International Normalized Ratio Range Research Articles

Machine learning guided prediction of warfarin blood levels for personalized medicine based on clinical longitudinal data from cardiac surgery patients: a prospective observational study.

Warfarin is a common oral anticoagulant, and its effects vary widely among individuals. Numerous dose-prediction algorithms have been reported based on cross-sectional data generated via multiple linear regression or machine learning. This study aimed to construct an information fusion perturbation theory and machine learning prediction model of warfarin blood levels based on clinical longitudinal data from cardiac surgery patients. The data of 246 patients were obtained from electronic medical records. Continuous variables were processed by calculating the distance of the raw data with the moving average (MA ∆vki(sj)), and categorical variables in different attribute groups were processed using Euclidean distance (ED ǁ∆vk(sj)ǁ). Regression and classification analyses were performed on the raw data, MA ∆vki(sj), and ED ǁ∆vk(sj)ǁ. Different machine-learning algorithms were chosen for the STATISTICA and WEKA software. The random forest (RF) algorithm was the best for predicting continuous outputs using the raw data. The correlation coefficients of the RF algorithm were 0.978 and 0.595 for the training and validation sets, respectively, and the mean absolute errors were 0.135 and 0.362 for the training and validation sets, respectively. The proportion of ideal predictions of the RF algorithm was 59.0%. General discriminant analysis (GDA) was the best algorithm for predicting the categorical outputs using the MA ∆vki(sj) data. The GDA algorithm's total true positive rate (TPR) was 95.4% and 95.6% for the training and validation sets, respectively, with MA ∆vki(sj) data. An information fusion perturbation theory and machine learning model for predicting warfarin blood levels was established. A model based on the RF algorithm could be used to predict the target international normalized ratio (INR), and a model based on the GDA algorithm could be used to predict the probability of being within the target INR range under different clinical scenarios.

Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial.

Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was ₹1,26,830 in the PGT arm compared to ₹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was ₹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of ₹ 71,630 well below one time GDP threshold of WTP used. Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.

Optimizing warfarin dosing for patients with atrial fibrillation using machine learning

While novel oral anticoagulants are increasingly used to reduce risk of stroke in patients with atrial fibrillation, vitamin K antagonists such as warfarin continue to be used extensively for stroke prevention across the world. While effective in reducing the risk of strokes, the complex pharmacodynamics of warfarin make it difficult to use clinically, with many patients experiencing under- and/or over- anticoagulation. In this study we employed a novel implementation of deep reinforcement learning to provide clinical decision support to optimize time in therapeutic International Normalized Ratio (INR) range. We used a novel semi-Markov decision process formulation of the Batch-Constrained deep Q-learning algorithm to develop a reinforcement learning model to dynamically recommend optimal warfarin dosing to achieve INR of 2.0–3.0 for patients with atrial fibrillation. The model was developed using data from 22,502 patients in the warfarin treated groups of the pivotal randomized clinical trials of edoxaban (ENGAGE AF-TIMI 48), apixaban (ARISTOTLE) and rivaroxaban (ROCKET AF). The model was externally validated on data from 5730 warfarin-treated patients in a fourth trial of dabigatran (RE-LY) using multilevel regression models to estimate the relationship between center-level algorithm consistent dosing, time in therapeutic INR range (TTR), and a composite clinical outcome of stroke, systemic embolism or major hemorrhage. External validation showed a positive association between center-level algorithm-consistent dosing and TTR (R2 = 0.56). Each 10% increase in algorithm-consistent dosing at the center level independently predicted a 6.78% improvement in TTR (95% CI 6.29, 7.28; p < 0.001) and a 11% decrease in the composite clinical outcome (HR 0.89; 95% CI 0.81, 1.00; p = 0.015). These results were comparable to those of a rules-based clinical algorithm used for benchmarking, for which each 10% increase in algorithm-consistent dosing independently predicted a 6.10% increase in TTR (95% CI 5.67, 6.54, p < 0.001) and a 10% decrease in the composite outcome (HR 0.90; 95% CI 0.83, 0.98, p = 0.018). Our findings suggest that a deep reinforcement learning algorithm can optimize time in therapeutic range for patients taking warfarin. A digital clinical decision support system to promote algorithm-consistent warfarin dosing could optimize time in therapeutic range and improve clinical outcomes in atrial fibrillation globally.

Optimal INR Level in Nonvalvular Atrial Fibrillation Patients in Thailand: A Multi-Site Study

Background: Warfarin is a common drug for thromboembolic prevention in patients with nonvalvular atrial fibrillation (NVAF). However, hemorrhagic complications are also a concern. The optimal international normalized ratio (INR) level is different in each ethnicity. Objective: To establish the INR range with lowest all adverse event, optimal INR, in Thai NVAF patients from large data, nationwide Warfarin Registry Network (WaRN). Materials and Methods: The present study was a retrospective cohort study. It analyzed the data of 31,704 Thai NVAF patient between January 1, 2010 and December 31, 2020. The numbers of thromboembolic and bleeding events were correlated to INR level at the time of event. The six groups of INR range were defined as less than 1.5, 1.5 to 1.9, 2.0 to 2.5, 2.6 to 3.0, 3.1 to 3.5, and greater than 3.5. Results: The data from 797 warfarin clinics were analyzed with an observation period of 21,328.52 patient-years. The median duration of follow-up was 519 days (IQR 172, 1,183). Of the 31,407 patients, 277 patients experienced 319 thromboembolic events, and 3,398 patients experienced 4,860 bleeding events. The thromboembolic events were 4.92, 1.89, 0.86, 0.72, 0.39, 0.36 per 100 patient-years in INR range of less than 1.5, 1.5 to 1.9, 2.0 to 2.5, 2.6 to 3.0, 3.1 to 3.5, and more than 3.5, respectively. The bleeding events were 12.69, 9.51, 8.41, 15.35, 36.38, 125.03 per 100 patient-years in INR range of less than 1.5, 1.5 to 1.9, 2.0 to 2.5, 2.6 to 3.0, 3.1 to 3.5, and more than 3.5, respectively. The all-adverse events were 17.61, 11.40, 9.27, 16.07, 36.77, 125.39 per 100 patient-years in the INR range of less than 1.5, 1.5 to 1.9, 2.0 to 2.5, 2.6 to 3.0, 3.1 to 3.5, and more than 3.5, respectively. Conclusion: The incidence density of all-adverse events was lowest in INR range of 2.0 to 2.5. This range should be the optimal therapeutic INR level for Thai NVAF patient. However, the INR range can extend to 1.5 to 2.5 in clinical practice. Keywords: Optimal INR; Nonvalvular Atrial Fibrillation, Bleeding, Thromboembolism

Multichannel resonant acoustic rheometry system for quantification of coagulation of multiple human plasma samples

Resonant Acoustic Rheometry (RAR), a newly developed ultrasound-based technique for non-contact characterization of soft viscoelastic materials, has shown promise for quantitative viscoelastic assessment of temporally changing soft biomaterials in real time, and may be used to monitor blood coagulation process. Here, we report the development of a novel, multichannel RAR (mRAR) system for simultaneous measurements of multiple temporally evolving samples and demonstration of its use for monitoring the coagulation of multiple small-volume plasma samples. The mRAR system was constructed using an array of 4 custom-designed ultrasound transducers at 5.0 MHz and a novel electronic driving system that controlled the generation of synchronized ultrasound pulses for real time assessment of multiple samples simultaneously. As a proof-of-concept of the operation of the mRAR system, we performed tests using pooled normal human plasma samples and anti-coagulated plasma samples from patients treated with warfarin with a range of International Normalized Ratio (INR) values as well-characterized samples with different coagulation kinetics. Our results show that simultaneous tracking of dynamic changes in 4 plasma samples triggered by either kaolin or tissue factor was achieved for the entire duration of coagulation. The mRAR system captured distinct changes in the samples and identified parameters including the clotting start time and parameters associated with the stiffness of the final clots that were consistent with INR levels. Data from this study demonstrate the feasibility of the mRAR system for efficient characterization of the kinetic coagulation processes of multiple plasma samples.

Drug interactions between ALK inhibitors and warfarin with concurrent use of bucolome: a case report

BackgroundAlectinib, crizotinib, and ceritinib, are anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) that exhibit high protein binding, and their metabolism is associated with the cytochrome P450 (CYP) isoenzymes 2C9 or 3A4. The plasma protein binding rate of warfarin, which is used to prevent and treat venous thromboembolism, is also high. Warfarin is a racemate of S-warfarin and R-warfarin, which are metabolized by CYP2C9 and CYP3A4, respectively. Reports on the drug interactions between each of the above-mentioned ALK-TKIs and warfarin with concurrent use of bucolome are currently lacking.Case presentation.We report a case of a patient receiving warfarin and bucolome, whose international normalized ratio (INR) increased after sequential treatment with alectinib, crizotinib, and ceritinib. The patient was a 61-year-old man with a history of aortic valve regurgitation, who was receiving warfarin treatment following aortic valve replacement. Bucolome, which can enhance the effect of warfarin, was also used simultaneously. The patient was diagnosed with primary lung adenocarcinoma, and ALK rearrangement was detected during second-line chemotherapy. After progression of the disease with chemotherapy, sequential treatment with alectinib, crizotinib, and ceritinib was initiated. Pretreatment INR values were in the therapeutic range (target INR of 2–3) but increased to supratherapeutic levels each time after initiation of alectinib, crizotinib, or ceritinib treatment. Adjustment of warfarin dose or discontinuation of bucolome were necessary to maintain the therapeutic INR range. There were no serious bleeding events or substantial changes in dietary intake.Displacement of plasma protein binding or competitive inhibition of metabolism by alectinib, crizotinib, and ceritinib could increase the plasma concentration of the unbound form of warfarin, resulting in high INR values. In addition, alectinib, crizotinib, and ceritinib might cause displacement of bucolome from plasma proteins, followed by displacement of warfarin or inhibition of warfarin metabolism caused by the unbound form of bucolome.ConclusionsClose monitoring of INR and adjustment of warfarin dosage are needed during treatment with alectinib, crizotinib, or ceritinib in patients who receive warfarin with concurrent use of bucolome.

Warfarin Time in Therapeutic INR Range and Direct Oral Anticoagulant Adherence for Venous Thromboembolism Across the Spectrum of Weight and Body Mass Index: Findings from Veterans Health Administration.

The evidence of direct oral anticoagulants (DOACs) usage for venous thromboembolism (VTE) in patients at extremes of body weight or mass index is limited. In such situations, warfarin may be more frequently used. We investigated warfarin time in the therapeutic international normalized ratio range (TTR) and DOAC adherence based on the calculated proportion of days covered (PDC) by pill coverage from a DOAC prescription in patients with VTE across all body sizes. Using data from the Veterans Health Administration (VA), we identified first-time patients with VTE between 2013 and 2018 treated with warfarin or DOACs. We analyzed 28,245 patients with warfarin TTR (N = 10,167) or DOAC PDC(N = 18,078). For warfarin-treated patients after index VTE, mean TTR was lower over shorter treatment durations (TTR 30 vs TTR 180 [mean ± SD]: 43.8% ± 33.5% vs 58.8% ± 23.5%). Mean TTR over 180 days after VTE was lowest for patients <60 kg (TTR 180 [mean ± SD]: <60kg: 49.3% ± 24.2% vs ≥60 to <100 kg: 57.8% ± 23.4%; P < .0001). For DOAC-treated patients over 180 days after index VTE, mean PDC was lowest for patients <60 kg (PDC 180 [mean ± SD]: < 60kg: 76.9% ± 33.2% vs ≥ 60 to <100 kg: 83.6% ± 27.7%; P < .0001).Most DOAC-treated patients attained sufficient adherence across the body size spectrum while warfarin-treated patients <60kg were at risk for low TTR.

Does ramadan fasting affect the therapeutic and clinical outcomes of warfarin? a systematic review and meta-analysis.

Warfarin's therapeutic effect is affected by many factors, including diet modifications. The impact of Ramadan fasting on warfarin is controversial. The aim of this systematic review and meta-analysis was to investigate the effect of Ramadan fasting on patients taking warfarin. A literature search was done in PubMed, WOS, Scopus, and Embase from inception to May 24, 2021. All relevant studies measuring the international normalized ratio (INR), time in therapeutic range (TTR), or the number of patients within therapeutic range before, during, and after Ramadan were assessed by full-text screening for achieving all of the inclusion criteria. We used the Newcastle-Ottawa Scale for quality assessment and RevMan 5.4 software for meta-analysis. A total of five studies with 446 patients were included in the meta-analysis. The patients served as their own control. Our pooled analyses showed no significant difference during Ramadan compared to pre-Ramadan (MD: 0.08; 95% CI: - 0.00, 0.15; P = 0.06) and post-Ramadan (MD: - 0.00; 95% CI: - 0.14, 0.14; P = 1.00, respectively). There was only a significant increase in the risk ratio of supratherapeutic INR when comparing post-Ramadan vs. pre-Ramadan (RR: 1.69; 95% CI: 1.22, 2.33; P = 0.001). However, there was no significant risk for supratherapeutic INR during Ramadan compared to pre-Ramadan or post-Ramadan; the number of patients within the therapeutic range of INR during Ramadan compared to pre-Ramadan; and TTR during Ramadan, pre-Ramadan, and post-Ramadan. Ramadan fasting did not affect INR level, TTR, or the number of patients within the therapeutic range before, during, and after Ramadan. However, there was a possibility of achieving a supratherapeutic INR post-Ramadan compared to pre-Ramadan. Therefore, INR monitoring and warfarin dose adjustments accordingly are recommended after Ramadan.

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

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

Evaluation of an education program of patients undergoing oral anticoagulation treatment

Anticoagulants are used in the treatment and prophylaxis of thromboembolic diseases. Acenocoumarol is a widely prescribed oral anticoagulant in the World. However, because of the narrow therapeutic index and life-threatening complications, patients must be regularly and continuously followed-up. The acenocoumarol dose is set according to the International Normalized Ratio (INR) level in the blood. To evaluate the therapeutic impact of an education program on patients undergoing acenocoumarol treatment. A group of 28 patients how are using acenocoumarol for at least two months, were invited to participate in an educational program in the Department of Internal Medicine. We compared the population before and after education in terms of treatment knowledge. All patients knew the trade name for acenocoumarol, were aware that it should be taken always at the same time and were able to describe its action in simple words. Before the education, 22 patients (78.5%) were aware of the reason for a regular INR test, only 11 patients (39.2%) knew the target range of INR, 8 patients (28.5%) were aware that the over-on-counter medication can interact with the acenocoumarol and that they should inform their doctor before starting any medication, and 7 patients (25%) were aware of the importance of maintaining a steady dietary intake of vitamin K which is commonly found in green leafy vegetables. Eighteen patients (64.2%) were able to identify bleeding and bruising as signs to watch for. After the education, a significantly greater number of patients were able to identify the target range of INR ( P < 0.001), and the possibility of interaction with diet ( P < 0.001) and medications ( P < 0.001). The results of this study suggest that patients who participate in a structured educational program about acenocoumarol use understand more about certain factors essential to safe therapy.

Frequency of Achieving Target INR in Patient on Warfarin for Atrial Fibrillation

Background: Warfarin has long been established as the oral anticoagulant of choice. The benefits of warfarin depend on maintaining the International Normalized Ratio (INR). It has been shown that the optimal INR target range is 2-3 for AF patients. Very less number of patients had been reported to achieve and remain in that target INR range. The prevalence of AF in the general population is about 1.6% in women and 2.4% in men and is generally lower in Asian countries Aim: To determine the frequency of achieving target INR in patient on warfarin for atrial fibrillation. Methodology: This is cross sectional study conducted at national institute of cardio vascular disease, Karachi from 31st May 2016 30th November 2016.The sample size of the study were 111, and nonprobability convenience sampling technique was used. Results: Among study population 61 (54.9%) were male and 50(45%) female patients. Mean duration of atrial fibrillation was 3.44±0.97 years. The mean duration of warfarin taken was 11.34±3.96 months. INR (2-3) target achieved in 72(64.9%) patients. Significant association of achieved INR target was observed with duration of atrial fibrillation, duration of warfarin, hypertension, stroke, and Left ventricular dysfunction. Conclusion: Target of INR was achieved in 64.9% patients when these patients were given warfarin doses of 5.0 to 7.5 mg/day. Keywords: Achieving Target INR, Warfarin, Atrial Fibrillation.

Effects of a pharmacist-managed anticoagulation outpatient clinic in Taiwan: evaluation of patient knowledge, satisfaction, and clinical outcomes

ABSTRACT Objective: The study aimed to evaluate the improvement of patient knowledge of warfarin use, satisfaction with pharmacists, and the quality of international normalized ratio (INR) control after the implementation of an anticoagulant clinic (ACC) service. Methods: This was a prospective single-group pre- and post-comparison study. Patients who were at least 20 years of age and participated in a pharmacist-managed ACC service were enrolled from February 2012 to September 2015. Each participant completed a self-administered questionnaire before and after the ACC service to evaluate changes in warfarin knowledge. Another questionnaire was distributed after the ACC to evaluate participants’ satisfaction with the pharmacist service in the ACC. The INR levels before and after the ACC intervention were obtained to calculate the proportion of time spent in the therapeutic INR range (time in therapeutic range, TTR). Paired t-tests were used to compare changes in participants’ knowledge related to warfarin use. Multiple linear regressions were performed to explore the predictors associated with the participants’ knowledge scores and TTR after the ACC intervention. Results: One hundred and forty-eight participants were enrolled in this study. A significant improvement (31.5%,p<0.001) in the knowledge of warfarin use was observed at the end of the ACC intervention. The interaction between warfarin and food was the most confusing factor for participants in warfarin use. More than 95% of the participants perceived a positive value of the pharmacist-managed ACC service. However, the consultation fee was the least satisfactory of the ACC service. The average TTR increased from 51.0±34.3% to 78.6±24.5% (p<0.001) after the ACC service was implemented. Participants’ education levels and baseline knowledge scores were significant determinants associated with the knowledge improvement in the appropriate warfarin use (p<0.001). Conclusions: A pharmacist-managed ACC improved patient knowledge of warfarin use and INR control, and led to high satisfaction with the pharmacist service in the ACC in Taiwan. Pharmacists should focus on patients with lower education levels to facilitate their understanding of the appropriate warfarin use for better health outcomes.

Patient-related factors associated with oral anticoagulation control: a population-based cohort study.

Time in therapeutic range (TTR) of ≥70% is a commonly used indicator of optimal anticoagulation control. This study aimed to determine the patterns and predictors of anticoagulation control in a population-based cohort of new users of warfarin. This was a retrospective cohort study. All adults (age ≥18 years) who had been newly initiated on warfarin therapy between January 2006 and March 2011were selected from administrative health databases. TTR was calculated using the Rosendaal method. Multivariable logistic regression models were used to identify patient-related factors associated with optimal TTR. Predictors of patients spending >30% of time above and below the therapeutic international normalised ratio (INR) range were also examined. A total of 6032 patients were included in this study. The mean TTR was 54.1 ± 18.8%, and 82.3% of patients had subthreshold TTR (<70%). Compared with New Zealand Europeans, Māori and Pacific people had decreased odds of achieving optimal TTR and increased odds of spending >30% of time below the therapeutic INR range. Patients aged 65-74 years and 75 years or older had increased odds of achieving optimal TTR but decreased odds of spending >30% of time below the therapeutic INR range than those <65 years. Compared with those living in the least socioeconomically deprived areas, those living in the most deprived areas had decreased odds of achieving optimal TTR. Anticoagulation control with warfarin is suboptimal in routine care in New Zealand. Age, ethnicity and deprivation index were significant predictors of TTR. It is important to ensure equitable access to appropriate, high-quality care for those living in deprived areas and those from ethnic minority groups.

Optimal International Normalized Ratio Range for Asian Patients on Anticoagulation Therapy

Introduction: Despite the recent emergence of direct oral anticoagulants, the use of warfarin will continue in patients on warfarin with stable control, those with mechanical heart valves, antiphospholipid syndrome and significant renal impairment. Warfarin therapy is challenging because of its narrow therapeutic window. The aim is to administer the lowest effective dose to maintain the target International Normalized Ratio (INR) in order to minimize bleeding and thromboembolic complications. The optimal INR of 2.0-3.0 has been validated in Western populations but not in Asians. It is common belief that Asians on warfarin having more bleeding complications and results of retrospective small scale studies conducted in Asian populations suggested a lower therapeutic INR range. Hence a lower target INRs had been advocated.1Objective: To determine the optimal INR range associated with the lowest thromboembolism and bleeding rates for a large multi-ethnic Asian population receiving warfarin therapy in Singapore.Methods:A retrospective cohort study was conducted among adult patients receiving warfarin from Singapore General Hospital and National Heart Centre Singapore, between 1 January 2010 and 31 December 2014. These patients were closely followed up with tight reporting and recording of adverse events. Medical records from clinics, hospitalisation and emergency room visits in both centres were analysed for warfarin-related thromboembolism and bleeding events and INR values at time of events. Thromboembolic events included ischemic stroke, deep vein thrombosis (DVT) and pulmonary embolism (PE). Bleeding events were differentiated into major and minor bleeds according to the International Society on Thrombosis and Haemostasis criteria.Results: A total of 1216 patients (650 males, 566 females) with 12,784 patient-years were included in the study. Racial distribution was 79.2 % Chinese, 12.6% Malays, 6.6% Indians and 1.6% others. 89.2% of the patients were above 50 years old, with 48.8% aged between 51 to 70 years and 40.3 % aged between 71 to 100 years. Indications for warfarin were atrial fibrillation (57.3%), prosthetic heart valve replacement (16.9%), intracardiac thrombus (5.4%), venous thromboembolism (16.6%), ischaemic strokes (1.6%), rheumatic heart disease (1.4%) and others (0.8%).There were 1776 thromboembolic and bleeding events. The event rates were 2.7 per 100 patient-years for major bleeds, 3.8 per 100 patient-years for thromboembolic events and 7.4 per 100 patient-years for minor bleeds. Using the Poisson Regression analysis, the INR range of 2.01-2.60 was found to correspond with a lowest combined major bleeding and thromboembolism risk of 2.9% (figure 1). When analysed to obtained a bootstrapped (n=1,000) estimate of the rate of events by 1-unit INR ranges, given a usual “good” time in target range of 60% achieved by our anticoagulation clinic, we found that the 2.0-3.0 INR range had the minimum rate of major bleed and thromboembolism events (figure 2), accounting for uncertainty in actual INR values at adverse events. This finding is likely to be further reinforced if one accounts for uncertainty in the actual rate of events by INR range.Conclusion:The major bleeding rate of 2.7 per 100 patient years in this Asian population is consistent and not higher than reports in recent western population cohort studies2,3.The optimal INR range for Asian patients on anticoagulation therapy in Singapore was 2.01-2.60 by the Poisson Regression analysis. However, such a narrow target INR range will be challenging to implement in practice. Except for those at extreme risks of bleeding or thrombosis, the data from our bootstrapped analysis supports the use of the recommended INR range of 2-3 for Asians. Thus while Asians may have an increased sensitivity to warfarin in requiring lower dosages, the target therapeutic INR range of 2-3 remains.

Indonesian registry on atrial fibrillation (OneAF).

Background:Data on the optimal therapeutic international normalized ratio (INR) for non-valvular and valvular atrial fibrillation (AF) in Indonesia is currently unavailable. Therefore, we designed the Indonesian Registry on Atrial Fibrillation (OneAF) registry in order to seek a safe and beneficial range of INR in Indonesian patients with non-valvular and valvular AF.Methods/design:The OneAF registry is a nationwide collaboration of the Indonesian Heart Rhythm Society (InaHRS) enrolling all hospitals with cardiac electrophysiologists in Indonesia. It is a prospective, multicentre, nationwide, observational study aiming to recruit non-valvular and valvular AF patients in Indonesia. The registry was started in January 2020 with a planned 2 years of recruitment. There are 2 respondents for this registry: non-cohort and cohort respondents. Non-cohort registry respondents are AF patients at hospitals who fulfill inclusion and exclusion criteria but did not consent for a 24 month follow up. Whereas patients who consented for a 24 month follow up were included as cohort registry respondents. Key data collected includes basic sociodemographic information, symptoms and signs, medical history, results of physical examination and laboratory test, details of diagnostics and treatment measures and events.Results:Currently, a total of 1568 respondents have been enrolled in the non-cohort registry, including 1065 respondents with non-valvular AF (67.8%) and 503 respondents with valvular AF (32.2%). We believe that the OneAF registry will provide insight into the regional variability of anticoagulant treatment for AF, the implementation of rhythm/rate control approaches, and the clinical outcomes concerning cardiocerebrovascular events.Trial registration:Registered at clinicaltrials.gov (NCT04222868).

Use and assessment of knowledge of Vitamin K antagonist therapy in cardiac patients: A Tertiary Care Hospital-based survey

Background: Safety and efficacy of Vitamin K antagonists (VKAs), the most widely used oral anticoagulant (OAC), is monitored by therapeutic international normalized ratio (INR). The current study was conducted to evaluate the proportion of patients achieving therapeutic range INR and assessment of the knowledge, and awareness among patients regarding OAC therapy, as well as identification of the challenges in the monitoring of INR. Materials and Methods: This hospital-based, single-center cross-sectional study was conducted at a tertiary care hospital in Delhi. Patients on anticoagulation with VKAs were interviewed and their records were reviewed. Information on sociodemographic characteristics, history of cardiac illness, INR range, knowledge, and awareness regarding VKA therapy were analyzed. Data management was done via CSPro and statistical analysis via STATA 13.0. Results: A total of 86 patients were evaluated. The mean age of the study participants was 49 ± 14.9 years. Only 29.1% of the study group achieved therapeutic INR. Overall awareness and knowledge regarding the need for VKA therapy, ideal INR range, complications of poor monitoring, and dietary restrictions were in the range of 31%–48%. Conclusion: Poor INR control is prevalent in Indian patients on VKAs therapy. Although the future practice may move toward newer anticoagulants, a substantial proportion of our population may still need VKAs. Hence, there is a need for improving the knowledge and awareness of patients on VKA therapy to improve therapeutic effectiveness.

Self-care training and informational support of patients with a mechanical heart valve on the international normalized ratio and bleeding complications.

AimThe aim of the study was to determine the effect of self-care training and informational support of patients with a mechanical heart valve on the international normalized ratio (INR) and bleeding complications.Material and methodsDesign: A quasi-experimental study. Participants were recruited via convenience sampling and were randomly divided into two groups: control (n = 80) and intervention (n = 80). Participants in the control group received only routine training; in addition, the intervention group received 6 sessions of self-care training and 6 months of informational support. Monthly the level of INR and incidence of bleeding were determined. Data were analyzed using the independent t-test and χ2 in SPSS16 software at a significance level of 0.05.ResultsDuring 6 months of follow-up, except for the third month, the frequency of INR levels in the therapeutic target range (2.5–3.5) in the intervention group was significantly higher than that in the control group (p < 0.05). Also in the intervention group, the incidence of bleeding complications was lower than that in the control group, but this difference was not statistically significant (p > 0.05).ConclusionsProper self-care training and informational support in patients with mechanical heart valve replacement have positive results. By maintaining self-care, the level of a therapeutic target range of INR can be maintained and the incidence of bleeding complications can be reduced.

Developing and Validating a Clinical Warfarin Dose-Initiation Model for Black-African Patients in South Africa and Uganda.

Warfarin remains the oral anticoagulant of choice in sub-Saharan Africa. However, dosing is challenging due to a highly variable clinical response for a given dose. This study aimed to develop and validate a clinical warfarin dose-initiation model in sub-Saharan Black-African patients. For the development cohort, we used data from 364 patients who were recruited from 8 outpatient clinics and hospital departments in Uganda and South Africa (June 2018-July 2019). Validation was undertaken using the International Warfarin Pharmacogenetics Consortium (IWPC) dataset (690 black patients). Four predictors (age, weight, target International Normalized Ratio range, and HIV status) were included in the final model, which achieved mean absolute errors (MAEs; mean of absolute differences between true dose and dose predicted by the model) of 11.6 (95% confidence interval (CI) 10.4-12.8) and 12.5 (95% CI 11.6-13.4) mg/week in the development and validation cohorts, respectively. Two other clinical models, IWPC and Gage, respectively, obtained MAEs of 12.5 (95% CI 11.3-13.7) and 12.7 (95% CI 11.5-13.8) mg/week in the development cohort, and 12.1 (95% CI 11.2-13.0) and 12.2 (95% CI 11.4-13.1) mg/week in the validation cohort. Compared with fixed dose-initiation, our model decreased the percentage of patients at high risk of suboptimal anticoagulation by 7.5% (1.5-13.7%) and 11.9% (7.1-16.8%) in the development and validation cohorts, respectively. The clinical utility of this model will be tested in a prospective study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? ☑ Warfarin dosing remains challenging due to a highly variable clinical response for a given dose. WHAT QUESTION DID THIS STUDY ADDRESS? ☑ Can a clinical dose-initiation model be developed and validated for sub-Saharan Black-African patients? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? ☑ We have developed the first warfarin dose-initiation clinical model for Black-African patients in Uganda and South Africa. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? ☑ We will be implementing and validating this model in a prospective cohort to inform future large-scale implementation. More optimized dosing should improve the quality of warfarin anticoagulation in these two developing countries.

Building a predictive model for warfarin dosing via machine learning

Abstract Background Warfarin titration via International Normalised Ratio (INR) monitoring can be a challenge for patients on long term anticoagulation due to its multiple drug interactions, long half life and patient's individual reponse, yet critically important due to its narrow therapeutic index. Machine learning may have a role in learning and replicating existing warfarin prescribing practices, to be potentially incorporated into an automated warfarin titration model. Purpose We aim to explore the feasibility of using machine learning to develop a model that can learn and predict actual warfarin titration practices. Methods A retrospective dataset of 4,247 patients with 48,895 data points of INR values were obtained from our institutional database. Patients who had less than 5 visits recorded, invalid or missing values were excluded. Variables studied included age, warfarin indication, warfarin dose, target INR range, actual INR values, time between titration and time in therapeutic range (TTR as defined by the Rosenthal formula). The machine learning model was developed on an unbiased training data set (1,805 patients), further refined on a handpicked balanced validation set (400 patients), before being evaluated on two balanced test sets of 100 patients each. The test sets were handpicked based on the criteria of TTR (“in vs out of range”) and stability of INR results (“low vs high fluctuation”) (Table 1). Given the time series nature of the data, a Recurrent Neural Network (RNN) was chosen to learn warfarin prescription practices. Long-short term memory (LSTM) cells were further employed to address the problem of time gaps between warfarin titration visits which could result in vanishing gradients. Results A total of 2,163 patients with 42,622 data points were studied (mean age 65±11.7 years, 54.7% male). The mean TTR was 65.4%. The total warfarin dose per week as predicted by the RNN was compared with actual total warfarin dose per week prescribed for each patient in the test sets. The coefficient of determination for the RNN in the “in vs out of range” and “low vs high fluctuation” test sets were 0.941 and 0.962 respectively (Figure 1). Conclusion This proof of concept study demonstrated that a RNN based machine learning model was able to learn and predict warfarin dosage changes with reasonable accuracy. The findings merit further evaluation of the potential use of machine learning in an automated warfarin titration model. Funding Acknowledgement Type of funding source: None

Optimal INR level in elderly and non-elderly patients with atrial fibrillation receiving warfarin: a report from the COOL-AF nationwide registry in Thailand.

BackgroundAsian population are at increased risk of bleeding during the warfarin treatment, so the recommended optimal international normalized ratio (INR) level may be lower in Asians than in Westerners. The aim of this prospective multicenter study was to determine the optimal INR level in Thai patients with non-valvular atrial fibrillation (NVAF).MethodsPatients with NVAF who were on warfarin for stroke prevention were recruited from 27 hospitals in the nationwide COOL-AF registry in Thailand. We collected demographic data, medical history, risk factors for stroke and bleeding, concomitant disease, electrocardiogram and laboratory data including INR and antithrombotic medications. Outcome measurements included ischemic stroke/transient ischemic attack (TIA) and major bleeding. Optimal INR level was assessed by the calculation of incidence density for six INR ranges (< 1.5, 1.5–1.99, 2–2.49, 2.5–2.99, 3–3.49, and ≥ 3.5).ResultsA total of 2, 232 patients were included. The mean age of patients was 68.5 ± 10.6 years. The mean follow-up duration was 25.7 ± 10.6 months. There were 63 ischemic stroke/TIA and 112 major bleeding events. The lowest prevalence of ischemic stroke/TIA and major bleeding events occurred within the INR range of 2.0–2.99 for patients < 70 years and 1.5–2.99 for patients ≥ 70 years.ConclusionsThe INR range associated with the lowest risk of ischemic stroke/TIA and bleeding in the Thai population was 2.0–2.99 for patients < 70 years and 1.5–2.99 for patients ≥ 70 years. The rates of major bleeding and ischemic stroke/TIA were both higher than the rates reported in Western population.