Therapeutic International Normalized Ratio Research Articles

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.

Assessment of Temporary Warfarin Reversal in Patients With Left Ventricular Assist Devices: the KVAD Study*

Patients with left ventricular assist devices (LVADs) require interruption of warfarin for invasive procedures, but parenteral bridging is associated with many complications. Four-factor prothrombin complex concentrate (4F-PCC) can temporarily restore hemostasis in patients undergoing anticoagulation with warfarin. This pilot study evaluated the strategy of using variable-dose 4F-PCC to immediately and temporarily reverse warfarin before invasive procedures without holding warfarin in patients with LVADs. The duration of effect of 4F-PCC on factor levels and time to reestablish therapeutic anticoagulation post procedure were assessed. Adult patients with LVADs and planned invasive procedures were enrolled from a single center. Warfarin was continued uninterrupted. The 4F-PCC dose administered immediately pre-procedure was based on study protocol. International normalized ratio (INR)- and vitamin K-dependent factor levels were collected before and during the 48 hours after 4F-PCC administration. The use of parenteral bridging, International Society for Thrombosis and Haemostasis major and clinically relevant nonmajor bleeding (CRNMB) and thromboembolic events at 7 and 30 days were collected. In 21 episodes of 4F-PCC reversal, median baseline INR was 2.7 (IQR 2.2-3.2). The median dosage of 4F-PCC administered was 1794 units (IQR 1536-2130). At 24 and 48 hours post 4F-PCC administration, median INRs were 1.8 (IQR 1.7-2.0) and 2.0 (IQR 1.9-2.4). Two patients required postoperative bridging. One patient experienced major bleeding within 72 hours, and 2 experienced CRNMB within 30 days. There were no thromboembolic events. Baseline and post 4F-PCC vitamin K-dependent factor levels corresponded with changes in INR values. The median time to achieve therapeutic INR post-procedure was 2.5 days (IQR, 1-4). Administration of 4F-PCC for temporary reversal of warfarin for invasive procedures in patients with LVADs allowed for continued warfarin dosing with minimal use of post-intervention bridging, limited bleeding and no thromboembolic events.

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.

Comprehensive Management of Anticoagulants Induced Decompensated Severe Anemia in Postmitral Valve Replacement

Abstract Mechanical prosthetic valve needs consideration for anticoagulation. The objective of this case report was to know how maintenance of oral anticoagulant therapy is very important in patients, especially with mechanical heart valve replacement. It is the holistic management of mitral valve replacement (MVR) patients with high international normalized ratio (INR) (&gt;100), which led bleeding into the peritoneal cavity and causes decompensated severe anemia. Although it is a rare presentation for a patient of MVR with high INR level but which is most commonly presented for cerebrovascular accident. Anemia is a thoughtful worldwide problem that disturbs the quality of life in persons of all ages. A 28-year-old Indian woman with follow-up case of post-MVR came to the hospital with complaints of breathing difficulty, altered sensorium, pulse rate of 150–170 bpm (beats/min) irregularly irregular, blood pressure (80/50 mmHg), palpitation, and abdominal pain. Blood test report revealed her hemoglobin (Hb) was 3.2 g%, suggestive of severe anemia, INR was &gt;100 s. Hence, patient diagnosed as follow-up case of MVR (#27 mm mechanical bileaflet mitral valve prosthesis) with peritoneal bleeding, an oral anticoagulant with decompensated severe anemia managment should be done. Ended the progression of her hospitalization, she received four units of packed red blood cell transfusions; Vitamin K was given intravenous once daily for 2 days and no anticoagulant was given, so far, INR was high with serial monitoring of INR and Hb. Her symptoms of breathing difficulty, pain in abdomen, weakness and giddiness resolute by the finish of her hospital stay, and she recompensed to her oral anticoagulant therapy with improved Hb and hemodynamics. Disapprovingly high INR levels are classically related with bleeding disorders revealed on imperative indicators and hemodynamic variability. To our understanding, one of the lowermost noted Hb is because of bleeding due to very high INR, so monitoring of therapeutic INR level with anticoagulants is very-very important.

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

Evaluation of Machine Learning Approaches for Predicting Warfarin Discharge Dose in Cardiac Surgery Patients: Retrospective Algorithm Development and Validation Study.

Warfarin dosing in cardiac surgery patients is complicated by a heightened sensitivity to the drug, predisposing patients to adverse events. Predictive algorithms are therefore needed to guide warfarin dosing in cardiac surgery patients. This study aimed to develop and validate an algorithm for predicting the warfarin dose needed to attain a therapeutic international normalized ratio (INR) at the time of discharge in cardiac surgery patients. We abstracted variables influencing warfarin dosage from the records of 1031 encounters initiating warfarin between April 1, 2011, and November 29, 2019, at St Michael's Hospital in Toronto, Ontario, Canada. We compared the performance of penalized linear regression, k-nearest neighbors, random forest regression, gradient boosting, multivariate adaptive regression splines, and an ensemble model combining the predictions of the 5 regression models. We developed and validated separate models for predicting the warfarin dose required for achieving a discharge INR of 2.0-3.0 in patients undergoing all forms of cardiac surgery except mechanical mitral valve replacement and a discharge INR of 2.5-3.5 in patients receiving a mechanical mitral valve replacement. For the former, we selected 80% of encounters (n=780) who had initiated warfarin during their hospital admission and had achieved a target INR of 2.0-3.0 at the time of discharge as the training cohort. Following 10-fold cross-validation, model accuracy was evaluated in a test cohort comprised solely of cardiac surgery patients. For patients requiring a target INR of 2.5-3.5 (n=165), we used leave-p-out cross-validation (p=3 observations) to estimate model performance. For each approach, we determined the mean absolute error (MAE) and the proportion of predictions within 20% of the true warfarin dose. We retrospectively evaluated the best-performing algorithm in clinical practice by comparing the proportion of cardiovascular surgery patients discharged with a therapeutic INR before (April 2011 and July 2019) and following (September 2021 and May 2, 2022) its implementation in routine care. Random forest regression was the best-performing model for patients with a target INR of 2.0-3.0, an MAE of 1.13 mg, and 39.5% of predictions of falling within 20% of the actual therapeutic discharge dose. For patients with a target INR of 2.5-3.5, the ensemble model performed best, with an MAE of 1.11 mg and 43.6% of predictions being within 20% of the actual therapeutic discharge dose. The proportion of cardiovascular surgery patients discharged with a therapeutic INR before and following implementation of these algorithms in clinical practice was 47.5% (305/641) and 61.1% (11/18), respectively. Machine learning algorithms based on routinely available clinical data can help guide initial warfarin dosing in cardiac surgery patients and optimize the postsurgical anticoagulation of these patients.

New insights into the role of VKORC1 polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model

Warfarin, an oral anticoagulant, has been used for decades to prevent thromboembolic events. The complex interplay between CYP2C9 and VKORC1 genotypes on warfarin PK and PD properties is not fully understood in special sub-groups of patients. This study aimed to externally validate a population pharmacokinetic/pharmacodynamic (PK/PD) model for the effect of warfarin on international normalized ratio (INR) and to evaluate optimal dosing strategies based on the selected covariates in Caribbean Hispanic patients. INR, and CYP2C9 and VKORC1 genotypes from 138 patients were used to develop a population PK/PD model in NONMEM. The structural definition of a previously published PD model for INR was implemented. A numerical evaluation of the parameter-covariate relationship was performed. Simulations were conducted to determine optimal dosing strategies for each genotype combinations, focusing on achieving therapeutic INR levels. Findings revealed elevated IC50 for G/G, G/A, and A/A VKORC1 haplotypes (11.76, 10.49, and 9.22 mg/L, respectively), in this population compared to previous reports. The model-guided dosing analysis recommended daily warfarin doses of 3–5 mg for most genotypes to maintain desired INR levels, although subjects with combination of CYP2C9 and VKORC1 genotypes * 2/* 2-, * 2/* 3- and * 2/* 5-A/A would require only 1 mg daily. This research underscores the potential of population PK/PD modeling to inform personalized warfarin dosing in populations typically underrepresented in clinical studies, potentially leading to improved treatment outcomes and patient safety. By integrating genetic factors and clinical data, this approach could pave the way for more effective and tailored anticoagulation therapy in diverse patient groups.

Early 6 months usage of single anTiplAtelet OR anTicoAgulant followed by single antiplatelet after transcatheter aortic valve replacement: protocol for a multicentre, open-label, randomised controlled clinical trial

IntroductionThe strategy for initiating antithrombotic therapy to prevent bioprosthetic valve thrombosis (BPVT) after transcatheter aortic valve replacement (TAVR) remains uncertain. There is still lacking evidence on the efficacy and safety...

Chinese stroke patients with atrial fibrillation used Robert's age-adjusted warfarin loading protocol obtained good INR results within therapeutic range

To assess whether Roberts’ age-adjusted warfarin loading protocol is effective in Chinese patients and whether the SAMeTT2R2 score can predict international normalized ratio (INR) control. Roberts’ protocol for warfarin titration was applied to patients with non-valvular atrial fibrillation (NVAF) complicated with ischemic stroke at the Department of Neurology between 2014 and 2019. Clinical and sociodemographic variables were recorded. A minimum of 1-year follow-up was used to calculate the time in therapeutic range (TTR) of the INR. A total of 94 acute ischemic stroke patients with NVAF were included in the study. Seventy-seven (81.9%) of the patients had attained stable INR (2.0–3.0) at the fifth dose, and 90.0% of the patients had achieved stable INR on the ninth day. Seventeen (18.1%) of the patients had an INR > 4 during dose-adjustment period. Patients with INR > 4 had significantly lower body weight (53.8 vs. 63.1 kg, P = 0.014), lower rate of achievement of stable INR (35.3% vs. 92.2%, P = 0.000), and lower rate of TTR ≥ 65% (23.5% vs. 70.1%, P = 0.001), but with no significant increase in bleeding risk. A total of 89 patients underwent long-term INR follow-up, of which 58 (65.2%) patients achieved TTR ≥ 65%. Patients with poor TTR had significantly lower body weight (56.3 vs. 63.7 kg, P = 0.020) and lower rate of stable INR achievement (64.5% vs. 89.7%, P = 0.002). All 94 patients had SAMeTT2R2 score ≥ 2. There was no linear association between SAMeTT2R2 score and the rate of TTR ≥ 65% (Ptrend = 0.095). Chinese ischemic stroke patients with NVAF on warfarin can safely and quickly achieve therapeutic INR using Roberts’ age-adjusted protocol and can obtain a good TTR. Lower body weight may be a predictor of poor TTR and INR > 4. Patients who have not attained stable INR after adjusting the dose five times are at high risk for poor TTR. SAMeTT2R2 score may not predict TTR in Chinese ischemic stroke patients with NVAF.

Efficacy of Warfarin Therapy Guided by Pharmacogenetics: A Real-world Investigation Among Han Taiwanese

The anticoagulation activity of warfarin in populations with CYP2C9, VKORC1, and CYP4F2 variants differs between individuals and is correlated with poor international normalized ratio (INR) control. Pharmacogenetics-guided warfarin dosing has been successfully developed for patients with genetic variations in recent years. However, few real-world data have been used to investigate the INR and warfarin dosage and the time to target INR. This study examined the largest collection of genetic and clinical real-world data related to warfarin to provide further evidence supporting the benefits of pharmacogenetics in clinical outcomes. We retrieved a total of 69,610 INR-warfarin records after the index date from 2,613 patients in the China Medical University Hospital database between January 2003 and December 2019. Each INR reading was obtained from the latest laboratory data after the hospital visit date. Patients with a history of malignant neoplasms or pregnancy before the index date were excluded, as were patients without data on INR measurements after the fifth day of prescription, genetic information, or gender variables. The primary outcomes were the INR and warfarin dosage during days 7, 14, 28, 56, and 84 after prescription. The secondary outcome was the time required to reach the INR ranges of 1.5 to 3.0 and >4.0. A total of 59,643 INR-warfarin records from 2188 patients were retrieved. The average INR was higher for homozygous carriers of the minor allele at CYP2C9 and VKORC1 during the first 7 days (1.83 [1.03] [CYP2C9*1] and 2.46 [1.44] [CYP2C9*3], P < 0.001; 1.39 [0.36] [rs9923231 G/G], 1.55 [0.79] [rs9923231 G/A], and 1.96 [1.13] [rs9923231 A/A], P < 0.001) than for the wild-type allele. These patients with variants required lower warfarin doses than those with the wild-type allele during the first 28 days. CYP4F2 variant patients seemed to require higher doses of warfarin than those in the wild-type group; however, no significant difference in the average INR was observed (1.95 [1.14] [homozygous V433 carriers], 1.78 [0.98] [heterozygous V433M carriers], and 1.66 [0.91] [homozygous M433 carriers], P=0.016). Our study indicates that genetic variants in the Han population may enhance warfarin responsiveness, which holds clinical relevance. An increased warfarin dosage was not linked to a shorter time to therapeutic INR between CYP4F2 variant patients and those with a wild-type allele. Assessing CYP2C9 and VKORC1 genetic polymorphisms before initiating warfarin treatment in real-world practice is essential for potentially vulnerable patients and is likely to optimize therapeutic dosing.

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.

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

The guide for the use of genotype-guided warfarin dosing in patients for the treatment of non-valvular atrial fibrillation (AF) is still lacking. We aimed to evaluate whether genotype-guided warfarin dosing is superior to conventional clinical dosing for the outcomes of interest in Chinese patients. 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. 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. 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.

Hyper-responsiveness to warfarin in a young patient with the VKORC1 -1639GA/CYP2C9*1*46 genotype: a case report

BackgroundWarfarin is the most widely used oral anticoagulant; nevertheless, dosing of warfarin is problematic for clinicians worldwide. Inter-individual variability in response to warfarin is attributed to genetic as well as non-genetic factors. Pharmacogenomics studies have identified variants in CYP2C9 and VKORC1 genes as significant predictors of warfarin dose, however, phenotypes of rare variants are not well characterized.Case presentationWe report a case of hyper-responsiveness to warfarin in a 22-year-old outpatient with Crohn's disease who presented with a swollen, red, and painful left calf. Deep venous thrombosis (DVT) in the left lower extremity was confirmed via ultrasonography, and hence, anticoagulation therapy of heparin and concomitant warfarin was initiated. Warfarin dose of 7.5 mg/day was estimated by the physician based on clinical factors. Higher than the expected international normalized ratio (INR) value of 4.5 necessitated the reduction of the warfarin dose to 5 and eventually to 2.5 mg/day to reach a therapeutic INR value of 2.6. Pharmacogenetic profiling of the VKORC1 -1639G > A and CYP2C9 *2, *3, *4, *5, *8, *14, *20, *24, *26, *33, *40, *41, *42, *43, *45, *46, *55, *62, *63, *66, *68, *72, *73 and *78 revealed a VKORC1-1639GA/CYP2C9*1*46 genotype. The lower catalytic activity of the CYP2C9*46 (A149T) variant was previously reported in in vitro settings.ConclusionsThis is the first report on a case of warfarin hyper-responsive phenotype of a patient with the heterozygous CYP2C9*1*46 polymorphism.

ANTICOAGULANT DRUG INDUCED SUPRA THERAPEUTIC INR AND ITS MANAGEMENT

This paper has the management of Drug Induced Supra therapeutic INR and a case presentation of 33-year-old Male patient who was on oral anticoagulant (Vitamin K antagonist-VKA) and antiplatelet therapy presented with supra-therapeutic international normalized ratio (INR) with history of Single episode of blood stained Sputum. The patient is known case of posterior circulation stroke with left ventricular clot, Cortical venous sinus thrombosis with left parietal hematoma and secondary seizure, ischemic heart disease (IHD) status post Percutaneous Transluminal Coronary Angioplasty (PTCA) to LAD with left ventricular ejection fraction (LVEF) - 30% and hyper-homocysteinemia. The patient presented with history of single episode of blood stain sputum and with no other complaints. His routine blood investigation revealed INR of 9.50 hence the patient was admitted and treated accordingly. Patients INR returned to normal after appropriate medical management. Patient was discharged with a titrated dose, advised on treatment, education and adherence counselling.

Impact of Initial Warfarin Dosing on Time in Therapeutic Range for Postoperative Left Ventricular Assist Device Patients.

Initial warfarin dosing and time in therapeutic range (TTR) are poorly characterized for early post-operative left ventricular assist device (LVAD) patients. This study evaluated TTR after LVAD implantation compared between patients receiving low-dose (<3 mg) and high-dose (≥3 mg) warfarin. This single-center, retrospective analysis included 234 LVAD patients who received warfarin within 5 days of implantation. The primary outcome was TTR during the 5 days following first international normalized ratio (INR) ≥2 compared between low-dose and high-dose groups. Secondary outcomes were hospital and intensive care unit length of stay, time to first INR ≥2, TTR after first INR ≥2, and reinitiation of parenteral anticoagulation. No difference in TTR was detected between warfarin groups (57.2% vs. 62.7%, P = 0.13). Multivariable analysis did not detect any factors predictive of TTR during the primary outcome timeframe, but age and body mass index were associated with the warfarin dose. The low-dose group received a mean warfarin dose of 1.9 mg (±0.64 mg), and the high dose group received 4.34 mg (±1.38 mg). Cohort TTR during the primary outcome timeframe was 60.5% and 56.5% for hospitalization. The low-dose group had longer intensive care unit length of stay, shorter time to therapeutic INR, and more frequently reinitiated parenteral anticoagulation. Patients with recent LVAD implantation are complex and have diverse warfarin sensitivity factors, which did not allow for optimal warfarin dose detection, although half of all patients received doses between 2.04 mg and 4.33 mg. Individualized dosing should be used, adjusting for patient-specific factors such as age, body mass index, and drug interactions.

Associated factors and safety of the rapidly achieving first therapeutic target of warfarin in hospitalized patients: a retrospective cohort study.

Warfarin is a commonly used anticoagulant drug in clinical practice. Rapidly achieving the first therapeutic international normalized ratio (INR) of warfarin may reduce the hospital length of stay. However, little research has been carried out to evaluate the influencing factors and the safety of rapidly achieving the first therapeutic INR target of warfarin. To investigate the associated factors and the safety of rapidly achieving the first therapeutic INR target of warfarin. A retrospective cohort study was conducted in inpatients who took warfarin from November 2018 to October 2019. Patients' information was retrieved from medical records. 487 patients were included. The mean achieving first therapeutic target time was 6.0 ± 3.2 days (median, 5.0 days). Age > 65 years, body mass index < 24kg/m2, and initial warfarin dose ≥ 3mg/d were independent factors associated with the rapidly achieving first INR target of warfarin therapy. The incidence of INR ≥ 4 was higher in patients achieving the first INR target rapidly than those achieving the first INR target slowly, while there were no significant differences in bleeding events between the two groups. Hospitalized patients aged > 65 years, with a body mass index < 24kg/m2, or receiving an initial warfarin dose ≥ 3mg/d were more likely to achieve the first INR target of warfarin rapidly. Closer INR monitoring and appropriate warfarin dose adjustment are recommended to improve the safety for patients achieving the first INR ≥ 1.8 within 6 days after beginning oral warfarin.

Pharmacist-Managed Anticoagulation Services for Warfarin Management in Tertiary Hospitals: The Egyptian Experience

Background: Warfarin is widely regarded as the main anticoagulant in lowering the risk of thromboembolism. This study used indicators to compare pharmacist-managed anticoagulation services, using a well-prepared protocol, with physician-managed anticoagulation services. Methods: A retrospective prospective pilot study was conducted to compare patient outcomes before and after transitioning patients to pharmacist-managed anticoagulation services, comparing the proportion of those with therapeutic international normalized ratio (INR), subtherapeutic INR, and supratherapeutic INR, as well as their bleeding occurrences as indicators of assuring quality care. Results: A significant improvement in anticoagulation management was noted in the transition to pharmacist-managed anticoagulation services. The proportion of those with subtherapeutic INR decreased from 61.8% to 11.8% (p &lt; 0.001), those with supratherapeutic INR decreased from 20.6% to 2.9% (p &lt; 0.001), those with therapeutic INR increased from 17.6% to 85.3% (p &lt; 0.001), and the occurrence of bleeding decreased from 11.8% to 0.0%, without significant difference in warfarin doses (median from 4 before the transition to 5 after); in addition, the time to reach therapeutic INR decreased from 12-24 weeks to 2-8 weeks after transitioning to pharmacist-managed anticoagulation services. Conclusion: Pharmacist-managed anticoagulation services are considered safer and more effective than physician-managed anticoagulation services alone in terms of patients’ adherence and satisfaction, which provide an excellent opportunity for quality assurance care.

The Impact of Pharmacist-Managed Service on Warfarin Therapy in Patients after Mechanical Valve Replacement.

Objective To evaluate the impact of pharmacist interventions on international normalized ratio (INR) control during the warfarin initiation phase after mechanical valve replacement. Methods This was a retrospective cohort study conducted in a cardiovascular surgery ward in a tertiary hospital from August 1, 2015, to July 31, 2019. Patients aged ≥20 years who were admitted for mechanical valve replacement were enrolled in this study and further classified into conventional and pharmacist-managed warfarin therapy (PMWT) groups. All participants were prospectively followed up until the first outpatient appointment after valve replacement. The effectiveness outcomes were time in therapeutic range (TTR), time to therapeutic INR, number of patients with therapeutic INR at discharge and at first outpatient appointment, and length of hospital stay. The safety outcome was the number of patients with any supratherapeutic INR during the hospital stay. Multivariate logistic regression analyses were also used to determine the predictors of a therapeutic INR at discharge or with any supratherapeutic INR during admission. Results A total of 39 and 33 patients were enrolled in the conventional and PMWT groups, respectively. At discharge, 18 patients (46.2%) in the conventional group and 24 patients (72.7%) in the PMWT group had achieved the therapeutic INR (P=0.023). Compared to the conventional group, fewer patients in the PMWT group had supratherapeutic INR during hospital stay (35.9% vs. 9.0%, P=0.008). No significant differences were found in TTR, time to therapeutic INR, number of patients with therapeutic INR at return appointment, and length of stay between the study groups. In the multivariate regression analyses, PMWT predicted achieving therapeutic INR at discharge (odds ratio (OR) and 95% confidence interval (CI), 3.14 [1.08–9.14]) and was inversely associated with supratherapeutic INRs during admission (OR = 0.21 [0.05–0.82]). Conclusions Among patients admitted for mechanical valve replacement, the implementation of PMWT was associated with optimal therapeutic INR at discharge and no supratherapeutic INR during admission. Therefore, pharmacist participation is essential for improving the quality of warfarin therapy.

A Multicentre Study on Average Warfarin Dose to Maintain Therapeutic International Normalised Ratio with Time in Therapeutic Range of More than 75% in Atrial Fibrillation Patients

Large interindividual variability and over-anticoagulation resulting bleeding complications due to narrow therapeutic index of warfarin has causes its pharmacodynamic activity to be highly variable. Studies shown that ethnicity, age and gender contribute to warfarin response variability. Good coagulation control of time in therapeutic range (TTR) &gt; 75% was chosen to determine the average warfarin dose in atrial fibrillation (AF) among ethnicity, age and gender. Data from Warfarin Medication Therapy Adherence Clinic of selected Pulau Pinang hospitals were used for the analysis of average warfarin dose in AF among ethnicity, age and gender. Patients who fulfilled the inclusion criteria from 2015–2016 were followed up for a year. Five hundred and seventy-six patients were included. Two hundred and ten patients had good coagulation control of TTR &gt; 75% with mean warfarin dose of 3.05 ± 1.25 mg. Only Chinese and Indian have significant difference in average warfarin dose with 2.86 ± 1.10 mg and 4.11 ± 1.40 mg, respectively (p = 0.008). Average warfarin dose was found not significantly different among gender and age. As for TTR achievement, 210 (36.4%) were able to achieve TTR &gt; 75%, 134 patients achieved TTR 60%–75% and 232 patients has TTR &lt; 60%. The median day to achieve three consecutive targeted international normalised ratio (INR) is 186.5 days for atrial fibrillation patient newly started on warfarin therapy in 2015 until 2016. Indian patients required a higher warfarin dose than Chinese patients. This study found that mean warfarin doses were not affected by age and sex.

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

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