Therapeutic International Normalized Ratio Range 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.

Risk of dentoalveolar surgery postoperative bleeding in patients taking direct oral anticoagulants and vitamin K antagonists: A prospective observational study

The aim of this study was to evaluate whether direct oral anticoagulants (DOAC) and vitamin K antagonists (VKA) increase the risk of postoperative bleeding after dentoalveolar surgery. Patients were classified into two groups: one taking DOAC and the other taking VKA with a therapeutic INR range. The control group comprised non-anticoagulated subjects. Participants were matched regarding dentoalveolar procedure. The primary predictor was anticoagulant status. The primary outcome was postoperative bleeding. The DOAC group comprised 77 patients, while the VKA group and control group each consisted of 103 participants. In each group, 103 dentoalveolar surgical procedures were conducted. Postoperative bleeding was recorded in 3/103 (2.9%), 5/103 (4.8%), and 1/103 (0.97%) occasions in the DOAC, VKA, and control groups, respectively, without significant difference (χ2; p = 0.54). The fully adjusted odds ratio for postoperative bleeding was 0.14 (CI 0.01–1.61; p = 0.05) for patients taking DOAC and 0.19 (CI 0.02–1.65; p = 0.285) for those taking VKA compared with non-anticoagulated controls. In conclusion, there was no increase in risk for clinically significant postoperative bleeding after dentoalveolar surgery in patients taking DOAC or VKA compared with non-anticoagulated subjects. Dentoalveolar surgery in patients taking DOAC and VKA can be performed safely without therapy cessation.The study was registered at Clinicaltrials.gov (NCT04505475).

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.

Challenges of a Patient with Thromboembolism

Challenges of a Patient with Thromboembolism

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.

Management, control, and decision making in unexpected recurrent venous thromboembolism in COVID-19: a case report

BackgroundCoronavirus disease 2019 was spread worldwide, as a pandemic, from December 2019. Venous thromboembolism events can inflict patients with coronavirus disease 2019 during the hospitalization or convalescent period. Therefore, monitoring of these patients, in terms of venous thromboembolism events signs and symptoms, and timely management of antithrombotic agents are of great importance.Case reportA 45-year-old Iranian man, who is the first author of this case report, was infected by severe acute respiratory syndrome coronavirus 2 and displayed the typical signs and symptoms of coronavirus disease 2019. Although reverse transcription polymerase chain reaction for coronavirus disease 2019, and specific immunoglobulin M and immunoglobulin G against severe acute respiratory syndrome coronavirus 2, were negative at first, chest computed tomography scan showed the characteristic pattern of lung involvement of a coronavirus disease 2019 infection including bilateral and multilobar ground-glass opacities. At that time, there were no signs or symptoms of deep-vein thrombosis or pulmonary thromboembolism, so these were not investigated. About 30 hours after hospital discharge, the patient presented back to the hospital with acute-onset chest pain. We instantly tested his blood for D-dimer, and sent him to take a Doppler sonography of his lower legs and a chest computed tomography angiography in search of pulmonary thromboembolism and deep-vein thrombosis. Although we could confirm pulmonary thromboembolism with computed tomography angiography in our patient, there were no signs or symptoms of venous thromboembolism in his lower legs, and color Doppler sonography of lower limbs was normal. So, the patient was treated with rivaroxaban as an antithrombotic agent. After some days, he was discharged in good condition. About 1 month later, he was referred to our hospital because of left lower limb edema. Although he was under antithrombotic therapy, color Doppler sonography of lower limbs revealed acute deep-vein thrombosis of the left leg. Hence, we decided to shift antithrombotic therapy from rivaroxaban to warfarin, as it is more potent than rivaroxaban in recurrent venous thromboembolism and when taking new oral anticoagulants. Unlike rivaroxaban, which needs no blood test to monitor its efficacy but has a warning for signs and symptoms of bleeding, warfarin therapy must be monitored carefully by regular blood tests for prothrombin time and international normalized ratio to maintain them in the therapeutic range. The patient was informed about the bleeding cautions, and required regular check of prothrombin time and international normalized ratio to maintain them in the proper and advised range of treatment (international normalized ratio therapeutic range 2–3).ConclusionIn the case of unexpected recurrent venous thromboembolism in coronavirus disease 2019, especially when patients are taking rivaroxaban or other new oral anticoagulants, such drugs should be substituted by warfarin, with routine follow-up, to maintain the value of prothrombin time and international normalized ratio within the therapeutic range.

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.

Abstract 12727: Ultrafiltration for Decompensated Heart Failure Using Aquadex® Without Heparin

Introduction: Anticoagulation therapy is necessary during ultrafiltration (UF) to prevent thrombus formation during the filtering process. Heparin is the anticoagulating agent recommended by Aquadex®. However, many patients are already within a therapeutic INR range due to warfarin anticoagulation. Here we present a unique case of Aquadex® UF without the use of heparin anticoagulation. Case Presentation: An 87-year-old male with a history of LVAD implant experienced 2 weeks of weight gain and dyspnea on exertion and at rest due to fluid retention despite GDMT and escalation of oral diuretics. On admission, physical exam revealed elevated JVP, ascites, and 3+ bilateral lower extremity pitting edema and 32 pounds weight gain. He was on a home dose of warfarin per LVAD protocol. Investigations revealed INR 2.9, HCT 29.6, BUN 58, and Cr 2.05. Aquadex® UF was initiated with a therapeutic INR range of 2-3. The patient tolerated UF well without complication and was transitioned back to oral diuretics after 4 days of UF, 24 pounds of weight loss, and 7 liters of fluid removal. He was stable at discharge, but was readmitted two weeks later with identical symptoms and INR 1.9, HCT 26, BUN 32, and Cr 1.69. Aquadex® UF was again initiated with a therapeutic INR range 1.5-2. He again tolerated UF well without complication for 4 days, lost 28 pounds, and had 8.9 liters of fluid removed on this second admission. Aquadex® fluid removal during both hospitalizations is depicted in Figure 1. Conclusions: Our case supports the utilization of UF without the use of heparinization on patients who are already anticoagulated with warfarin. Further, successful UF without clotting complications is possible in INR ranges between 1.5-2 and 2-3 as evidenced during the two hospitalizations. Figure 1. INR levels were maintained within therapeutic ranges using warfarin anticoagulation during Aquadex® UF.

GARFIELD-AF: risk profiles, treatment patterns and 2-year outcomes in patients with atrial fibrillation in Germany, Austria and Switzerland (DACH) compared to 32 countries in other regions worldwide.

The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is a worldwide non-interventional study of stroke prevention in patients with non-valvular AF. 52,080 patients with newly diagnosed AF were prospectively enrolled from 2010 to 2016. 4121 (7.9%) of these patients were recruited in DACH [Germany (n = 3567), Austria (n = 465) and Switzerland (n = 89) combined], and 47,959 patients were from 32 countries in other regions worldwide (ORW). Hypertension was most prevalent in DACH and ORW (85.3% and 75.6%, respectively). Diabetes, hypercholesterolaemia, carotid occlusive disease and vascular disease were more prevalent in DACH patients vs ORW (27.6%, 49.4%, 5.8% and 29.0% vs 21.7%, 40.9%, 2.8% and 24.5%). The use of non-vitamin K antagonist oral anticoagulants (NOACs) increased more in DACH over time. Management of vitamin K antagonists was suboptimal in DACH and ORW (time in therapeutic range of INR ≥ 65% in 44.6% and 44.4% of patients or ≥ 70% in 36.9% and 36.0% of patients, respectively). Adjusted rates of cardiovascular mortality and MI/ACS were higher in DACH while non-haemorrhagic stroke/systemic embolism was lower after 2-year follow-up. Similarities and dissimilarities in AF management and clinical outcomes are seen in DACH and ORW. The increased use of NOAC was associated with a mismatch of risk-adapted anticoagulation (over-and-undertreatment) in DACH. Suboptimal control of INR requires educational activities in both regional groups. Higher rates of cardiovascular death in DACH may reflect the higher risk profile of these patients and lower rates of non-haemorrhagic stroke could be associated with increased NOAC use.

Compliance amongst recipients of warfarin to treat non-valvular atrial fibrillation: a cross-sectional study

BackgroundVitamin K antagonists, such as warfarin, are the most prescribed anticoagulation medication for the treatment of non-valvular atrial fibrillation (NVAF). The prevalence of NVAF ranges from 0·5% to 1·0% in the general population. We investigated compliance with warfarin treatment among patients with NVAF in Gaza Strip. MethodsThis was a cross-sectional study done from January, 2017, to October, 2017, at the Indonesian Hospital, Gaza Strip, occupied Palestinian territory. Eligible patients were those admitted to the medical department who were taking warfarin for NVAF, with or without comorbidities, and aged 20–85 years. Patients taking warfarin for other diseases (eg, antiphospholipid syndrome) were excluded. We developed a questionnaire to assesses patients’ knowledge about warfarin therapy. The questionnaire was administered by one clinical pharmacist [HM] in face-to-face interviews to avoid difficulties arising from illiteracy, visual impairment, and technical questions. Laboratory data (international normalised ratio [INR], serum creatinine, random blood sugar, systolic and diastolic blood pressure, and liver chemistry) were obtained from clinical records. Continuous data are presented as the mean (SD) and the categoric variables as numbers and percentages. We used binary univariate analysis to assess relationships between quantitative variables. Significant results had two-tailed p values less than 0·05. All data were analysed using SPSS version 20. The study was approved by the Ministry of Health and Helsinki Committee of Gaza Strip. All patients provided written informed consent. Findings100 patients were enrolled in the study (53% men, 47% women), with a mean age of 55 (SD 7) years. 43% of patients had hypertension, 15% had diabetes, and 42% were smokers. 43% of the patients knew of the risks of warfarin treatment whereas 39% understood the benefits. Only 38% of patients were within the therapeutic INR range of 2–3 and 35% had INR values higher than this range. 66% of patients did not have INR monitored regularly and 28% had no regular contact with health-care providers for INR follow up. 21% of patients did not take their daily dose and 36% had developed haemorrhages; only 4% knew how to deal with this complication. Of those who developed haemorrhages, the most common manifestations were epistaxis (44%) and gastrointestinal bleeding (36%). There were no instances of CNS haemorrhage. We found significant relationships between creatinine concentration, diastolic blood pressure, systolic blood pressure, and INR (all p<0·05) InterpretationThe findings of this study show that most of patients were unaware of the risks and benefits of warfarin therapy. We recommend that an anticoagulation clinic is established to provide INR monitoring and education qualified health-care providers. A limitation of this study was low number of patients, but no funding was available for follow-up. However, the accuracy of data give strength to the results, which are representative of the real-world experience of patients with NVAF in our region. FundingNone.

Development of an interview-based warfarin nomogram predicting the time spent in the therapeutic INR range: A cost-effective, and non-invasive strategy building from a cross sectional study in a low resource setting

A cross-sectional study was conducted to predict time in therapeutic range (TTR) using clinical history, examination, and socioeconomic data. Study included warfarin-receiving patients from outpatient-clinic. In 203 patients studied, mean warfarin start-dose was 2.55 mg/day and maintenance-dose/week was 30.79 mg. Body mass index (BMI) (p = 0.03), warfarin maintenance dose/day (p = 0.02), and comorbidity presence (p = 0.04) were significantly associated with TTR. Occupation (p = 0.53), income (p = 0.83), education (p = 0.55), and socioeconomic score (p = 0.73) showed non-significant association with TTR. A TTR predicting nomogram was built from clinical history and examination findings.

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.

Abstract 11742: Knowledge on Anticoagulation Use in Atrial Fibrillation With Left Atrial Appendage Thrombus Among Medicine Residents

Introduction: Left atrial appendage (LAA) thrombus increases thromboembolic risk in patients with atrial fibrillation (AF). Importantly, 40% of LAA thrombus patients will have an inadequate response to anticoagulation during follow-up. Of note, these patients are frequently followed by medicine residents in the clinic. Therefore, we aimed to explore residents' knowledge on anticoagulation use for the treatment of LAA thrombus. Hypothesis: Insufficient knowledge on anticoagulation for the treatment of LAA thrombus could contribute to inadequate treatment response during patients' follow-up. Methods: All medicine residents (n=96) at Rutgers University New Jersey Medical School were emailed a 26-question survey on the indication, dosing, pharmacokinetics and clinical experience using direct oral anticoagulants (DOACs) and vitamin-K-antagonists (VKA) in AF patients with LAA thrombus. Results: Of 62 responders, 42 (68%) have been prescribing DOACs in the clinic with apixaban being most commonly prescribed. Thirty-seven (61%) indicated DOACs as the first-line agents for LAA thrombus whereas 24 (39%) chose VKA. Nineteen (33%) responders indicated apixaban dosing correctly, and 51 (84%) indicated appropriately relation of apixaban with meals. If follow-up imaging reconfirmed LAA thrombus, 54 (89%) would switch to VKA whereas 7 (11%) would use other DOACs. Nineteen (32%) responders indicated rivaroxaban dosing correctly and only 10 (16%) indicated appropriately how to administer rivaroxaban with meals. If follow-up imaging reconfirmed LAA thrombus, 43 (71%) would switch to VKA whereas 18 (29%) would use other DOACs. Forty-one (72%) responders indicated dabigatran dosing correctly and 36 (58%) indicated no relation to food intake. If follow-up imaging reconfirmed LAA thrombus, 40 (65%) responders would switch to VKA whereas 22 (35%) would use other DOACs. For VKA, 51 (88%) indicated therapeutic INR range of 2-3 and 7 (12%) chose 2.5-3.5. If follow-up imaging reconfirmed LAA thrombus, 38 (61%) would increase INR goal whereas 24 (39%) would switch to DOACs. Conclusions: This survey identified knowledge gaps in dosing and pharmacokinetics of DOACs among medicine residents despite being more likely to prescribe DOACs over VKA to treat LAA thrombus.

Direct Oral Anticoagulant Adherence of Patients With Atrial Fibrillation Transitioned from Warfarin.

BackgroundReduced time in international normalized ratio therapeutic range (TTR) limits warfarin safety and effectiveness. In patients switched from warfarin to direct oral anticoagulants (DOACs), patient factors associated with low TTR could also increase risk of DOAC nonadherence. We investigated the relationship between warfarin TTR and DOAC adherence in warfarin‐treated patients with atrial fibrillation switched to DOAC.Methods and ResultsUsing data from the Veterans Health Administration, we identified patients with atrial fibrillation switched from warfarin to DOAC (switchers) or treated with warfarin alone (non‐switchers). Logistic regression was used to evaluate association between warfarin TTR and DOAC adherence. We analyzed 128 605 patients (age, 71±9; 1.6% women; CHA2DS2‐VASc 3.5±1.6); 32 377 switchers and 96 228 non‐switchers. In 8016 switchers with international normalized ratio data to calculate 180‐day TTR before switch, TTR was low (median 0.45; IQR, 0.26–0.64). Patients with TTR <0.5 were more likely to be switched to DOAC (odds ratio [OR],1.68 [95% CI,1.62–1.74], P<0.0001), as were those with TTR <0.6 or TTR <0.7. Proportion of days covered ≥0.8 was achieved by 76% of switchers at 365 days. In low‐TTR individuals, proportion of days covered ≥0.8 was achieved by 70%, 72%, and 73% of switchers with TTR <0.5, 0.6, and 0.7, respectively. After multivariable adjustment, TTR <0.5 decreased odds of achieving 365‐day proportion of days covered ≥0.8 (OR, 0.49; 0.43–0.57, P<0.0001), with similar relationships for TTR <0.6 and TTR <0.7. In non‐switchers with TTR <0.5, long‐term TTR remained low.ConclusionsIn patients with atrial fibrillation switched from warfarin to DOAC, most achieved adequate DOAC adherence despite low pre‐switch TTRs. However, TTR trajectories remained low in non‐switchers. Patients with low warfarin TTR more consistently achieved treatment targets after switching to DOACs, although adherence‐oriented interventions may be beneficial.

Performance of the microINR Point-of-Care System Used by Self-Testing Patients: A Multicenter Clinical Trial.

Introduction Anticoagulation monitoring is a major practical and clinical challenge. We assessed the performance of the microINR system in patient self-testing (PST). Methods This study was performed at four US medical centers. After the training visit of warfarin anticoagulated patients ( n = 117) on microINR system, PST was performed at home and in two visits to the medical centers. At the medical centers, both PST and healthcare professionals (HCPs) performed duplicate tests with the microINR System. A venous blood sample for the laboratory testing was also extracted. Accuracy and precision were assessed. Results The comparison between microINR PST results and microINR HCP results revealed an equivalence with a slope of 1.00 (95% confidence interval [CI]: 1.00–1.00), and an intercept of 0.00 (95% CI: 0.00–0.00). When compared with the laboratory analyzer, microINR PST results also showed good correlation with a slope of 0.94 (95% CI: 0.86–1.04) and an intercept of 0.14 (95% CI: -0.09–0.34). Predicted bias values at international normalized ratio (INR) 2.0, 3.5, and 4.5 were 0% against HCP and ≤2.5% against the laboratory. Analytical agreement with both HCP and laboratory was 100% according to ISO17593 and 99.1 and 100% according to CLSI POCT14 with HCP and laboratory, respectively. Clinical agreement with HCP regarding 2.0–4.0 as INR therapeutic range was 98% (within range). The precision (coefficient of variation) of microINR system used by PST was comparable to HCP. Conclusion The microINR results when used by self-testing patients show satisfactory concordance to both HCP results and laboratory analyzer. The microINR system is adequate for self-testing use.

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.

Low Quality of Warfarin Therapy is Associated With Female Gender but Not With Polypharmacy in Patients With Atrial Fibrillation.

Background: We examined the impact of polypharmacy on the quality of the anticoagulation therapy in patients with atrial fibrillation. We also examined the factors that affect the stability of warfarin therapy. Methods and Results: This retrospective study was conducted using data from 157 consecutive outpatients with atrial fibrillation in a single tertiary referral hospital. Patients who were prescribed warfarin continuously and for whom PT-INR was examined at least three times in a year were included in this study. We examined the quality of warfarin therapy using time in the therapeutic INR range (TTR), percentage of PT-INR determinations in range (PINRR), and the coefficient variation (CV) of PT-INR. We found that the number of prescribed medicines was significantly associated with high BMI and low eGFR, but not with TTR, PINRR, and the coefficient variation of PT-INR in patients with atrial fibrillation. We also found that female gender was independently associated with low PINRR in this study population. Conclusion: Polypharmacy did not deteriorate the quality of warfarin therapy in patients with atrial fibrillation treated in the tertiary referral hospital. Female gender was an independent predictor of the low quality of warfarin therapy.

Evaluating the effects of socioeconomic status on stroke and bleeding risk scores and clinical events in patients on oral anticoagulant for new onset atrial fibrillation.

BackgroundThe risk of thromboembolism and bleeding before initiation of oral anticoagulant (OAC) in atrial fibrillation patients is estimated by CHA2DS2-VASc and HAS-BLED scoring system, respectively. Patients’ socioeconomic status (SES) could influence these risks, but its impact on the two risk scores’ predictive performance with respect to clinical events remains unknown. Our objective was to determine if patient SES defined by area deprivation index (ADI), in conjunction with CHA2DS2-VASc and HAS-BLED scores, could guide oral anticoagulation therapy.Methods and findingsThe study cohort included newly diagnosed patients with AF who were treated with warfarin. The cohort was stratified by the time in therapeutic range of INR (TTR), ADI, CHA2DS2-VASc, and HAS-BLED risk scores. TTR and ischemic and bleeding events during the first year of therapy were compared across subpopulations. Among 7274 patients, those living in the two most deprived quintiles (ADI ≥60%) had a significantly higher risk of ischemic events and those in the most deprived quintile (ADI≥80%) had a significantly increased risk of bleeding events. ADI significantly improved the predictive performance of CHA2DS2-VASc but not HAS-BLED risk scores.ConclusionADI can predict increased risk for ischemic and bleeding events in the first year of warfarin therapy in patients with incident AF.