Tacrolimus's Time Below Therapeutic Range Is Associated With Acute Pancreatic Graft Rejection and the Development of De Novo Donor-specific Antibodies.

Tacrolimus is pivotal in pancreas transplants but poses challenges in maintaining optimal levels due to recipient differences. This study aimed to explore the utility of time spent below the therapeutic range and intrapatient variability in predicting rejection and de novo donor-specific antibody (dnDSA) development in pancreas graft recipients. This retrospective unicentric study included adult pancreas transplant recipients between January 2006 and July 2020. Recorded variables included demographics, immunosuppression details, HLA matching, biopsy results, dnDSA development, and clinical parameters. Statistical analysis included ROC curves, sensitivity, specificity, and predictive values. A total of 131 patients were included. Those with biopsy-proven acute rejection (BPAR, 12.2%) had more time (39.9% ± 24% vs. 25.72% ± 21.57%, p = 0.016) and tests (41.95% ± 13.57% vs. 29.96% ± 17.33%, p = 0.009) below therapeutic range. Specific cutoffs of 31.5% for time and 34% for tests below the therapeutic range showed a high negative predictive value for BPAR (93.98% and 93.1%, respectively). Similarly, patients with more than 34% of tests below the therapeutic range were associated with dnDSA appearance (38.9% vs. 9.4%, p = 0.012; OR 6.135, 1.346-27.78). In pancreas transplantation, maintaining optimal tacrolimus levels is crucial. Suboptimal test percentages below the therapeutic range prove valuable in identifying acute graft rejection risk.

Blood Pressure Time in Target Range and its Impact on Clinical Outcomes.

PURPOSE OF REVIEW: To examine the concept of time in target range for blood pressure (BP) management, exploring its calculation methods, implications for patient outcomes, and potential use in patient care. RECENT FINDINGS: Recent post-hoc analyses of clinical trials and observational studies highlight the importance of BP time in target range in predicting cardiovascular outcomes. Higher time in target range correlates with reduced risks of major adverse cardiovascular events including heart failure, stroke, myocardial infarction and all-cause mortality. Additionally, longer time in target range decreases the risk of incident atrial fibrillation and risk of developing dementia. BP time in target range is a novel metric offering valuable insights into BP control and its impact on clinical outcomes. Higher time in target range is consistently associated with better cardiovascular outcomes across various patient populations. However, the clinical application of BP time in target range requires further investigation through prospective clinical trials and real-world studies. Integrating wearable devices for continuous BP monitoring could enhance the practical utility of BP time in target range in hypertension management.

Pharmacogenetics of warfarin dosing in Chinese adults with nonvalvular atrial fibrillation.

BACKGROUND: The guide for the use of genotype-guided warfarin dosing in patients for the treatment of non-valvular atrial fibrillation (AF) is still lacking. AIM: We aimed to evaluate whether genotype-guided warfarin dosing is superior to conventional clinical dosing for the outcomes of interest in Chinese patients. METHOD: Our study consisted of 508 newly recruited and 471 existing Chinese AF patients. Among the total 979 patients, 585 patients received their dose of warfarin determined by a genetic and clinical factor (gene group), while the remaining 394 patients whose dosing was determined empirically in control group. We incorporated CYP2C9 and VKORC1 genotypes into the gene group. The international normalized ratio (INR) measurement and standard protocols were used for further dose adjustment in both groups. The primary outcomes were the percentage of time in the therapeutic range (%TTR) and INR during 12-month follow-up. Secondary safety outcome included bleeding and thrombotic events. RESULTS: Compared with the control group, the average TTR of the gene group was higher [68.4 ± 20.6% vs 48.5 ± 21.6%, P < 0.001]. The average INR monitoring times to reach the therapeutic time in the gene group was lower (P < 0.001). The risk ratios (RR) for cumulative incidence of total bleeding events, minor bleeding events, gastrointestinal bleeding, and intracerebral bleeding events were not significantly different between the two groups (P > 0.05). Comparing to the analysis using existing 471 patients, the analysis using total 979 patients showed that the gene group experienced a lower (RR 0.4 (95% CI 0.2 to 0.8), P = 0.008) incidence of cumulative ischemic stroke. CONCLUSION: Genotype-guided warfarin administration increases the average TTR, reaches higher TTR levels in the early anticoagulant phase, and significantly reduces the risk of ischemic stroke events.

A regional anticoagulation program improves safety and outcomes for both children and adults.

BACKGROUND: Evidence-based anticoagulation programs usually serve a local, adult patient population. Here we report outcomes for a regional combined pediatric-adult program. AIMS: The aims of this study were: (1) Compare the pre- vs. post-implementation quality of therapy (% time in therapeutic range (%TTR) and compliance). (2) Assess anticoagulant-relevant outcomes (bleeding and thrombotic complications). METHODS: Data were collected for the years 2014-2019. Rosendaal linear interpolation was used to calculate %TTR. Bleeding complications were categorized using ISTH-SSC standard nomenclature and new thrombotic events were reviewed. RESULTS: The patients were divided into a long-term warfarin group (N = 308), 80.2% of whom had cardiac-related therapeutic indications (median age 24y), and a second group (N = 114) comprised of short-term and non-warfarin long-term anticoagulation (median age 16y). Median %TTR for those on long-term warfarin was 78.9%. The incidence of major and clinically relevant non-major bleeding events was 1.65 and 2.43 /100 person-years of warfarin use, respectively. Thromboembolism (TE) incidence was 0.78/100 patient-years of warfarin use. Neither bleeding nor thrombosis was associated with %TTR (p = 0.48). Anticoagulant indication was the only variable associated with bleeding risk (p = 0.005). The second group had no on-therapy TE events but 7.9% experienced bleeding. Complete data were available for a randomly sampled pre-program warfarin group (N = 26). Median %TTR improved from 17.5 to 87% pre- vs. post-implementation. Similarly, compliance (defined as ≥ 1 INR/month) improved by 34.3%. CONCLUSIONS: In conclusion, this program significantly improved and sustained %TTR and compliance. The lack of association between bleeding and thrombosis events and %TTR may be related to the high median %TTR (> 70%) achieved by this approach.

Higher OAK (Oral Anticoagulation Knowledge) score at baseline associated with better TTR (Time in Therapeutic Range) in patients taking warfarin.

A lack in patient knowledge of warfarin therapy is associated with poor adherence. This knowledge gap may result in a lower INR Time in Therapeutic Range (TTR). To investigate association between patient anticoagulation knowledge and warfarin control. Michigan Anticoagulation Quality Improvement Initiative (MAQI2) is a Blue Cross Blue Shield of Michigan sponsored consortium of six anticoagulation management services. Patients prescribed warfarin at two MAQI2 sites completed a voluntary Oral Anticoagulation Knowledge (OAK) questionnaire at warfarin initiation and 6-month follow-up. The results of 20 OAK questions and TTRs (excluding 1st month post-initiation) were compared using chi-square tests, t-tests and multivariate analysis adjusting for SAMe-TT2R2 and days on warfarin. Of 1836 surveys distributed at warfarin initiation, 481 (26.2%) patients completed the baseline questionnaire (within 1 month post-initiation): mean OAK score: 14.6 ± 3.4. Of those, 147 (30.6%) completed 6-month follow-up surveys (OAK: 12.7 ± 5.8). Patients with TTR ≥ 70% at baseline scored higher on OAK tests than patients with TTR < 70% in unadjusted analyses (15.1 ± 3.2 v. 14.2 ± 3.5, p = 0.003) and adjusted analysis (p = 0.020). There was no unadjusted or adjusted difference in OAK scores at 6-month follow-up between patients with TTR ≥ 70% and TTR < 70%. For patients who completed baseline and follow-up surveys, there was a decrease of 2.4 points in OAK score between baseline and 6-month follow up (p < 0.001). Higher baseline, but not follow-up, OAK score is associated with better warfarin control and average OAK scores decreased between baseline and follow-up. Further studies are needed to determine what type of patient education may improve patient knowledge retention and warfarin control.

Higher tacrolimus trough levels and time in the therapeutic range are associated with the risk of acute rejection in the first month after renal transplantation.

BACKGROUND: Tacrolimus trough levels (C0) are used in most transplant centres for therapeutic drug monitoring (TDM) of tacrolimus (Tac). The target range of Tac C0 has been remarkably changed, with a target as low as 3-7 ng/ml in the 2009 European consensus conference and a target of 4-12 ng/ml (preferably to 7-12 ng/ml) following the second consensus report in 2019. Our aim was to investigate whether reaching early Tac therapeutic targets and maintaining time in the therapeutic range (TTR) according to the new recommendations may be necessary for preventing acute rejection (AR) during the first month after transplantation. METHODS: A retrospective study including 160 adult renal transplant patients (113 men and 47 women) with a median age of 36.3 (20-44) years was conducted between January 2018 and December 2019 at 103 Military Hospital (Vietnam). Tac trough levels were recorded in the first month, and episodes of AR were confirmed by kidney biopsy. Tac TTR was calculated as the percentage of time within the target range of 7-12 ng/ml, according to the 2019 second consensus report. Multivariate Cox analysis was performed to identify the correlation between the Tac target range and TTR with AR. RESULTS: In the first month after RT, 14 (8.8%) patients experienced AR. There was a significant difference in the incidence of AR between the Tac level groups of < 4, 4-7 and > 7 ng/ml (p = 0.0096). In the multivariate Cox analysis, after adjusting for related factors, a mean Tac level > 7 ng/ml was associated with an 86% decreased risk of AR compared with that of 4-7 ng/ml in the first month (HR, 0.14; 95% CI, 0.03-0.66; p = 0.0131). Every 10% increase in TTR was associated with a 28% lower risk of AR (HR, 0.72; 95% CI, 0.55-0.94; p = 0.014). CONCLUSION: Gaining and maintaining Tac C0 according to the 2019 second consensus report might reduce the risk of AR in the first month following transplantation.

Relationship between Chronic Kidney Disease, Time-in-Therapeutic Range, and Adverse Outcomes in Atrial Fibrillation: A post hoc Analysis from the AMADEUS Trial.

BACKGROUND: The benefit of anticoagulation therapy in atrial fibrillation (AF) and chronic kidney disease (CKD) remains controversial. We aimed to evaluate the impact of renal function on the quality of anticoagulation control, and the effects of both these factors on outcomes in AF. METHODS: Post hoc analysis of the AMADEUS trial. Trial-related outcomes were adjudicated and we studied the composite of first stroke/major bleeding/all-cause mortality, ischaemic stroke, major bleeding, all-cause mortality, and cardiovascular mortality. RESULTS: We included 2,282 vitamin K antagonist (VKA)-treated patients {n = 787 (34.5%) females; median age 72 (interquartile ranges [IQR] 64-77) years}. Median follow-up was 365 (IQR 189-460) days. There were 1,922 (84.2%) non-CKD and 360 (15.8%) CKD patients. Renal function was inversely correlated with time-in-therapeutic range (r = -0.047, p = 0.025). There was no statistical difference in terms of crude study outcomes based on renal function. Multivariable regression analysis demonstrated that moderate renal failure with estimated glomerular filtration rate of less than 60 mL/min/1.73 m2 (p = 0.032) and percentage of time-in-therapeutic range (p = 0.011) were independent predictors for the composite outcome of stroke, major bleeding, and all-cause mortality. CONCLUSION: Deteriorated renal function has a small negative impact on the quality of anticoagulation control with VKA which is linked to poor outcomes in AF. However, moderate renal failure itself was an independent risk factor for increased risk of stroke, major bleeding, and all-cause mortality amongst patients with AF.

Variables affecting the quality of anticoagulation in atrial fibrillation patients newly initiating vitamin K antagonists: insights from the national and multicentre SULTAN registry.

AIMS: Vitamin K antagonists (VKAs) are effective drugs reducing the risk for stroke in atrial fibrillation (AF), but the benefits derived from such therapy depend on the international normalized ratio (INR) maintenance in a narrow therapeutic range. Here, we aimed to determine independent variables driving poor anticoagulation control [defined as a time in therapeutic range (TTR) <65%] in a 'real world' national cohort of AF patients. METHODS AND RESULTS: The SULTAN registry is a multicentre, prospective study, involving patients with non-valvular AF from 72 cardiology units expert in AF in Spain. At inclusion, all patients naïve for oral anticoagulation were started with VKAs for the first time. For the analysis, the first month of anticoagulation and those patients with <3 INR determinations were disregarded. Patients were followed up during 1 year. A total of 870 patients (53.9% male, the mean age of 73.6 ± 9.2 years, mean CHA2DS2-VASc and HAS-BLED of 3.3 ± 1.5 and 1.4 ± 0.9, respectively) were included in the full analysis set. In overall, 7889 INR determinations were available. At 1-year, the mean TTR was 63.1 ± 22.1% and 49.2% patients had a TTR < 65%. Multivariate Cox regression analysis showed that coronary artery disease [odds ratio (OR) 1.81, 95% confidence interval (CI) 1.14-2.87; P = 0.012] and amiodarone use (OR 1.54, 95% CI 1.01-2.34; P = 0.046) were independently associated with poor quality of anticoagulation (TTR <65%). CONCLUSION: This study demonstrated that the quality of anticoagulation in AF patients newly starting VKAs is sub-optimal. Previous coronary artery disease and concomitant use of amiodarone were identified as independent variables affecting the poor quality of VKA therapy during the first year.

Extending INR testing intervals in warfarin patients at a multi-center anticoagulation clinic.

Warfarin has been used as an anticoagulant by millions of patients due to its effectiveness, availability, and low cost. Evidence on the safe extension of international normalized ratio (INR) testing frequency remains an area of interest, especially during the recent COVID-19 pandemic. The purpose of this study is to safely extend INR testing intervals in patients throughout a multisite, system-wide anticoagulation clinic. Updates were made to the pharmacist's collaborative practice agreement (CPA) and nurse protocol to optimize practice and allow INR testing interval extension up to a maximum of 8-weeks. The primary outcome was the change in duration between INR tests (INR testing interval) measured before and after providing staff education on clinic updates. The mean duration between INR tests (SD) was 23.69 days (11.29) in the pre-intervention period and 25.58 days (13.91) in the post-intervention period. During the COVID-19 pandemic (post2), intervals were extended further to 27.81 days (14.96), demonstrating a statistically significant increase in INR testing interval from pre-intervention to post-intervention and to post2 (p < 0.001 and p < 0.001, respectively). A secondary outcome indicated the mean time in therapeutic range (SD) showed no significant difference in pre-intervention 70.11% (25.95) versus post-intervention of 69.76% (25.69) with a difference of - 0.35% (29.93) (p = 0.956) or versus the post2 of 68.82% (27.20) with a difference of - 1.29% (33.20) (p = 0.120). This study showed that changes to the CPA and protocol allowed for a significant increase in INR testing interval while simultaneously maintaining a mean time in therapeutic range > 60% for the clinic population.

Blood pressure control measures and cardiovascular outcomes: a prospective hypertensive cohort.

PURPOSE: We investigated whether blood pressure (BP) control measures, visit-to-visit BP variability, and time in therapeutic range (TTR) are associated with future cardiovascular outcomes in hypertensive patients. MATERIALS AND METHODS: Among 1,408 hypertensive patients without cardiovascular disease, we prospectively evaluated the incident major cardiovascular events over 6 years. In newly diagnosed patients, antihypertensive drug treatment was initiated. We estimated two markers of on-treatment BP control, (1) visit-to-visit BPV as the coefficient of variation of office systolic BP (BP-CV), and (2) TTR calculated as the percentage of office systolic BP measurements within 120-140mmHg across visits. RESULTS: The hypertensive cohort (672 males, mean age 60 years, 31% newly diagnosed) had a mean systolic/diastolic BP of 142/87 mmHg. The mean number of visits was 4.9 ± 2.6, while the mean attained systolic/diastolic BP during follow-up was 137/79 mmHg using 2.7 ± 1.1 antihypertensive drugs. The BP-CV and TTR were 9.1 ± 4.1% and 45 ± 29%, respectively, and the incidence of the composite outcome was 8.3% (n = 117). After adjustment for relevant confounders and standardization to z-scores, BP-CV and TTR were associated with a 43% (95% CI, 27-62%) increase and a 33% (95% CI, 15-47%) reduction in the outcome. However, the joint evaluation of TTR and BP-CV in a common multivariable model indicated that a standardized change of TTR was associated with the outcome to a greater extent than BP-CV (mean hazard ratios of 30% vs. 24%, respectively). When combined with the higher BP standardized-CV quartile, the lower TTR quartile predicted the outcome by 2.3 times (95% CI, 1.1-5.4) compared to the inverse TTR and BP-CV quartile pattern. CONCLUSION: High BP-CV or low TTR was associated with future cardiovascular events in a cohort of treated hypertensive patients. As a determinant, the extent of TTR value appears greater than BP-CV when these measures are considered in the same multivariable model.

Time to Stable Therapeutic Range on Initiation of Warfarin as an Indicator of Control.

OBJECTIVES: Warfarin remains widely used with a time in therapeutic range (TiTR) above 65% recommended for best outcomes. Patients not achieving or maintaining this warfarin control may be better suited to alternate anticoagulants. Despite this, there is limited data defining a suitable trial time in patients initiating warfarin therapy, therefore the aim of this study was to determine the mean time to stable therapeutic range (TtSTR). MATERIALS AND METHODS: Retrospective data was collected for patients with atrial fibrillation enrolled in a dedicated warfarin program at a private pathology practice within 7 days of warfarin initiation. TiTR at specified timepoints was calculated and median TtSTR determined as defined by TiTR ≥ 65% over three months. Comparisons were made of populations with TtSTR above or below the median. RESULTS: The 566 patients included in the study had a mean TiTR of 64.9±16.5% at month three and median TtSTR of six months. Patients with TtSTR≤6 months achieved a mean TiTR of 68.9±12.8% at month two and maintained a TiTR over 75% from month 3 to 24. Patients with a TtSTR>6 months obtained a TiTR of 66.4±10.6% at month nine and continued to achieve lower TiTR throughout the 24 months study period. CONCLUSIONS: A majority of patients can achieve a stable TiTR above 65% within six months so review at six to nine months is likely to be a good indicator of warfarin control and to determine if patients should continue warfarin or switch to alternate anticoagulant therapy.

Comparison of Anticoagulation Quality between Acenocoumarol and Warfarin in Patients with Mechanical Prosthetic Heart Valves: Insights from the Nationwide PLECTRUM Study.

Vitamin K antagonists are indicated for the thromboprophylaxis in patients with mechanical prosthetic heart valves (MPHV). However, it is unclear whether some differences between acenocoumarol and warfarin in terms of anticoagulation quality do exist. We included 2111 MPHV patients included in the nationwide PLECTRUM registry. We evaluated anticoagulation quality by the time in therapeutic range (TiTR). Factors associated with acenocoumarol use and with low TiTR were investigated by multivariable logistic regression analysis. Mean age was 56.8 ± 12.3 years; 44.6% of patients were women and 395 patients were on acenocoumarol. A multivariable logistic regression analysis showed that patients on acenocoumarol had more comorbidities (i.e., ≥3, odds ratio (OR) 1.443, 95% confidence interval (CI) 1.081-1.927, p = 0.013). The mean TiTR was lower in the acenocoumarol than in the warfarin group (56.1 ± 19.2% vs. 61.6 ± 19.4%, p < 0.001). A higher prevalence of TiTR (<60%, <65%, or <70%) was found in acenocoumarol users than in warfarin ones (p < 0.001 for all comparisons). Acenocoumarol use was associated with low TiTR regardless of the cutoff used at multivariable analysis. A lower TiTR on acenocoumarol was found in all subgroups of patients analyzed according to sex, hypertension, diabetes, age, valve site, atrial fibrillation, and INR range. In conclusion, anticoagulation quality was consistently lower in MPHV patients on acenocoumarol compared to those on warfarin.

Clinical Impact of the Time in Therapeutic Range on Early Hospital Readmission in Patients with Acute Heart Failure Treated with Oral Anticoagulation in Internal Medicine.

Background and objectives: Patients with heart failure (HF) often present with non-valvular atrial fibrillation and require oral anticoagulation with coumarin anticoagulants such as acenocoumarol. The objective of this study was to evaluate the relationship between time in therapeutic range (TTR) and the risk of early readmission. Materials and Methods: A retrospective descriptive study was carried out on hospitalized patients with a diagnosis of HF between 2014 and 2018 who had adverse effects due to oral anticoagulation with acenocoumarol (underdosing, overdosing, or hemorrhage). Clinical, analytical, therapeutic, and prognostic variables were collected. TTR is defined as the duration of time in which the patient's International Normalized Ratio (INR) values were within a desired range. Early readmission was defined as readmission within 30 days after hospital discharge. Patients were divided into two groups depending on whether or not they had a TTR less than 60% (TTR < 60%) over the 6 months prior to the adverse event. Results: In the cohort of 304 patients, the mean age was 82 years, 59.9% of the patients were female, and 54.6% had a TTR < 60%. Patients with TTR < 60% had a higher HAS-BLED score (4.04 vs. 2.59; p < 0.001) and INR (6 vs. 5.31; p < 0.05) but lower hemoglobin (11.67 vs. 12.22 g/dL; p < 0.05). TTR < 60% was associated with early readmission after multivariate analysis (OR: 2.05 (CI 95%: 1.16-3.61)). They also had a higher percentage of hemorrhagic events and in-hospital mortality but without reaching statistical significance. Conclusions: Patients with HF and adverse events due to acenocoumarol often have poor INR control, which is independently associated with a higher risk of early readmission.

Analysis of the quality of anticoagulation with vitamin K antagonists in three clinical scenarios in Mexico.

INTRODUCTION: Vitamin K antagonists (VKA) are a therapeutic alternative in patients with venous thromboembolic disease; however, numerous factors affect their pharmacology. OBJECTIVE: To evaluate the quality of VKA anticoagulation at three different time periods in Mexico. METHODS: Prospective study, nested in patient cohorts at three different clinical scenarios between 2013 and 2019. Outpatients with indication for treatment with VKAs for at least 12 months were included. Patients were managed according to the criteria of the treating physician. RESULTS: Patient general characteristics were similar between groups, except for the VKA indication. The results of 4,148 patients and 38,548 INR assessments were analyzed. The times in therapeutic range during the three phases of the study and pooled data were significantly higher for the anticoagulation clinic. Only the number of patient visits was significantly associated with the results, unlike age, gender, and type of VKA. CONCLUSIONS: VKAs are widely used, but it is difficult for therapeutic goals to be achieved, especially in non-specialized clinical services. Creation of anticoagulation clinics is an urgent need for the Mexican health system.

INTRODUCCIÓN: Los antagonista de la vitamina K (AVK) son una alternativa terapéutica en los pacientes con enfermedad tromboembólica venosa; sin embargo, numerosos factores afectan su farmacología. OBJETIVO: Evaluar la calidad de la anticoagulación AVK durante tres diferentes periodos en México. MÉTODOS: Estudio prospectivo, anidado en cohortes de pacientes en tres escenarios clínicos entre los años 2013-2019. Se incluyeron pacientes no hospitalizados con indicación para recibir AVK por al menos 12 meses, quienes fueron manejados de acuerdo con el criterio del médico tratante. RESULTADOS: Las características generales de los pacientes fueron similares entre los grupos, excepto por la indicación para usar los AVK. Se analizaron los resultados de 4148 pacientes y 38 548 evaluaciones de INR. Los tiempos en rango terapéutico durante las tres fases del estudio y los datos acumulados fueron significativamente mayores en la clínica de anticoagulación. Solo el número de visitas de control de los pacientes se asoció significativamente con los resultados, a diferencia de la edad, el sexo y el tipo de AVK. CONCLUSIONES: Los AVK se utilizan ampliamente, pero es difícil alcanzar la meta terapéutica, sobre todo en servicios clínicos no especializados. La creación de clínicas de anticoagulación es una necesidad urgente en el sistema mexicano de salud.

Determinants of low-quality warfarin anticoagulation in patients with mechanical prosthetic heart valves. The nationwide PLECTRUM study.

Quality of warfarin therapy in patients with a mechanical prosthetic heart valve (MPHV) has been barely investigated. We analysed determinants of low time in the therapeutic range (TiTR <60%) in 2111 patients with MPHVs from the nationwide PLECTRUM study by the Italian Federation of Anticoagulation Clinics. Overall, 48·5% of patients had a TiTR of < 60%. At logistic regression analysis, arterial hypertension (odds ratio [OR] 1·502, P < 0·001), diabetes (OR 1·732, P < 0·001), heart failure (OR 1·484, P = 0·004), mitral site (vs. aortic) (OR 1·399, P = 0·006), international normalised ratio (INR) ranges of 2·5-3·5 (OR 2·575, P < 0·001) and 3·0-4·0 (OR 8·215, P < 0·001) associated with TiTR < 60%. TiTR is substantially suboptimal in MPHV patients, particularly in higher INR ranges.

Time in therapeutic range, quality of life and treatment satisfaction of patients on long-term warfarin for non-valvular atrial fibrillation: a cross-sectional study.

BACKGROUND: The use of warfarin in patients with non-valvular atrial fibrillation (NVAF) can be challenging. In this study, we evaluate the time in therapeutic range (TTR), health-related quality of life (HRQoL) and treatment satisfaction of patients on long-term warfarin for NVAF. The HRQoL and treatment satisfaction were compared based on the TTR. METHODS: A cross-sectional study was conducted among patients on warfarin for NVAF who attended the anticoagulant clinic of a tertiary cardiology referral center in Sarawak from 1st June 2018 to 31st May 2019. Patients' TTR was calculated by using Rosendaal technique, while their HRQoL and treatment satisfaction were assessed by using Short Form 12 Health Survey version 2 (SF12v2) and Duke Anticoagulant Satisfaction Scale (DASS), respectively. RESULTS: A total of 300 patients were included, with mean TTR score of 47.0 ± 17.3%. The physical component summary (PCS) and mental component summary (MCS) score of SF-12v2 were 47.0 ± 9.0 and 53.5 ± 9.6, respectively. The total score for DASS was 55.2 ± 21.3, while the score for limitations (L), hassles and burdens (H&B) and positive psychological impacts (PPI) were 18.0 ± 10.0, 15.6 ± 9.1 and 21.6 ± 5.9, respectively. Seventy-three (24.3%) patients had good TTR (≥ 60%), with mean of 70.2 ± 8.7%; while 227 (75.5%) patients with poor TTR had significantly lower mean of 39.5 ± 11.9% (p = 0.006). There was no significant difference in the score of PCS (p = 0.150), MCS (p = 0.919) and each domain of SF-12v2 (p = 0.184-0.684) between good and poor TTR, except for social functioning (p = 0.019). The total DASS score was also not significantly different between group (p = 0.779). Similar non-significant difference was also reported in all the DASS sub dimensions (p = 0.502-0.699). CONCLUSIONS: Majority of the patients on long-term warfarin for NVAF in the current study have poor TTR. Their HRQoL and treatment satisfaction are independent of their TTR. Achieving a good TTR do not compromise the HRQoL and treatment satisfaction. Therefore, appropriate measures should be taken to optimise INR control, failing which direct oral anticoagulant therapy should be considered.

Effect of SAMe-TT2R2 score and genetic polymorphism on the quality of anticoagulation control in Qatari patients treated with warfarin.

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.

Randomized controlled trial of genotype-guided warfarin anticoagulation in Chinese elderly patients with nonvalvular atrial fibrillation.

WHAT IS KNOWN AND OBJECTIVE: Warfarin is an oral anticoagulant which has been widely used to treat and prevent thromboembolic events. Managing warfarin therapy requires careful monitoring and dose titration. This randomized controlled study was designed to assess the effect of genotype-guided warfarin anticoagulation in Chinese elderly patients with nonvalvular atrial fibrillation. METHODS: 507 adults were randomized to receive initial dosing as determined by an algorithm containing genetic (VKORC1 and CYP2C9) plus clinical information or only clinical information. The primary endpoint was the time in therapeutic range (TTR) over 90 days. Secondary end points included haemorrhagic events, thrombotic events and mortality. RESULTS: The TTR was significantly different between genetic group and control group. The average TTR was (70.80 ± 24.39) % in the genotype-guided group as compared with (53.44 ± 26.73) % in the control group. This represents a difference of 17.36% (95% CI, 11.82 to 22.89, P < .001). The cumulative incidence of total haemorrhagic events, minor haemorrhagic events, gastrointestinal bleeding and intracerebral bleeding events was not significantly different between two groups (P > .05). Follow-up showed that the cumulative incidence of ischaemic stroke events occurred in the genetic group was significantly lower than that in the control group (2.39% vs 6.82%), and the genetic group had a significant lower risk than control group in cumulative incidence of ischaemic stroke events [HR 0.22, (95% CI 0.065 to 0.77), P < .05]. WHAT IS NEW AND CONCLUSION: Genotype-guided dosing could improve the average TTR, and follow-up result showed that genotype-guided therapy resulted in a significantly lower risk of ischaemic stroke events. Further research is required to focus on the clinical benefit of genotype-guided dosing.

The importance of time in therapeutic range in switching from vitamin K antagonist to non-vitamin K antagonist oral anticoagulants in atrial fibrillation.

AIMS: Patients with non-valvular atrial fibrillation (NVAF) receiving vitamin K antagonists (VKAs) with time in therapeutic international normalized ratio (INR) range (TTR) <70%, despite good adherence, are by guidelines recommended to switch to non-VKA oral anticoagulants (NOACs). The aim was to assess if patients are switched from VKA to NOAC when TTR is <70% in a real-world setting. METHODS AND RESULTS: Non-valvular atrial fibrillation patients receiving VKA (1 January 2010 to 31 December 2012) were identified in nationwide registries. Time in therapeutic range was calculated by the Rosendaal method by a minimum of three INR values. Time in therapeutic range of patients continuing VKA (non-switchers) were compared with patients switched from VKA to dabigatran or rivaroxaban (switchers), the only NOACs available at that time. Factors associated with switching were analysed in a multivariable logistic regression model. 7276 patients with NVAF receiving VKA were included; of these, 6437 (88.5%) patients continued VKA [57.9% male, median age 76.7 years (Q1-Q3 68.9-83.5)] and 839 (11.5%) switched to NOAC [54.0% male, median age 76.5 years (Q1-Q3 68.4-83.6)]. No significant differences in CHA2DS2-VASc and HAS-BLED scores were seen between the groups. The mean TTR for non-switchers was 64.0 [standard deviation (SD) 27.8] and 52.9 (SD 28.1) for switchers. Among non-switchers, 51% had a TTR <70% vs. 69% among switchers. 85% of patients with TTR <70%, were not switched contrary to recommendations. Time in therapeutic range <70% was associated with the switch [odds ratio 2.28, 95% confidence interval (1.92-2.72)]. CONCLUSION: A TTR below 70% was associated with switching from VKA to NOAC, yet by guidelines, most patients were still not switched.

Warfarin in nonvalvular atrial fibrillation-Time for a change?

Warfarin is the most commonly prescribed anticoagulant in hemodialysis (HD) patients with nonvalvular atrial fibrillation (NVAF). Recent trends show that Nephrologists are increasingly prescribing novel oral anticoagulants, despite the fact that no randomized clinical trials have been conducted in dialysis patients. Difficulties maintaining international normalized ratio in the therapeutic range, increased risk of intracranial hemorrhage and concerns regarding warfarin-induced vascular calcification and calciphylaxis may be responsible. Anticoagulation quality is poor in HD patients. A variety of factors contribute to this: increased antibiotic exposure; comorbid illness; decreased adherence and vitamin K deficiency. Attempts to address this with standardized protocols have been uniformly unsuccessful. In nonadherent patients, thrice weekly observed therapy improved quality. Low-dose vitamin K supplementation improves time in the therapeutic range (TTR) in those with normal kidney function and should be studied in HD patients given their high frequency of vitamin K deficiency. Vascular and valvular calcification associated with warfarin could result from reduced carboxylation of matrix Gla protein (MGP), a well-known inhibitor of vascular calcification. Multiple observational studies also link calciphylaxis to warfarin; warfarin-induced hypercoagulability and decreased carboxylation of MGP could explain this. A large observational study, two meta-analyses, and a systematic review in HD patients with NVAF showed reduced bleeding with apixaban compared to warfarin with similar efficacy in reducing stroke and systemic embolism. Given these results, apixaban is a reasonable alternative to warfarin for anticoagulation of HD patients with NVAF, especially in those with low TTR, until data from randomized clinical trials become available.