Factors Affecting Quality of Anticoagulation Control Among Patients With Atrial Fibrillation on Warfarin: The SAMe-TT2R2 Score

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Relationship of the SAMe-TT2 R2 Score to Poor-Quality Anticoagulation, Stroke, Clinically Relevant Bleeding, and Mortality in Patients With Atrial Fibrillation

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

Stroke prevention, achieved with oral anticoagulation therapy (OAT), is central to the management of patients with atrial fibrillation (AF). Well-managed OAT, as reflected by a long time in therapeutic range (TTR), is associated with good clinical outcomes. The SAME-TT2R2 score has been proposed to identify patients who will maintain a high average TTR on vitamin K antagonists (VKA) treatment. The objective of the study was to validate this score in a cohort of AF patients followed by an anticoagulation clinic. We applied the SAME-TT2R2 score to 1,089 patients with AF on VKAs followed by two anticoagulation clinics. The median TTR overall for the whole cohort was 73.0%. There was a significant decline in mean (or median) TTR in relation to the SAME-TT2R2 score (p=0.042). When the SAME-TT2R2 scores were categorized we find a TTR 74.0% for score ≤2 and 68.0% for score >2 (p=0.006). The rate of major bleeding events and stroke/TIA was 1.78×100 patient-years (pt-yrs) and 1.26×100 pt-yrs, respectively. No relationship exists between the SAME-TT2R2 score and adverse events. We describe the first validation of the SAME-TT2R2 score in AF patients where, despite an overall good quality of anticoagulation, the SAME-TT2R2 score is able to identify the patients who are less likely to do well on VKA therapy if this is the chosen OAT.

Patients with non-valvular atrial fibrillation (NVAF) have a substantial risk of stroke and thromboembolism compared with age-matched people in sinus rhythm. This risk ranges from less than 1% to more than 20% per year depending on associated comorbidities and demographic characteristics (1). Thus, the prime challenge facing physicians caring for patients with NVAF is to identify patients at substantial risk for stroke and thromboembolism, and provide appropriate antithrombotic treatment whether as primary or secondary prevention. This has led to the development of stroke risk stratification schema, such as the CHADS2 score, whereby ‘high risk’ patients can be targeted for oral anticoagulation therapy; this is despite limitations of simple risk scores (2, 3). Until recently the vitamin K antagonists (VKAs) were the only orally administered agents able proven to lower the risk of stroke and mortality in patients with NVAF, although these benefits were balanced against small changes in the annual rate of major haemorrhage, including intracranial bleeding (4, 5). One recent ‘real world’ nationwide cohort analysis found that the net clinical benefit (balancing stroke against intracranial haemorrhage) was only negative for warfarin compared to no treatment in ‘truly low risk’ patients, defined using the ESC guidelines (1). Given the improvement in efficacy and safety with the new oral anticoagulants, the net clinical benefit is likely to be even greater. The absolute reduction in stroke risk attributable to oral anticoagulation highlights the effectiveness of anticoagulation, which is even greater amongst elderly subjects. Nonetheless, treatment with VKAs has important caveats. Indeed, the optimal anticoagulation intensity for patients with NVAF has been a subject of debate, although anticoagulation intensities with international normalised ratios (INRs) between 2.0 and 3.0 appear to provide the best protection from stroke and death, when balanced against the risk of bleeding (6, 7). Even with the optimal anticoagulation intensity established, keeping patients in the VKAs therapeutic range has not been an easy task. In general, implementation of evidence in practice has been proved slow and incomplete in the field of stroke prevention in AF. As a result, a large proportion of patients at high risk are either not treated or suboptimally treated with VKAs. Thus, it become crucial to evaluate the quality of anticoagulation and the time in therapeutic range (TTR) emerged as the most promising index. The TTR is the ratio of estimated duration of anticoagulation intensity within a pre-determined range to total duration, and Rosendaal et al. designed a method to calculate TTR based on the assumption that anticoagulation intensity shifts linearly between any two consecutive measurements (8). TTR is recognised as a marker of the quality of anticoagulation control in patients taking VKAs, and used to demonstrate the effectiveness of patient education and self-monitoring (9, 10). Moreover TTR has been used to appraise the quality of anticoagulation in the VKA arms of randomised clinical trials that evaluated the efficacy of novel antithrombotic drugs. In the latter setting it become apparent that even in the ideal environment of clinical trials the mean time spent in the therapeutic range rarely exceeds 65% (11). In the current issue of Thrombosis and Haemostasis, Gallagher et al. (12) evaluated the association between TTR and the risk of stroke and mortality, in a study cohort that included 37,907 AF patients from the UK General Practice Research Database. The large sample size allowed the authors to compare outcomes of VKA users with different percentages of time spent within therapeutic range. The authors concluded that good anticoagulation control was associated with a reduction in the risk of stroke versus no therapy, whilst TTR was a strong predictor of the risk of stroke. Indeed, poorer anticoagulation control was generally associated with a much larger risk of stroke (12). Previous studies have reported similar results regarding the importance of TTR on the outcome of VKA-treated patients with NVAF. For example, in an ancillary analysis of the ACTIVE W trial the benefit of anticoagulation compared with antiplatelet therapy was demonstrated only at medical centres where the average TTR was above 65% (the mean TTR for all patients in the study was 63.4%) (13). Similarly, a metaanalysis that included data from 21 studies and a total of 6,248 patients concluded that in patients with NVAF, the risk of ischaemic stroke with insufficient VKA anticoagulation (defined as INR 3) are significantly higher relative to patients with AF maintained within the recommended INR (14). Beyond the anticipated concluding remarks, the study by Gallagher et al. (12) has important unique points, including the use of data from the ‘real world’ practice. Until now, most data on the impact of TTR on the outcome of VKA-treated patients have come from the VKA arms of randomised clinical trials (15). Secondly, in this ‘real

The SAMe-TT2R2 score and quality of anticoagulation in atrial fibrillation: a simple aid to decision-making on who is suitable (or not) for vitamin K antagonists.

Background and PurposeAdvantages of new oral anticoagulations may be greater in atrial fibrillation (AF) patients of poor anticoagulation control with warfarin. The SAMe-TT2R2 scoring system, based on clinical variables, was recently developed to aid in identifying these patients. In this study, we investigated the association of this clinical composite score with genetic factors related warfarin dosing and the quality of anticoagulation control.MethodsClinical and genetic data were collected from 380 consecutive Korean patients with AF (CHA2DS2-VASc score, 3.5±1.8) who were followed for an average of 4 years. We evaluated factors associated with time in therapeutic range (TTR, INR 2-3), including the CYP2C9 and VKORC1 genotypes and the SAMe-TT2R2 score (Sex female, Age <60 years, Medical history [>two co-morbidities], Treatment [interacting drugs, e.g., amiodarone], Tobacco use within 2 years [doubled], and Race non-white [doubled]).ResultsThe average SAMe-TT2R2 score was 3.4±0.9, range 2-7; and 153 patients (40.2%) had SAMe-TT2R2 scores ≥4. Time in specific INR ranges varied depending on the VKORC1 genotype but not with the CYP2C9 genotype or the SAMe-TT2R2 score. TTR was higher in patients with the VKORC1 1173C>T than in VKORC1 TT (61.7±16% vs. 56.7±17.4%, P=0.031). Multivariate testing showed that VKORC1 genotype but not the SAMe-TT2R2 score was significantly associated with labile INRs. There was no correlation between the SAMe-TT2R2 scores and pharmacogenetic data.ConclusionsA genetic factor, but none of the common clinical and demographic factors, as combined in the SAMe-TT2R2 score, was associated with the quality of anticoagulation control in Korean patients with AF.

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

Objective: To predict the quality of anticoagulation control in patients with atrial fibrillation (AF) receiving warfarin in Thailand. Materials and Methods: The present study retrospectively recruited Thai AF patients receiving warfarin for three months or longer between June 2012 and December 2017 in Central Chest Institute of Thailand. The patients were classified into those with SAMe-TT₂R₂ of 2 or less, and 3 or more. The Chi-square test or Fisher’s exact test was used to compare the proportion of the patients with poor time in therapeutic range (TTR) between the two groups of SAMe-TT₂R₂ score. The discrimination performance of SAMe-TT₂R₂ score was demonstrated with c-statistics. Results: Ninety AF patients were enrolled. An average age was 69.89±10.04 years. Most patients were persistent AF. An average CHA₂DS₂-VASc, SAMe-TT₂R₂, and HAS-BLED score were 3.68±1.51, 3.26±0.88, and 1.98±0.85, respectively. The present study showed the increased proportion of AF patients with poor TTR with higher SAMe-TT₂R₂ score. The AF patients with SAMe-TT₂R₂ score of 3 or more had a larger proportion of patients with poor TTR than those with SAMe-TT₂R₂ score of 2 or less with statistical significance when TTR was below 70% (p=0.03) and 65% (p=0.04), respectively. The discrimination performance of SAMe-TT₂R₂ score was demonstrated with c-statistics of 0.60, 0.59, and 0.55 when TTR was below 70%, 65% and 60%, respectively. Conclusion: Thai AF patients receiving warfarin had a larger proportion of patients with poor TTR when the SAMe-TT₂R₂ score was higher. The score of 3 or more could predict poor quality of anticoagulation control in those patients. Keywords: Time in therapeutic range, Poor quality of anticoagulation control, Warfarin, SAMe-TT₂R₂, Labile INR

Oral anticoagulation therapy with vitamin K antagonists (VKA) such as warfarin and acenocoumarol is recommended in patients with atrial fibrillation (AF) and risk factors for embolism. The quality of anticoagulation control with VKA may be assessed by the time in therapeutic range (TTR). In our country, there are no data available about the quality of anticoagulation in patients with AF. The primary goal of our study was to assess the level of effective anticoagulation in a multicenter network of anticoagulation clinics in Argentina, which included patients with nonvalvular AF (NVAF) treated with VKA oral anticoagulants. The TERRA trial is a multicenter, cross-sectional study involving 14 anticoagulation clinics that were invited to participate and recruit 100 consecutive patients with NVAF treated with VKA for more than 1 year. The international normalized ratio (INR) values were retrospectively obtained from patient charts, and TTR was calculated using the Rosendaal method. A total of 1190 patients were included in the analysis. Mean age was 74.9 ± 9.9 years, and 52.5% of the patients were male. Median TTR was 67.5% (interquartile interval 54-80). During 55% of the TTR, INR was >3. Interinstitution variability was substantial, with a range of 57.7% ± 17% to 87.7% ± 17%, P < .001. The 10th percentile of TTR was 41%, the 20th percentile was 50%, the 30th was 58%, and the 35th percentile was 60%. In 40% of patients, TTR was <70%. In this multicenter study, mean TTR values in patients with AF under VKA were similar to those in international therapeutic clinical trials (55%-65%). Marked variations among institutions were observed and, although average results obtained were high, one third of the patients exhibited a TTR below 60%. This cutoff value is conservative according to current recommendations, and guidelines suggest that when management with VKA cannot be improved, patients should be switched to direct oral anticoagulants. The addition of TTR calculation to clinical practice may help improve the quality of oral anticoagulation in patients with AF, thus improving anticoagulation outcomes.

Objective: To assess the major clinical factors affecting the quality of anticoagulation and evaluate the predictive value of the SAMe-TT2R2 score to identify patients who will achieve a high average time in therapeutic range (T.T.R.) with vitamin K antagonist (V.K.A.) treatment. Research design and methods: This observational, cross-sectional, retrospective and nationwide multicenter study included 1524 patients from the primary care setting with non-valvular atrial fibrillation receiving V.K.A. (≥12 months). We performed a bivariate analysis to identify factors individually associated with the T.T.R. and a multiple regression analysis to identify the independent predictive factors. For the validation of the SAMe-TT2R2 score, the receiver operating characteristic (R.O.C.) curve was calculated and the Hosmer–Lemeshow test was used to test calibration. Results: A total of 94.8% of patients received acenocumarol (4.8% warfarin). A progressive decrease in mean T.T.R. was found when the SAMe-TT2R2 score increased from 0 points (72.1 ± 17.1%) to 4 points (64.1 ± 23.2%), p < 0.001. Other risk scores (CHADS2 and CHA2DS2-VASc, HAS-BLED) were also associated with the mean T.T.R. We found a significant association between low T.T.R. and the following clinical factors: female sex, three or more comorbidities, amiodarone treatment, dietary habits, bleeding history and the intake of ≥7 tablets per day besides V.K.A. (p < 0.01). Regarding SAMe-TT2R2 score validation, the R.O.C. curve showed significant capability, although not high, of discriminating good anticoagulation control (T.T.R. ≥65%) with an area under the curve of 0.562 (95% C.I. 0.533–0.592, p < 0.001) which increased, remaining modest, to 0.594 (95% C.I. 0.564–0.624, p < 0.001) when the factors not included in SAMe-TT2R2 score were added. Conclusion: In this cohort, the SAMe-TT2R2 score had a significant, although modest, ability to assess the likelihood of good international normalized ration (I.N.R.) control, and its predictive value might slightly improve by adding other simple clinical factors. Further research is needed to refine the predictive scales.

There is no strong evidence on pharmacogenetics role on the quality of INR control after the initiation phase and on the maintenance of stable INR on the long term as measured by the time in therapeutic range (TTR). The benefit of a score such as SAMe-TT2R2 is that it can preemptively guide clinicians on whether to start the patient on warfarin or direct oral anticoagulant. To determine the association between genetic variants in CYP2C9, VKORC1, and CYP4F2 and TTR. To validate SAMe-TT2R2 score predictive ability on the quality of anticoagulation in Qatari patients. This is an observational nested case–control study that was conducted on a cohort of Qatari patients treated with warfarin with previously identified genotype for the CYP2C9, VKORC1, and CYP2F4. The sample size of this cohort was 148 patients. Mean TTR was 62.7 ± 21%. TTR was not significantly different among carriers of the CYP2C9*2 &*3, VKORC1(–1639G>A) or CYP4F2*3 compared to their non-carriers alleles. None of the factors in the SAMe-TT2R2 score had a significant effect on the TTR except for the female gender where TTR was significantly lower in females (n = 89) compared to males (n = 59) (59.6 ± 21% vs. 67.2 ± 20%, p = 0.03). Furthermore, patients with SAMe-TT2R2 score of zero had significantly better TTR compared to those with higher scores (76.5 ± 17% vs. 61.8 ± 21%, p = 0.04). Logistic regression analysis showed that high SAMe-TT2R2 score was the only statistically significant predicting factor of poor INR control (odds ratio (OR) 5.7, 95% confidence interval (CI) 1.1–28.3, p = 0.034). Genetic variants have no contribution to the quality of INR control. SAMe-TT2R2 score was predictive for the poor quality of anticoagulation in a cohort of Qatari patients.

The efficacy and safety of vitamin K antagonists (VKAs) as oral anticoagulants (OACs) depend on the quality of anticoagulation control, as reflected by the mean time in therapeutic range (TTR). Several factors may be involved in poor TTR such as comorbidities, high inter-individual variability, interacting drugs, and non-adherence. Recent studies suggest that gut microbiota (GM) plays an important role in the pathogenesis of cardiovascular diseases, but the effect of the GM on anticoagulation control with VKAs is unknown. In the present review article, we propose different mechanisms by which the GM could have an impact on the quality of anticoagulation control in patients taking VKA therapy. We suggest that the potential effects of GM may be mediated first, by an indirect effect of metabolites produced by GM in the availability of VKAs drugs; second, by an effect of vitamin K-producing bacteria; and finally, by the structural modification of the molecules of VKAs. Future research will help confirm these hypotheses and may suggest profiles of bacterial signatures or microbial metabolites, to be used as biomarkers to predict the quality of anticoagulation. This could lead to the design of intervention strategies modulating gut microbiota, for example, by using probiotics.

Chronic kidney disease (CKD) has been related to poor anticoagulation control and an increased risk of bleeding. This study aims to evaluate the association between impaired renal function (eGFR <60mL/min/1.73m2 ) and anticoagulation control in patients with non-valvular atrial fibrillation (AF) on vitamin K antagonists (VKA) therapy. We also assessed whether the predictive value of the SAMe-TT2 R2 score prevailed for subgroups both with and without CKD. This is an ancillary analysis of 1381 patients from the PAULA study, which was a cross-sectional, retrospective and nationwide multicenter study. A total of 370 patients had eGFR <60mL/min/1.73m2 . Anticoagulation control levels progressively worsened across each stage of CKD. Multiple linear regression analysis showed CKD as an independent predictor of time in therapeutic range (TTR). In the subgroup of patients with preserved renal function, female sex, diet affecting INR, polypharmacy and amiodarone were associated with poorer TTR. The SAMe-TT2 R2 score had a significant but modest predictive value for TTR<65% (AUC, area under the curve 0.558, P=.002). In the subgroup of patients with CKD, the SAMe-TT2 R2 (>2 points) showed no significant predictive capacity for TTR (AUC 0.528, P=.354). The average TTR was similar for both sexes (P=.255), but with a higher percentage of males subjects with TTR ≥65% (P=.013). Chronic kidney disease is associated with poor anticoagulation control in patients with non-valvular AF taking VKA. The SAMe-TT2 R2 score was not predictive of poor TTR in the subgroup with CKD, although a modest predictive value for poor TTR was found in those without CKD.