Stable International Normalized Ratio Research Articles

Validity, sensitivity and specificity of a measure of medication adherence instrument among patients taking oral anticoagulants.

Although self-report instruments are currently considered a valuable tool for measuring adherence, due to their low cost and ease of implementation, there are still important factors that impact measurement accuracy, such as social desirability and memory bias. Thus, the Global Assessment of Medication Adherence Instrument (GEMA) was developed to provide an accurate measure of this construct. The aim of this study was to evaluate the properties of the measurement of the Global Evaluation of Medication Adherence Instrument (GEMA) among patients with chronic diseases. A methodological study was conducted in the public hospital of the state of São Paulo, Brazil. The adherence to anticoagulants as well as the international normalized ratio (INR) was assessed on 127 patients. Besides GEMA, two other instruments were used to assess adherence: the Morisky Medication Adherence Scale-8 (MMAS-8) and the Measurement of Adhesion to Treatments (MAT). The GEMA presented a satisfactory level of specificity (0.76) to identify adherents among those with a stable INR, low sensitivity (0.43) for the identification of non-adherents among those with an unstable INR, and a Positive Predictive Value of 0.70. Positive and weak to moderate correlations were observed between the proportion of doses assessed with GEMA and the scores on the MMAS-8 (r = .26 and r = .22, respectively) and the MAT (r = .22 and r = .30, respectively). The GEMA presented good practicality, acceptability, and evidence of specificity regarding the stability of the INR. The validity of the construct was partially supported by the relationship with self-reported measures of adherence.

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.

Anti-SARS-CoV-2 vaccination does not influence anticoagulation levels in stable long-term warfarin treatment.

Since the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, administration of the currently available vaccines has mostly been recommended for subjects at high risk, including elderly populations on long-term oral anticoagulation therapy (OAT) with warfarin. However, there is no clear evidence of the stability of the International Normalised Ratio (INR) after vaccine administration in those subjects on long-term OAT. The present study aimed to investigate the effects of COVID-19 vaccination on anticoagulation levels in patients on long-term OAT. INR values of patients on long-term OAT who had undergone anti-SARS-CoV-2 vaccination from January to June 2021 were monitored for a total of 90 days follow-up after the first vaccination dose. These were then compared with INR values before vaccination. The second dose, when required, was administered during follow-up. Inclusion criterion was stable long-term INR for at least 6 months before vaccination. Exclusion criteria were recent surgery, intercurrent diseases, or treatment with medication that could compromise findings in the 3 months before vaccination and during follow-up. No differences were observed in the anticoagulation levels before and after COVID-19 vaccination in any of the patients studied: mean INR values were 2.39 (range 2.20-2.63) before vaccination and 2.40 (range 2.16-2.76) after vaccination (p=0.5). There was no difference in anticoagulation levels in relation to age, sex, indication for OAT, or type of vaccine (p>0.5). No bleeding or thrombotic complications were documented during follow-up. These are the first data to be reported on anticoagulation levels in patients on stable OAT after COVID-19 vaccination. No influence on the quality of OAT was detected after the vaccination; no bleeding or thrombotic complications were recorded in the follow-up. No difference between the four available COVID vaccines was found. Dose adjustment was only required in a few cases, thus confirming the stability of anticoagulation levels.

Quality of Oral Anticoagulation in Atrial Fibrillation Patients at a Tertiary Hospital in Brazil.

ResumoFundamento A fibrilação atrial (FA) afeta de 0,5% a 2,0% da população geral e geralmente está associada a doenças estruturais cardíacas, comprometimento hemodinâmico e complicações tromboembólicas. A anticoagulação oral previne eventos tromboembólicos e é monitorada pela razão normalizada internacional (RNI).Objetivos Avaliar a estabilidade do RNI em pacientes com FA não valvar tratados com anticoagulante varfarina, avaliar complicações tromboembólicas ou hemorrágicas e identificar o grupo com risco mais alto de eventos tromboembólicos ou hemorrágicos.Métodos Dados de prontuários médicos de 203 pacientes atendidos em um hospital terciário no Brasil foram analisados e o tempo de intervalo terapêutico (TTR) foi calculado usando-se o método Rosendaal. Em seguida possíveis fatores que influenciam o TTR foram analisados e a relação entre TTR e eventos tromboembólicos ou hemorrágicos foi calculada. O nível de significância foi 5%.Resultados O TTR médio foi 52,2%. Pacientes com instabilidade de RNI na fase de adaptação tinham um TTR médio mais baixo (46,8%) do que aqueles sem instabilidade (53,9%). Entre os pacientes estudados, 6,9% sofreram eventos hemorrágicos e 8,4% tiveram um acidente vascular cerebral. O grupo com risco mais alto de acidente vascular cerebral e sangramento era composto de pacientes com instabilidade de RNI na fase de adaptação.Conclusões A qualidade da anticoagulação nesse hospital terciário no Brasil é semelhante à de centros de países em desenvolvimento. Pacientes com instabilidade de RNI maior na fase de adaptação evoluíram para um TTR médio mais baixo durante o acompanhamento, tinham uma chance de acidente vascular cerebral 4,94 vezes maior e uma chance de sangramento 3,35 vezes maior. Portanto, para esse grupo de pacientes, individualizar a escolha de tratamento anticoagulante seria recomendado, considerando-se a relação custo-benefício.

Influence of Vitamin D Status on the Maintenance Dose of Warfarin in Patients Receiving Chronic Warfarin Therapy.

IntroductionConsidering the anticoagulant actions of vitamin D, we hypothesize that vitamin D status might affect the required dose of warfarin for maintaining the therapeutic international normalized ratio (INR).MethodsIn a retrospective single-center cohort study, serum levels of 25-hydroxyvitamin D were assessed for 89 subjects receiving a stable dose of warfarin for 3 months or longer and had a stable INR between 2 and 3.5 for at least three consecutive visits. A warfarin sensitivity index (WSI), defined as the steady-state INR divided by the mean daily warfarin dose, was used for measuring the warfarin dose response. The relation between the serum level of 25-hydroxyvitamin D and WSI value and the difference in the mean WSI value between the subjects with different vitamin D status categories (sufficient, insufficient, and deficient) were assessed.ResultsTwenty-one subjects had vitamin D deficiency, 43 had vitamin D insufficiency, and only 25 had normal levels of 25-hydroxyvitamin D. Based on the multiple linear regression analysis, there was a significant but weakly positive correlation between WSI and 25-hydroxyvitamin D serum levels, as the value of WSI increases by almost 0.0027434 for every unit increase in 25-hydroxyvitamin D serum level (p value = 0.041). Using one-way ANOVA analysis, there was a trend in a significant difference between the groups with different vitamin D status categories regarding the mean WSI value (F = 2.95, p value = 0.057), as subjects with sufficient vitamin D state compared to those with vitamin D deficiency had a higher WSI value.ConclusionsAlthough the study’s limitations limit our ability to draw definite conclusions, the present data suggest that in addition to other traditional factors, vitamin D status might also affect warfarin sensitivity and maintenance dose requirement. However, to more clearly explain this link, further studies with high involvement subjects are required.

Feasibility study of the Fearon Algorithm in anticoagulation service guided warfarin management

BackgroundPatients receiving warfarin who spend a lower proportion of time in therapeutic international normalized ratio (INR) range (TTR) have a higher risk of both bleeding complications and thromboembolic events. Using warfarin dosing algorithms is one intervention associated with improved INR stability. ObjectiveTo determine the feasibility of an individualized warfarin dosing algorithm (Fearon Algorithm) under anticoagulation management service (AMS) care and compare measures of INR control using the algorithm with standard care. MethodsA pre/post intervention feasibility study consisting of the 12 months prior to patient enrollment (pre-study phase) and 6 months in which patients used the Fearon Algorithm under the supervision of an AMS pharmacist (AMS phase). The primary study outcome was the change in individual TTR. ResultsA total of 30 patients were enrolled in the study, 26 (87%) of whom successfully completed the AMS study phase using the Fearon Algorithm. Median corrected individual TTR increased significantly from 53% (IQR: 39%, 64%) during the year prior to enrollment to 63% (IQR: 57%, 73%) during the AMS phase (p < 0.01) The uncorrected TTR also increased significantly from 52% (IQR: 39%, 64%) to 61% (IQR: 57%, 72%) (p < 0.01). The Fearon Algorithm specified a smaller warfarin tablet strength in half the patients. ConclusionThe Fearon Algorithm is feasible for an AMS to implement in patients receiving long-term warfarin therapy and appears to improve TTR.

Urine Metabolites as a Predictor of Warfarin Response Based on INR in Atrial Fibrillation.

Warfarin is an anticoagulant with wide inter-individual variations in drug responses monitored based on the International Normalized Ratio (INR). It is commonly prescribed for Atrial Fibrillation (AF) and stroke. Oral anticoagulants (e.g., warfarin) reduce the risk of getting a stroke but increase the risk of hemorrhage. The proton Nuclear Magnetic Resonance (1H-NMR) pharmacometabonomics technique is useful for determining drug responses. Furthermore, pharmacometabonomics analysis can help identify novel biomarkers of warfarin outcome/ INR stability in urine. The focus of this research was to determine if urine metabolites could predict the warfarin response based on INR in patients who were already taking warfarin (identification; phase I) and to determine if urine metabolites could distinguish between unstable and stable INR in patients who had just started taking warfarin (validation; phase II). A cross-sectional study was conducted. Ninety urine samples were collected for phase 1, with 49 having unstable INR and 41 having stable INR. In phase II, 21 urine samples were obtained, with 13 having an unstable INR and eight having a stable INR. The metabolites associated with unstable INR and stable INR could be determined using univariate and multivariate logistic regression analysis. Multivariate Logistic Regression (MVLR) analysis showed that unstable INR was linked with seven regions. The urine pharmacometabonomics technique utilized could differentiate between the urine metabolite profiles of the patients on warfarin for INR stability. 1H-NMR-based pharmacometabonomics can help lead to a more individualized, controlled side effect for warfarin, thus minimizing undesirable effects in the future.

AVK overdose in Covid-19 infected patients.

During the Covid-19 pandemic, four patients were admitted to a healthcare centre. They were treated with vitamin K antagonists (AVK). We observed a substantial increase in their International Normalised Ratio (INR). The mean age of these patients was 90 (± 8 years). All had different usual long-term therapy treatments but had fixed doses of AVK to reach a stable INR. No changes to the background regimen were implemented. One patient presented a cough whereas the three others were asymptomatic. In the context of the pandemic, a reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 was carried out for each patient. The results of the RT-PCR rests were all positive and were associated with a substantially increased INR. Mr H. was admitted with an INR of 2.25 which increased to 5.93 the day after RT-PCR positivity. AVK treatment was stopped but the INR one day after was 7.89. Ms J. presented INR values between 1.96 and 4.58, 10 days later. a PCR test was conducted and AVK treatment was stopped, but the INR still increased to 5.85. The INR of Mr R. increased from 1.82 to 8.05, 24 hours after a positive PCR result. Ms F. presented a gradual increase in INR from 1.5 to 3.36, 72 hours after a positive PCR result and three days after discontinuation of AVK. This study suggest a link between the Covid-19 infection and an increased INR. It has been established that SARS-CoV-2 infection induces hypercoagulability in severe forms. Inversely, these four cases show a haemorrhagic risk as the INR increases. There could be a risk of overdose when patients are treated with AVK and are positive for Covid-19. This raises the question of discontinuing AVK and substituting it with another anticoagulant, or performing INR checks more frequently in the context of Covid-19. Moreover, an unexpected increase in INR should indicate the need to conduct a Covid-19 RT-PCR test in the context of this pandemic context.

The Effect of Serum Magnesium Level on Stable Anticoagulation in Patients Using Warfarin for Various Cardiac Indications.

Warfarin is a vitamin K antagonist agent that inhibits clotting factors used for long-term anticoagulation. Time in therapeutic range (TTR) in patients using warfarin is one of the primary treatment effectiveness requirements. We aim to investigate the relationship between serum magnesium levels, the international normalized ratio (INR) values, and TTR values in people using warfarin for various indications. Our study is a single-center, cross-sectional, and retrospective study that included 169 patients between 18 and 70 who used warfarin for various indications. Demographic data, biochemical analysis, and coagulation parameters, including TTR calculation, were evaluated for all patients. Those with a TTR value below 60 were defined as labile INR, and those with 60 and above as stable INR group and compared. The mean INR value was higher in the labile INR group than the stable INR group (3.7 ± 2.9, 3.2 ± 0.3, respectively; p = 0.030). The Mg values are significantly lower in the labile INR group than the stable group (1.8 ± 0.2mg/dL, 2.0 ± 0.1mg/dL, respectively; p < 0.001). In binary multivariate logistic regression analysis, magnesium value was the most influential INR stabilization factor (p < 0.001). As a result of our study, it was concluded that magnesium levels are an influential factor in stabilizing INR. We can state that we have contributed to the literature and can be a reference for future studies.

VKA overdose in Covid-19 infected patients

During the Covid-19 pandemic, four patients were admitted in a healthcare center. They were treated by vitamin K antagonists (VKA). We observed a substantially increased of their International Normalized Ratio (INR) The mean age of patients was 90 (± 8). All had different usual long-term therapy treatments but had fixed doses of VKA to reach a stable INR. No change of background treatment were realized. One patient presented cough whereas the three others were asymptomatic. In the pandemic context, a reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 was realized for each patients. RT-PCR were all positives and were associated with a substantially increased INR. Mr H. was admitted with an INR of 2.25 and it increased to 5.93 the day after RT-PCR positivity. The VKA treatment was stopped but the INR one day after was 7.89. Mrs J. presented INR value from 1.96 to 4.58, 10 days later. PCR have been realized and VKA treatment was stopped: INR still increased up to 5.85. The INR of Mr R. increased from 1.82 to 8.05, 24h after positive PCR results. Mrs F. presented a gradually increase of INR from 1.5 to 3.36, 72h after PCR results three days after VKA discontinuation. Finally, this study suggest a link between the Covid-19 infection and an increased INR. It has been established that SARS-CoV-2 infection induces hypercoagulability in severe forms. Inversely, these four cases show a hemorrhagic risk with the elevation of the INR. It could have a risk of overdose when patients treated with VKA and positive to Covid-19. This raises the question of discontinuing VKA and substituting them with another anticoagulant, or performing INR controls more frequently in the context of Covid-19. Moreover, an unexpected increase of INR could lead to realize a Covid-19 RT-PCR in this pandemic context.

Acenocoumarol Pharmacogenetic Dosing Algorithm versus Usual Care in Patients with Venous Thromboembolism: A Randomised Clinical Trial.

Patients with venous thromboembolism (VTE) require immediate treatment with anticoagulants such as acenocoumarol. This multicentre randomised clinical trial evaluated the effectiveness of a dosing pharmacogenetic algorithm versus a standard-of-care dose adjustment at the beginning of acenocoumarol treatment. We included 144 patients with VTE. On the day of recruitment, a blood sample was obtained for genotyping (CYP2C9*2, CYP2C9*3, VKORC1, CYP4F2, APOE). Dose adjustment was performed on day 3 or 4 after the start of treatment according to the assigned group and the follow-up was at 12 weeks. The principal variable was the percentage of patients with an international normalised ratio (INR) within the therapeutic range on day 7. Thirty-four (47.2%) patients had an INR within the therapeutic range at day 7 after the start of treatment in the genotype-guided group compared with 14 (21.9%) in the control group (p = 0.0023). There were no significant differences in the time to achieve a stable INR, the number of INRs within the range in the first 6 weeks and at the end of study. Our results suggest the use of a pharmacogenetic algorithm for patients with VTE could be useful in achieving target INR control in the first days of treatment.

COVID-19 Pandemic: Can We Adapt a System-wide Warfarin Monitoring Program and Maintain Safety

The novel coronavirus disease-2019 (COVID-19) was first reported in Ohio on March 9, 2020. We instituted policies regarding essential/nonessential visits and procedures and limiting patient and provider contact. Our 11 center hospital-based anticoagulation monitoring service (AMS) used a multifaceted approach to limit in-office visits for international normalized ratio (INR) monitoring: encouraging use of alternative agents, redistributing patients to lower volume centers, increased visit intervals for low risk patients with stable INR, and home point-of-care testing (POCT) for vulnerable patients.

A network meta-analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype-based warfarin dosing strategies compared to traditional.

Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype-based warfarin dosing. We carried out a network meta-analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, with CYP2C9 alone and CYP2C9, VKORC1, with CYP4F2 dosing strategies. Electronic records were searched for RCTs comparing genotype-based warfarin with traditional-dosing strategies. Key outcomes included were the time to first therapeutic international normalized ratio (INR); time to stable INR or warfarin dose; percent time in therapeutic range (TTR); and the proportion of patients with supra-therapeutic INR. Weighted mean differences (WMD) and odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates. Twenty-six studies (7898 patients) were included. CYP2C9-based warfarin dosing was associated with a shorter time to first therapeutic INR (WMD: -2.73, 95% CI: -3.41, -2.05) and stable INR/warfarin dose (WMD: -8.1, 95% CI: -12.54, -3.66). CYP2C9 and VKORC1 were observed with a shorter time to first therapeutic INR (WMD: -1.92, 95% CI: -3.23, -0.61) and stable INR/warfarin dose (WMD: -4.6, 95% CI: -6.87, -2.34) along with a longer TTR (%) (WMD: 3.91, 95% CI: 1.18, 6.63). CYP2C9, VKORC1 and CYP4F2 were observed with a reduced proportion of patients with supra-therapeutic INR (OR: 0.68, 95% CI: 0.49, 0.93). Trial sequential analysis confirms the superior benefits of CYP2C9 with VKORC1 genotype. The present evidence is supportive of personalizing warfarin dose based only on CYP2C9 and VKORC1 genotypes compared to traditional strategies. More RCTs are needed to delineate any benefit for adding CYP4F2 to provide sufficient power for pooled analysis. No convincing evidence exists supporting the role of CYP2C9 alone.

Clinical Impact of COVID-19 on Anticoagulation Management at the William S. Middleton Memorial Veterans Hospital

BACKGROUNDThe COVID-19 pandemic has extensively impacted the delivery of routine medical care including anticoagulation management. The Veterans Affairs Clinical Pharmacy Practice Office (VA CPPO) has provided guidance to assist anticoagulation clinic providers in developing action plans to determine the risk vs benefit of delaying routine monitoring to reduce patient risk of COVID-19 exposure in the health care system.Frequent laboratory monitoring of the International Normalized Ratio (INR) is needed to reduce the risk of bleeding and thromboembolic events for patients on warfarin. The Madison VA standard of care (SOC) includes routine INR monitoring at least every 6 weeks for stable patients taking warfarin. Alternatively, the benefit of routine laboratory monitoring for direct oral anticoagulants (DOACs) is less clear. Currently, the Madison VA recommends a complete blood count (CBC), serum creatinine (SCr), and liver function tests (LFTs) within 30 days prior to DOAC initiation, repeat CBC +/- SCr 1-3 months after DOAC initiation, then CBC/SCr every 6-12 months, monitored via the VA DOAC population management tool (PMT).Per the 2012 American Society of Hematology (ASH) and the American College of Chest Physicians (CHEST) guidelines, for warfarin, 12-week follow-up may be considered in patients with chronically stable INRs (Kearon et. al. Chest 2012). Additionally, the Madison VA completed a prior prospective study of 12-week INR follow-up for patients taking warfarin which demonstrated safety of extended follow-up intervals. However, the number of participants able to achieve (56%) and maintain (34%) a 12-week INR follow-up were lower than anticipated (Porter et. al. J Thromb Thrombolysis 2016).As of 3/30/2020, the Madison VA anticoagulation clinic followed 783 patients for warfarin management and 1742 patients for DOAC management.STUDY DESIGN AND METHODSA retrospective chart review to assess practice changes during the COVID-19 pandemic was conducted on anticoagulation patients with visits from 3/16/20 and 6/18/20 who were either on warfarin, transitioned to a DOAC, or newly initiated on DOAC therapy.For patients on warfarin with 2 therapeutic INRs obtained at least 4 weeks apart, follow-up was extended to 8-12 weeks. Conversion to a DOAC was considered for eligible warfarin patients, excluding presence of mechanical heart valves, moderate to severe mitral valve stenosis, significant liver disease (Child Pugh C), or pregnancy/breastfeeding. As there are no accepted standards for DOAC laboratory monitoring, per the VA CPPO, stable baseline labs within the prior 6-12 months were acceptable. Routine laboratory monitoring after initiation could also be deferred and patients were transitioned to the DOAC PMT.The data collected in the retrospective study was analyzed using descriptive statistics.OBJECTIVESThe objective of this study was to assess patient safety and INR stability using the proposed COVID-19 extended follow-up parameters. If patient safety and stability could be maintained, it may lead to long term practice changes to extend follow-up and improve the anticoagulation clinic workload efficiency.ENDPOINTSThe primary endpoint of the warfarin intervention was to determine the percentage of warfarin patients with therapeutic INRs after an extended interval. Secondary endpoints included the average length of the extended interval, bleeding or thromboembolic events during extended interval or within 30 days after the extended INR result. Other secondary endpoints included review of patient misadventures during the extended interval (e.g. patient taking incorrect warfarin doses), the percentage of patients with phone follow-up between extended INRs, and clinic time in therapeutic range (TTR).The primary endpoint of the DOAC transition intervention was to determine the percentage of warfarin patients transitioned to DOACs during the specified timeframe. Secondary endpoints included the average time since last CBC/SCr for those transitioning from warfarin or newly initiating DOAC, percentage of patients without an INR at time of transition, and bleeding or thromboembolic events within 30 days of transition.DisclosuresNo relevant conflicts of interest to declare.

Plasma Metabolites as Predictors of Warfarin Outcome in Atrial Fibrillation.

Warfarin is prescribed as an oral anticoagulant to treat/prevent thromboembolism in conditions such as atrial fibrillation. As there is a narrow therapeutic window, treatment with warfarin is challenging. Pharmacometabonomics using nuclear magnetic resonance (NMR) spectroscopy may provide novel techniques for the identification of novel biomarkers of warfarin. The aim was to determine the metabolic fingerprint that predicts warfarin response based on the international normalized ratio (INR) in patients who are already receiving warfarin (phase I: identification) and to ascertain the metabolic fingerprint that discriminates stable from unstable INR in patients starting treatment with warfarin (phase II: validation). A total of 94 blood samples were collected for phase I: 44 patients with stable INR and 50 with unstable INR. Meanwhile, 23 samples were collected for phase II: nine patients with stable INR and 14 with unstable INR. Data analysis was performed using multivariate analysis including principal component analysis and partial least square-discriminate analysis (PLS-DA), followed by univariate and multivariate logistic regression (MVLR) to develop a model to identify unstable INR biomarkers. For phase I, the PLS-DA model showed the following results: sensitivity 93.18%, specificity 91.49% and accuracy 92.31%. In the MVLR analysis of phase I, ten regions were associated with unstable INR. For phase II, the PLS-DA model showed the following results: sensitivity 66.67%, specificity 61.54% and accuracy 63.64%. We have shown that the pharmacometabonomics technique was able to differentiate between unstable and stable INR with good accuracy. NMR-based pharmacometabonomics has the potential to identify novel biomarkers in plasma, which can be useful in individualizing treatment and controlling warfarin side effects, thus, minimizing undesirable effects in the future.

Genetic variations in the transcription factors GATA4 and GATA6 and bleeding complications in patients receiving warfarin therapy.

Purpose: GATA4 and GATA6 are known to have potential roles in vascular regulation by affecting vascular smooth muscle cell differentiation and atrial natriuretic peptide levels. The aim of this retrospective study was to investigate the associations between GATA4 and GATA6 polymorphisms and bleeding complication risk at a therapeutic international normalized ratio (INR) in patients with mechanical heart valves.Patients and methods: Study patients were included from the Ewha-Severance Treatment (EAST) Group of Warfarin. It consisted of 229 patients who received warfarin therapy after undergoing mechanical heart valve replacement and maintained a stable INR (INR of 2.0–3.0 for at least three consecutive times). Twenty single-nucleotide polymorphisms including VKORC1, CYP2C9, GATA4, and GATA6 were analyzed. Multivariate logistic regression analysis was employed to investigate the independent risk factors for bleeding complications. To evaluate the potential clinical value of genotyping for preventing bleeding complications in patients with high-risk genotype, the number needed to genotype (NNG) was also calculated.Results: One hundred forty-two patients were included in this study, 21 of whom had bleeding complications. After adjusting covariates, TT genotype carriers of rs13273672 in GATA4 and CC genotype carriers of rs10454095 in GATA6 showed 5.0- (95% CI, 1.6–15.7) and 3.1-fold (95% CI, 1.1–8.7) higher bleeding complications than carriers of C allele and T allele, respectively. NNG for preventing one patient from experiencing bleeding complications in patients with TT genotype of rs13273672 and CC genotype of rs10454095 was 22.2 and 17.5, respectively. Patients with both TT genotype in rs13273672 and CC genotype in rs10454095 showed 8.7-fold (95% CI, 1.7–46.1) higher bleeding complications than those with other genotypes. NNG in patients having both TT genotype in rs13273672 and CC genotype in rs10454095 was calculated to be 40.0.Conclusions: This study showed that GATA4 and GATA6 gene polymorphisms could affect bleeding complications during warfarin treatment in patients with mechanical heart valves.

Time-driven activity-based cost analysis for outpatient anticoagulation therapy: direct costs in a primary care setting with optimal performance

Objectives: To determine how overall cost of anticoagulation therapy for warfarin compares with that of Novel Oral Anticoagulants (NOACs). Also, to demonstrate a scientific, comprehensive, and an analytical approach to estimate direct costs involved in monitoring and management of anticoagulation therapy for outpatients in an academic primary care clinic setting, post-initiation of therapy.Methods: A population-based cross-sectional study was conducted in conjunction with observations of patient care processes between August 2014 and January 2015. The study was conducted in an academic primary care outpatient setting at Mayo Clinic’s warfarin anticoagulation clinic, Rochester, MN. The anticoagulation clinic serves patients 18 years of age or older in Warfarin therapy management, for any indication, after referral from the patient’s primary care provider. The study included anticoagulation clinic enrollment data on a population of 5,526 patients. Time-Driven Activity-Based Costing (TDABC) technique was applied. Detailed process flow maps which showed process steps for all the anticoagulation program components and care continuum phases were created. Staff roles associated with each of the process steps were identified and displayed on the maps. Process times and costs were captured and analyzed. The main outcome was direct cost of monitoring and management of anticoagulation therapy, post-initiation of therapy.Results: The cost of warfarin management for patients who display unstable International Normalized Ratio (INR) is more than three times those who display stable INR over time. (Comparator to distinguish stability: Frequency of point-of-care visits needed by patients.) For complex anticoagulation patients, total cost of medication and monitoring for warfarin anticoagulation therapy is similar to that for NOACs.Conclusion: Despite warfarin being significantly less expensive to purchase than NOACs, overall warfarin management incurs higher costs due to laboratory monitoring and provider time than NOACs. NOAC treatment, therefore, may not be more expensive than warfarin therapy management for complex anticoagulation patients.

Effects of formulation types on pharmacodynamics of warfarin in patients with cerebral infarction and dysphagia.

PurposeThe purpose of this study was to investigate the effects of the type of formulation on the efficacy of warfarin.Materials and methodsThe electronic medical records of patients with cerebral infarction, who were administered tablet or powder formulations of warfarin from 2013–2015, were retrospectively analyzed. Clinical data, changes in the international normalized ratio (INR), the warfarin dose, and the time to reach the plasma warfarin concentration that could induce an adverse effect, such as bleeding, were evaluated. Coefficients of variation of INR and of the warfarin dose, as well as the warfarin sensitivity index (WSI), were used to evaluate the INR stability. Statistical analysis of the data was performed using a independent t-test. Additionally, survival analysis was performed.ResultsThe data showed that 57 and 137 patients were administered warfarin as powder and tablet formulations, respectively. We noted that INR, WSI, and INR/dose × body weight differed significantly between the two groups of patients. The median survival times to reach the plasma warfarin concentration that could induce adverse effects were 3.6 and 4.2 days of treatment with the powder and tablet formulations, respectively. The efficacy of warfarin was higher when the drug was administered as a powder than when it was administered as a tablet.ConclusionThe findings of this study indicate that INR should be carefully monitored in the first 4 days of warfarin administration as a powder formulation.

Circannual variations in the international normalized ratio (INR) among mechanical heart valve surgery patients on life-long warfarin

The aim of our study was to explore if there exists a circannual rhythm in INR as fluctuations in anti-coagulation can have serious consequences in patients with mechanical heart valve prosthesis. This is a retrospective study performed in patients with stable INR value for at least 30 days post heart valve surgery in the period 2015–2016 attending a nurse-managed, cardiologist-supervised anti-coagulation clinic at King Abdul Aziz Cardiac Center.we determined average seasonal INR values for each patient, separately for aortic and mitral valve replacement patients. Data were analyzed using JMP Version 7.1, p < 0.05 considered significant. Results are expressed as mean ± SEM, differences between means were analyzed using Wilcoxon-rank sums test and chi-square as appropriate. Seasonal changes in INR were analyzed using analysis of variance of repeated measures (MANOVA), adjusting for potential confounders. Data Collected for 397 patients (mean age 50 ± 0.7 years, 56% male) with a total of 6,220 INRs; 4149 in the high target (2.5–3.5) and 2021 in the low target (2–3) patients. There was no significant difference in the number of INR determinations performed across seasons. INR decreased significantly with time, from the highest value in the summer at 2.8 ± 0.07 to lowest in winter at 2.6 ± 0.02 (p < 0.0001), irrespective of the target INR (p = 0.36). There was no significant interaction between time-related changes in INR and age, gender, INR target, renal impairment, concomitant anti-platelet treatment except for smoking, which showed a significant interaction with INR variation over time (p < 0.001). To the best of our knowledge. This is the first study in the Middle-East extending European and North-American data on circannual changes in INR. Our results confirm the existence of such a rhythm; however the mechanism is unknown. Our findings recognize winter as a challenging season for maintaining optimum anti-coagulation, possibly requiring higher number of outpatient visits and INR determinations, with implications for health care costs.

Genotype-guided warfarin dosing vs. conventional dosing strategies: a systematic review and meta-analysis of randomized controlled trials.

Previous trials on the effectiveness of genotype-guided warfarin dosing vs. conventional dosing have been inconclusive. We conducted a systematic review and meta-analysis of randomized trials comparing genotype-guided to conventional dosing strategies. PubMed and the Cochrane Library were searched up to 23 October 2017. A total of 76 and 94 entries were retrieved were retrieved from PubMed and the Cochrane Library, respectively. A total of 2626 subjects in the genotype-guided dosing (mean age 63.3 ± 5.8years; 46% male) and 2604 subjects in the conventional dosing (mean age 64.7 ± 6.1years; 46% male) groups (mean follow-up duration 64days) from 18 trials were included. Compared with conventional dosing, genotype-guided dosing significantly shortened the time to first therapeutic international normalized ratio (INR) (mean difference 2.6days, standard error 0.3days; P < 0.0001; I2 0%) and time to first stable INR (mean difference 5.9days, standard error 2.0days; P < 0.01; I2 94%). Genotype-guided dosing also increased the time in therapeutic range (mean difference 3.1%, standard error 1.2%; P < 0.01; I2 80%) and reduced the risks of both excessive anticoagulation, defined as INR ≥4 [risk ratio (RR) 0.87; 95% confidence interval (CI) 0.78, 0.98; P < 0.05; I2 : 0%), and bleeding (RR 0.82; 95% CI 0.69, 0.98; P < 0.05; I2 31%). No difference in thromboembolism (RR 0.84; 95% CI 0.56, 1.26; P = 0.40; I2 0%) or mortality (RR 1.16; 95% CI 0.46, 2.91; P = 0.76; I2 0%) was observed between the two groups. Genotype-guided warfarin dosing offers better safety with less bleeding compared with conventional dosing strategies. No significant benefit on thromboembolism or mortality was evident.