%) Stroke 2.52 (1.34–4.67) 1.62 (1.00–2.63) Major Bleeding 2.43 (1.49–3.96) 1.61 (1.10–2.36) CV Death 1.50 (0.87–2.59) 1.54 (1.07–2.24) All-Cause Death 1.79 (1.21–2.66) 1.55 (1.17–2.05) CI = Confidence Interval; CV = Cardiovascular; HR = Hazard Ratio; INR-SD = International Normalized Ratio Standard Deviation. Conclusions INR variability, expressed as INR-SD, was significantly correlated and associated with TTR. Both continuous INR-SD and INR-SD ≥0.85 were significantly associated with a higher risk of all study adverse outcomes. Acknowledgement/Funding None

Control of Anticoagulation Therapy in Patients with Atrial Fibrillation Treated with Warfarin: A Study from the Chinese Atrial Fibrillation Registry

BackgroundSeveral factors determine the efficacy of warfarin anticoagulation in patients with non-valvular atrial fibrillation (NVAF). This study aimed to use data from the Chinese Atrial Fibrillation Registry study to assess the control of anticoagulation therapy in Chinese patients with NVAF treated with warfarin.Material/MethodsFrom the Chinese Atrial Fibrillation Registry study the anticoagulant use and dosing, the time in therapeutic range (TTR) of the international normalized ratio (INR), and standard deviation of the observed INR values (SDINR), and their influencing factors were evaluated.ResultsThe median INR and SDINR were 2.04 (IQR 1.71–2.41) and 0.50 (IQR, 0.35–0.69), respectively. The median TTR was 51.7% (IQR, 30.6–70.1%) and only 25.1% had a TTR ≥70%. Age was ≥70 years (OR, 0.72; 95% CI, 0.55–0.94; P=0.015), bleeding history (OR 0.48; 95% CI, 0.23–0.89; P=0.029), the use of a single drug (OR, 0.62; 95% CI, 0.42–0.92; P=0.016), more than drug (OR, 0.60; 95% CI, 0.41–0.88; P=0.009), and lack of assessment of bleeding risk (OR, 0.72; 95% CI, 0.54–0.97; P=0.033) were associated with TTR <70% (INR 2.0–3.0). Coronary heart disease (CHD) and peripheral artery disease (PAD) (OR, 0.69; 95% CI, 0.52–0.90; P=0.007) and diabetes mellitus (OR, 0.79; 95% CI, 0.62–0.99; P=0.044) were associated with increased variability in INR (SDINR ≥0.5).ConclusionsIn Chinese patients with NVAF, warfarin anticoagulation was associated with lower TTR and less stable anticoagulation than in current guidelines, and risk factors for reduced safety and efficacy were identified.

How to Generate a More Accurate Laboratory-Based International Normalized Ratio: Solutions to Obtaining or Verifying the Mean Normal Prothrombin Time and International Sensitivity Index.

Although the landscape of anticoagulation therapy is evolving, vitamin K antagonists (VKAs) such as warfarin remain an anticoagulant of choice for many clinicians and their patients. Nevertheless, management of VKA therapy remains challenging, largely because of patient variability and drug and food interactions; thus, VKA dosing has to be personalized. This is achieved by regular monitoring using a test called the prothrombin time (PT), mathematically converted to an international normalized ratio (INR). The INR system is meant to harmonize laboratory test results by taking into account reagent and instrumentation variability that is otherwise expected to give rise to variable PT values, but which should accordingly lead to less variable INR values. Of clinical importance, too low an INR is suggestive of increased thrombotic risk and typically means the VKA dose should be increased, whereas too high an INR is suggestive of increased bleeding risk and typically means the VKA dose should be temporarily withheld and/or decreased. However, evidence continues to show that variability in INR values between laboratories remains unacceptably high. Given that modern instrumentation provides for robust analytical values-meaning highly reproducible intralaboratory clotting times or PTs in this case-the most likely cause of high INR variability is inconsistency in the INR test components-meaning the MNPT (mean normal PT) and ISI (international sensitivity index) values used by laboratories to generate a given INR. In other words, there are doubts as to the accuracy of some INR values because there are corresponding doubts about the accuracy of MNPT and/or ISI values that have been assigned by some laboratories for their reagent/instrument combination. The current report is intended to provide some solutions around the problems of inaccurate INRs, ISIs, and MNPTs, thus aiming to drive laboratory INRs closer to "truth," and thus promote better patient management. The novel strategies include a primary process of transference to obtain/verify MNPT and/or ISI values for a new reagent using an existing reagent as reference, and a secondary process whereby external quality assessment data can be used to correct bias or existing errors in assigned MNPT and/or ISI values.

Clinical usefulness of the SAMe-TT2R2 score: A systematic review and simulation meta-analysis.

BackgroundVitamin K antagonist (VKA) therapy is safer and more effective when patients have a high time within the therapeutic range and low international normalised ratio variability. The SAMe-TT2R2 score aims to identify those at risk for poor VKA control.ObjectivesTo evaluate the predictive value and clinical usefulness of the SAMe-TT2R2 score to identify those at risk for poor VKA control.MethodsWe performed a systematic review in MEDLINE and Embase for original research papers assessing the SAMe-TT2R2’s relation to poor TTR. We performed a meta-analysis where scores ≥ 2 and ≥ 3 predicting TTR < 70%. When studies evaluated other cutoffs for TTR or SAMe-TT2R2, they were harmonised by multiple simulations with patient characteristics from the individual studies, if the data were available.Results16 studies were identified and used in the meta-analysis: 4 and 2 times directly, 8 and 8 times harmonised for scores ≥ 2 and ≥ 3, respectively (not all studies provided information about both cutoffs). The sensitivities and specificities were too heterogeneous to pool. The positive likelihood ratios were 1.25 (1.14-1.38) for a score ≥ 2, and 1.24 (1.09-1.40) for a score ≥ 3; the negative ones were 0.87 (0.82-0.93) and 0.96 (0.91-1.02), respectively. This shows that the post-test probabilities hardly differ from the prior probability (prevalence).ConclusionThe SAMe-TT2R2 score does predict low TTR, but the effect is small. Its effect on individual patients is too limited to be clinically useful.

Population Impact of Drug Interactions with Warfarin: A Real-World Data Approach.

To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels. Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 (N = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t-test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3). Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%). Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users.

Predictors of International Normalized Ratio Variability in Patients With Atrial Fibrillation Under Warfarin Therapy.

Variability in the international normalized ratio (INR) of prothrombin time has been suggested to be related to outcome in patients with atrial fibrillation (AF) under warfarin therapy, but its determinants remain unclear.Methods and Results:The study population consisted of 626 AF patients under warfarin therapy in the Shinken Database (n=22,230). INR variability was calculated by Fihn's method. Determinants of high log INR variability (defined as over mean+standard deviation) were determined by logistic regression analyses. Symptomatic heart failure (odds ratio [OR] 3.974, 95% confidence interval [CI] 2.510-6.292), older age (≥75 years old; OR 2.984, 95% CI 1.844-4.826) and severe renal dysfunction (eGFR <30 mL/min/1.73 m2; OR 3.918, 95% CI 1.742-8.813) were identified as independent predictors of high INR variability on multivariate logistic regression analysis. The determinants of INR variability in AF patients under warfarin therapy could assist Japanese clinicians in identifying patients likely to show unstable warfarin control irrespective of the definition of the target INR range.

Quality of oral anticoagulation with vitamin K antagonists in 'real-world' patients with atrial fibrillation: a report from the prospective multicentre FANTASIIA registry.

The efficacy and safety of oral anticoagulation (OAC) using the vitamin K antagonists (VKA) are closely associated with the quality of anticoagulation, reflected by time in therapeutic range (TTR). The SAMe-TT2R2 is a risk score developed to predict the quality of anticoagulation control among VKA users. To analyse the quality of anticoagulation and its clinical determinants based on different methods in a prospective cohort of atrial fibrillation patients on VKA treatment participating in the multicentre Spanish observational registry FANTASIIA. Estimated TTR was calculated from Rosendaal, direct method, international normalized ratio variability, and NICE criteria. Time in therapeutic range values were compared for those patients with a SAMe-TT2R2 score 0-2 and >2. One thousand four hundred and seventy patients were analysed (56.4% male, mean age 74.1 ± 9.5 years). Mean TTR was 61.5 ± 25.1 with Rosendaal and 64.7 ± 24.2 with direct method. There was a high correlation between both methods (ρ = 0.805). The prevalence of poor anticoagulation control was 55%. Diabetes mellitus [odds ratio (OR) 1.38; P = 0.008], peripheral artery disease (PAD, OR 1.62; P = 0.048), and HAS-BLED (OR 1.13; P = 0.022) were independently associated with TTR < 70%. SAMe-TT2R2 score 0-2 had a higher mean TTR than patients with SAMe-TT2R2 >2 (P = 0.044), with a specificity of > 90% for predicting TTR < 70%. Patients with TTR < 70% had higher risk of events (21.7 vs. 16.8%; P = 0.021). In a multicentre prospective registry, 55% of AF patients had poor anticoagulation control with diabetes mellitus, PAD, and HAS-BLED being independently associated with TTR < 70%. A high SAMe-TT2R2 scores had a high specificity for predicting a TTR < 70% as an indicator of poor quality anticoagulation.

Design and rationale for the WARFA trial: a randomized controlled cross-over trial testing the therapeutic equivalence of branded and generic warfarin in atrial fibrillation patients in Brazil

BackgroundWarfarin is a commonly used anticoagulant. Whether a given dose of the different formulations of Brazilian warfarin will result in the same effect on the international normalized ratio (INR) is uncertain. The aim of the WARFA trial is to determine whether the branded and two generic warfarins available in Brazil differ in their effect on the INR.MethodsWARFA is a cross-over RCT comparing three warfarins. The formulations tested are the branded Marevan® (Uniao Quimica/Farmoquimica) and two generic warfarin (manufactured respectively by Uniao Quimica Farmaceutica Nacional and Laboratorio Teuto Brasileiro). All of them were manufactured in Brazil, are available in all settings of the Brazilian healthcare system and were purchased from retail drugstores. Eligible participants had atrial fibrillation or flutter, had been using warfarin for at least 2 months with a therapeutic range of 2.0–3.0 and had low variability in INR results during the 1st period of the trial. Our primary outcome, for which we have an equality hypothesis, is the difference between warfarins in the mean absolute difference between two INR results, obtained after three and 4 weeks with each drug. Our secondary outcomes, that will be tested for inequality (except for the mean INR, which will be tested for equality), include the difference in the warfarin dose, and time in therapeutic range. Clinical events and adherence were also recorded and will be reported.DiscussionTo our knowledge, WARFA will be the first comparison of the more readily applicable INR results between branded and generic warfarins in Brazil. WARFA is important because warfarins are commonly switched between in the course of a chronic treatment in Brazil. Final results of WARFA are expected in May 2017.Trial registrationClinicalTrials.gov NCT02017197 . Registered 11 December 2013.

Patient-Specific Tailored Intervention Improves INR Time in Therapeutic Range and INR Variability in Heart Failure Patients

BackgroundMany patients with heart failure need anticoagulants, including warfarin. Good control is particularly challenging in heart failure patients, with <60% of international normalized ratio (INR) measurements in the therapeutic range, thereby increasing the risk of complications. This study aimed to evaluate the effect of a patient-specific tailored intervention on anticoagulation control in patients with heart failure. MethodsPatients with heart failure taking warfarin therapy (n = 145) were randomized to either standard care or a 1-time intervention assessing potential risk factors for lability of INR, in which they received patient-specific instructions. Time in therapeutic range (TTR) using Rosendaal's linear model was assessed 3 months before and after the intervention. ResultsThe patient-tailored intervention significantly increased anticoagulation control. The median TTR levels before intervention were suboptimal in the interventional and control groups (53% vs 45%, P = .14). After intervention the median TTR increased significantly in the interventional group compared with the control group (80% [interquartile range, 62%-93%] vs 44% [29%-61%], P <.0001). The intervention resulted in a significant improvement in the interventional group before versus after intervention (53% vs 80%, P <.0001) but not in the control group (45% vs 44%, P = .95). The percentage of patients with a TTR ≥60%, considered therapeutic, was substantially higher in the interventional group: 79% versus 25% (P <.0001). The INR variability (standard deviation of each patient's INR measurements) decreased significantly in the interventional group, from 0.53 to 0.32 (P <.0001) after intervention but not in the control group. ConclusionsPatient-specific tailored intervention significantly improves anticoagulation therapy in patients with heart failure.

Low target-INR anticoagulation is safe in selected aortic valve patients with the Medtronic Open Pivot mechanical prosthesis: long-term results of a propensity-matched comparison with standard anticoagulation.

To investigate the long-term results of a low international normalized ratio (INR)-anticoagulation program in selected patients after aortic valve replacement (AVR) with the Medtronic Open Pivot mechanical heart valve (OPMHV). From January 1993 to December 2012, 909 OPMHV valves were used for single AVR. Patients with preserved sinus rhythm and left ventricular function (Low-INR, n = 552), were managed to an INR of 1.5-2.5 and compared to patients (Standard-INR, n = 357) treated with standard anticoagulation (INR 2.5-3.5). Long-term outcome was analysed for survival and valve-related events, on propensity score matched pairs of 169 patients/group. Within a follow-up cumulating 3096 patient-years, 10- and 15-year survival was significantly better for Low-INR patients: 79% and 63% vs 63% and 34% ( P < 0.001). Multivariate analysis of late mortality identified older age [odds ratio (OR) = 1.05], chronic pulmonary disease (OR = 1.90) and coronary artery disease (OR = 1.57) as patient-related risk factors, and erratic INR (OR = 2.57) as anticoagulation-related factor. The linearized thromboembolic rate was 0.72%/patient-year in Low-INR patients, vs 0.87%/patient-year in Standard-INR patients ( P = 0.59), revealing INR variability as sole predictor (OR 3.54, 95% confidence interval (CI) 1.20-10.51, P = 0.022). The linearized bleeding incidence was respectively 0.61%/patient-year and 1.21%/patient-year for Low-INR and Standard-INR patients ( P = 0.04), retaining older age (OR 1.06, 95% CI 1.02-1.12, P = 0.009), hypertension (OR 2.06, 95% CI 1.00-4.25, P = 0.05) and erratic INR (OR 9.83, 95% CI 5.21-18.56, P < 0.001) as independent risk factors. This study demonstrated that application of an anticoagulation regimen, aiming a low INR, individualized to selected aortic OPMHV patients, is safe and effective over more than 20 years, without increasing the thromboembolic complication rate while lowering the haemorrhagic events. However, INR variability remains worrisome because of its deleterious effect on outcome.

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.