Variation Of International Normalized Ratio Research Articles

Analysis of acenocoumarol and levofloxacin interaction in elderly institutionalized patients

ObjectiveTo analyze the interaction between acenocoumarol and levofloxacin in the elderly. We also assessed how hypoalbuminemia affects international normalized ratio variation. MethodRetrospective study carried on elderly institutionalized patients who were prescribed levofloxacin concomitantly with acenocoumarol. International normalized ratio variation during levofloxacin treatment was analyzed with the t-Student test. Correlation between albuminemia and international normalized ratio variation was calculated using Pearson's correlation coefficient. ResultsThe mean international normalized ratio previous to treatment with levofloxacin was 2.5 (standard deviation: 0.6) and during treatment it was 4.7 (standard deviation: 1.9) (p < 0.05). In 54.3% of the cases, the international normalized ratio value was equal to or greater than 4.5. Not linear association between albuminemia and international normalized ratio increase was found using Pearson's test (R = –0.16). ConclusionsIn more than half of the occasions international normalized ratio raised to clinically rellevant values (≥ 4.5). No influence of hypoalbuminemia in the increase in international normalized ratio was shown.

Comparative Assessment of Routine Haemostasis Parameters of Diabetics with or Without Hypertension Attending Sokoto Specialist Hospital, Nigeria

Background: The pathological events during diabetes mellitus (DM) and hypertension (HTN) could induce hyper-vascular injuries and coagulopathies in affected patients. Thus, this prospective comparative study aims to assess the prothrombin time (PT), partial thromboplastin time with kaolin (PTTK) and international normalized ratio (INR) as biomarkers of potential coagulopathies in diabetics with hypertension (test group) and those without hypertension (control group) at Specialist Hospital Sokoto, North-western Nigeria. Materials and methods: Whole blood samples were obtained from 74 diabetic patients with hypertensive and 37 diabetic patients without hypertension and analysed for the PT, PTTK and INR values using commercially available kits. The sociodemographic variables of the enrolled participants were collated and statistically analysed against the coagulometric values using suitable tests. Results: Participants between 50-59 years (39.2%) were the most frequently enrolled participants, followed by 40-49 years (29.73%). Females comprised 56.8% while males were 43.2% of the participants. The PT, PTTK and INR were not statistically significant between diabetes with hypertension and diabetes without hypertension which were (9.22 ± 1.78, 30.27 ± 18.18 and 0.70 ± 0.15) and (9.51 ± 1.85, 36.57 ± 17.17 and 0.72 ± 0.14) respectively (p = 0.532, p = 0.061 and p= 0.575). The age group of the subjects showed a significant increase in PTTK when compared with PT and INR (p = 0.392, p = 0.002 and p = 0.467). There were increases but statistically non-significant in PTTK when compared with PT and INR based on occupation (p =0.833, p = 0.000 and p = 0.779) respectively. Conclusion: Findings from this study showed no significant variation in PT, PTTK and INR of diabetics and diabetics with hypertension. However, future studies could be done to focus on platelet factors and other highly sensitive biomarkers of the coagulation system of these populations. Nevertheless, monitoring the PTTK in older diabetic patients with diabetes mellitus is important to prevent hypercoagulation.

Semi-empirical anticoagulation model (SAM): INR monitoring during Warfarin therapy.

The International Normalized Ratio (INR) monitoring is an essential component to manage thrombotic disease therapy. This study presents a semi-empirical model of INR as a function of time and assigned therapy (Warfarin, k-vitamin). With respect to other methodologies, this model is able to describe the INR using a limited number of parameters and is able to describe the time variation of INR described in the literature. The presented methodology showed great accuracy in model calibration [(trueness (precision)]: 0.2% (0.1%) to 1.2% (0.3%) for coagulation factors, from 5% (9%) to 9.7% (12%) for Warfarin-related parameters and 38% (40%) for K-vitamin-related parameters. The latter value was considered acceptable given the assumptions made in the model. It has two other important results: the first is that it was able to correctly estimate INR with respect to daily therapy doses taken from the literature. The second is that it introduces a single numeric semi-empirical parameter that is able to correlate INR/dose response to physiological and environmental condition of patients.

You cannot always warfawin: a case of significant INR fluctuation with brand to generic conversion of warfarin

Background: Warfarin is affected by many variables such as diet, alcohol, and medications; however, it is unclear if brand to generic conversion may also play a role. This case reports a patient with fluctuating international normalized ratio (INR) while being switched from brand to generic temporarily. Case Presentation: A 60-year-old obese white male taking brand name Jantoven© (warfarin) at home for 9 years at a consistent dose for atrial fibrillation was in hospital for treatment of cellulitis. He was switched to generic warfarin at his home dose on admission. While in hospital, he required dose escalation to three times his home dose to achieve a therapeutic INR. Conclusion: Generic warfarin may have different effects on INR when compared to brand name Jantoven©. More research is warranted to determine if differences may truly exist and potential ways to address the issue. Until then, providers should be cognizant of interchanging the two products to monitor for INR variation.

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.

Qualitative study of patient experiences of responsibility in warfarin therapy.

Results of a study to characterize the experiences of warfarin-treated patients, including their experiences in taking medication, communicating with clinical pharmacists, and International Normalized Ratio (INR) monitoring, are reported. A qualitative analysis of data obtained during interviews with 40 patients at a Veterans Affairs medical center warfarin clinic was conducted. In semistructured interviews, the patients were asked to describe the process whereby their INR values were monitored by pharmacists and their understanding of self-management responsibilities, including medication adherence and implementation of lifestyle modifications that might influence the effectiveness of anticoagulation therapy. Analysis of interview results indicated that patients' experience in the event of variation in INR levels is characterized by misperceptions of the instructions regarding appropriate dietary and lifestyle behaviors, misattribution of responsibility for abnormal readings, and provider uncertainty in ascertaining causation for out-of-range INR values. Patients frequently reported that they interpret pharmacist questions to imply that they are responsible for variable INR values. This perception may indirectly lead to adverse consequences such as withholding of information from anticoagulation care providers and skipping clinic appointments, which could in turn result in suboptimal clinical outcomes. Analysis of results of qualitative interviews of patients receiving warfarin indicated that patients may interpret routine questioning about INR variation as implying that they are to blame for poor anticoagulation control.

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.

International normalized ratio (INR) testing in Europe: between-laboratory comparability of test results obtained by Quick and Owren reagents.

Abstract Background: This study was designed to obtain an overview of the analytical quality of the prothrombin time, reported as international normalized ratio (INR) and to assess the variation of INR results between European laboratories, the difference between Quick-type and Owren-type methods and the effect of using local INR calibration or not. In addition, we assessed the variation in INR results obtained for a single donation in comparison with a pool of several plasmas. Methods: A set of four different lyophilized plasma samples were distributed via national EQA organizations to participating laboratories for INR measurement. Results: Between-laboratory variation was lower in the Owren group than in the Quick group (on average: 6.7% vs. 8.1%, respectively). Differences in the mean INR value between the Owren and Quick group were relatively small (&lt;0.20 INR). Between-laboratory variation was lower after local INR calibration (CV: 6.7% vs. 8.6%). For laboratories performing local calibration, the between-laboratory variation was quite similar for the Owren and Quick group (on average: 6.5% and 6.7%, respectively). Clinically significant differences in INR results (difference in INR&gt;0.5) were observed between different reagents. No systematic significant differences in the between-laboratory variation for a single-plasma sample and a pooled plasma sample were observed. Conclusions: The comparability for laboratories using local calibration of their thromboplastin reagent is better than for laboratories not performing local calibration. Implementing local calibration is strongly recommended for the measurement of INR.

Population Impact of Drug Interactions with Warfarin: A Real-World Data Approach.

To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels. Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 (N = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t-test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3). Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%). Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users.

Coagulometer international sensitivity index (ISI) derivation, a rapid method using the prothrombin time/international normalized ratio (PT/INR) Line: a multicenter study

The original WHO procedure for prothrombin time (PT) standardization has been almost entirely abandoned because of the universal use of PT coagulometers. These often give different international normalized ratio (INR) results from the manual method, between individual makes of instruments and with instruments from the same manufacture. A simple procedure is required to derive local INR with coagulometers. The PT/INR Line method has recently been developed using five European Concerted Action on Anticoagulation (ECAA) certified plasmas to derive local INR. This procedure has been modified to derive a coagulometer PT/INR Line providing International Sensitivity Index (ISI) and mean normal PT (MNPT) for coagulometers and give local INR. Results have been compared with conventional ISI calibrations at the same laboratories. With human thromboplastins, mean ISI by local calibration was 0.93 (range: 0.77-1.16). With the PT/INR Line, mean coagulometer ISI was higher, for example 0.99 (0.84-1.23) but using the PT/INR Line derived MNPT there was no difference in local INR. Between-centre INR variation of a certified validation plasma was reduced with human and bovine reagents after correction with local ISI calibrations and the PT/INR Line. The PT/INR Line-ISI with its derived MNPT is shown to provide reliable local INR with the 13 different reagent/coagulometer combinations at the 28 centres in this international study.

Improved Oral Anticoagulation After a Dietary Vitamin K–Guided Strategy

Dietary vitamin K is thought to be an important factor that interferes with anticoagulation stability, but the clinical applicability of this interaction has not been evaluated adequately in prospective studies. In a randomized controlled trial that enrolled outpatients with a recent international normalized ratio (INR) outside the therapeutic target, we compared 2 strategies to optimize long-term oral anticoagulation: (1) a conventional approach based on changes in anticoagulant prescription and (2) a dietary vitamin K-guided strategy based on simple modifications of the amount of vitamin K-rich foods ingested per week. The primary efficacy end point was the percentage of patients who achieved a prespecified INR target at 90 days after randomization. Study population (n=132) predominantly included men with mechanical heart prostheses (58%) or atrial fibrillation (35%). Over time, patients allocated to the vitamin K-guided strategy reached the prespecified INR more frequently so that after 90 days of follow-up, 74% were on target compared with 58% of patients managed conventionally (P=0.04). Patients allocated to the dietary vitamin K-guided strategy had the same magnitude and direction of INR variation as those observed with the conventional approach in the short term (15 days) for both underanticaogulated and overanticoagulated patients. Minor bleeding or use of parenteral vitamin K were also marginally less frequent in patients managed according to the dietary intervention (1 [1.5%] versus 7 [11%]; P=0.06). A vitamin K-guided management strategy to adjust long-term oral anticoagulation is feasible and safe and may result in an increased chance of reaching target levels of INR.

Intrahospital Correlation of the International Normalized Ratio

Background. Monitoring of oral anticoagulant therapy (OAT) is usually accomplished by measuring prothrombin time and the international normalized ratio (INR). However, thromboplastins have different responsiveness and sensitivity to vitamin K-dependent coagulation factors depletion. Several studies have shown INR variation when low sensitive thromboplastins are used. This study compared INR variability between two laboratories using highly sensitive thromboplastins. Methods. A total of 237 plasmas were tested, half of them from patients under OAT. Samples were tested simultaneously in two laboratories: in laboratory A, a Behring Coagulation Timer instrument and a human recombinant thromboplastin (Innovin, Dade Behring) (ISI 1.01) were used. In laboratory B, a Thrombolyzer Compact (Behnk Elektronik) and a rabbit brain thromboplastin (Simplastin Excel S, Organon Teknika) with an ISI of 1.30 were used. Statistical analysis was carried out according to the method of Bland and Altman. Results. Even though high correlation coefficients were obtained when comparing both laboratories, Bland-Altman analysis showed a variation of INR between laboratories ranging from -0.77 to +1.07. After logarithmic transformation of data, these values yielded a variation of the INR either 25% below or 44% above. Conclusions. These results are clearly inadequate for clinical use because such a variation would most probably induce the clinician to make a change in warfarin dose. Standardization of instruments, reagents, and controls is warranted to decrease this variation.

Changes in International Normalized Ratio (INR) and Model for Endstage Liver Disease (MELD) Based on Selection of Clinical Laboratory

Priority for liver transplantation is based on the Model for Endstage Liver Disease (MELD) score, a mathematical function which includes international normalized ratio (INR). We present an analysis to determine the lab-to-lab variation in INR at 14 clinical laboratories across the United States. We performed a survey to identify representative clinical laboratories across the United States, where INR was measured in the determination of MELD score. Five 'standard' samples for INR were formulated and were sent to the 14 clinical laboratories to determine variation in INR and MELD score. Among the 14 clinical laboratories, the range in INR for the five samples was: sample 1 (1.2-2.0), sample 2 (1.4-2.5), sample 3 (1.7-3.4), sample 4 (1.9-3.7) and sample 5 (2.4-5.1). The range in calculated MELD score was: sample 1 (8-14), sample 2 (10-17), sample 3 (12-20), sample 4 (14-21) and sample 5 (16-25). The selection of the clinical laboratory used to determine INR may result in substantial changes in MELD score independent of severity-of-illness. These data suggest that further review of interlaboratory variation in MELD should be undertaken because of the potential impact on prioritization for liver transplantation.

The influence on INRs and coagulation factors of the time span between blood sample collection and intake of phenprocoumon or acenocoumarol: Consequences for the assessment of the dose

Managing treatment with vitamin K antagonists, the prothrombin time (PT), expressed as international normalized ratio (INR), may not represent the INR during the entire 24 hour (h) period, and this variation may be different between long-acting phenprocoumon and short-acting acenocoumarol. For both drugs we investigated the variation in 24 h of the PT/INR, the consequencesfor the assessment of the doses and which vitamin K-dependent factor causes the daily variation. Patients on self-management took their medication at 6 p.m. and determined their INRs for eight weeks, once a week and three times daily (8.30 a.m., 6 p.m. and 11 p.m., thus 14.5 h, 24 h and 29 h after taking the medication, respectively). Acenocoumarol showed a significant variation in INRs over the 24 h period, with 22 out of 80 INRs >20% lower at 11 p.m. versus 8.30 a.m. Phenprocoumon showed only few variations. Patients managed by the anticoagulation clinic took their medication at 6 p.m. for four weeks and then at 8 a.m. for four weeks, 15 h and 25 h, respectively, before the weekly blood collection. PT/INR and coagulation factors VII, X and II were determined. With acenocoumarol, taken 25 h before blood collection, the INRs were significantly different compared to 15 h, especially attributed to plasma levels of factor VII. Those on phenprocoumon were equal. These variations of INRs during 24 h may have major effects on the prescribed dose of short-acting vitamin K antagonists, such as acenocoumarol, especially for INRs at the limits of the therapeutic ranges.

In a MELD-based economy, how can we fight off inflation?

In a MELD-based economy, how can we fight off inflation?

Are Brand-Name and Generic Warfarin Interchangeable? Multiple N-of-1 Randomized, Crossover Trials

Warfarin is a commonly used anticoagulant in North America. Several generic formulations have been approved, raising concern over the safety and efficacy of these products compared with brand-name Coumadin. To ensure that generic warfarin products can be safely interchanged with Coumadin. Multiple n-of-1 randomized, double-blind, crossover trials switched outpatients (N = 7) between a generic warfarin formulation (Apo-warfarin) and Coumadin over 30 weeks. Study patients took each drug for five 3-week periods, with international normalized ratio (INR) measurements taken twice per period. Inter- and intrapatient differences between generic warfarin and Coumadin were compared, and overall study patient results were compared with those of a Coumadin control group. There were no differences between warfarin products in terms of mean INR results or number of dosage adjustments required. There also was no difference in INR variation based on warfarin formulation (p > 0.69), nor was a patient and warfarin interaction found (p > 0.81). The INR results were not influenced by whether patients were maintained on Coumadin only (control group) or interchanged between Coumadin and generic warfarin (p = 0.98). It appears that patients can safely and effectively switch between generic warfarin and Coumadin.

Are brand-name and generic warfarin interchangeable?

Although Health Canada approved generic warfarins in Year 2000, there is still controversy over the interchangeability of these products with brand-name Coumadin. Since a large population of patients require warfarin and it has a narrow margin of efficacy and safety, it is vital to ensure that generic brands can be safely interchanged with Coumadin. Multiple N-of-1 randomized double blind crossover trials switched outpatients between generic warfarin and Coumadin over a period of thirty weeks. Study patients were on each drug for 5 × 3-week periods with International Normalized Ratio (INR) measurements twice per period. Outcomes included mean INR results and proportion of dosage adjustments that were required with each brand. Inter-patient and intra-patient differences between generic warfarin and Coumadin were compared. Study patient results were also compared with those of a retrospective control group, maintained on Coumadin only. The 6 patients (96% power to detect a difference of greater than 0.5 INR units between warfarin brands) showed no significant difference between warfarin brands in terms of mean INR results (p = 0.485) and proportion of dosage adjustments required with each brand (p = 0.264). Study patients experienced less inter- and intra-subject INR variation than the historical control group, though the difference was not statistically significant. Patients can safely and effectively switch between generic warfarin and Coumadin. Clinical Pharmacology & Therapeutics (2004) 75, P27–P27; doi: 10.1016/j.clpt.2003.11.103

Biological variation of International Normalized Ratio for prothrombin times, and consequences in monitoring oral anticoagulant therapy: computer simulation of serial measurements with goal-setting for analytical quality

Oral anticoagulant therapy (OAT) has a well-established efficacy in prophylaxis and treatment of thromboembolic disorders. Because complications are related to intensity of OAT, optimal control of treatment is mandatory. In studies of OAT, as many as 30% of International Normalized Ratio (INR) measurements for prothrombin times fall outside the therapeutic interval. Preanalytical, analytical, and biological variation all contribute to this. Computer simulations of serial INR measurements were performed for various assumed in-treatment setpoints within the therapeutic interval INR 2.0-3.0 and for an "in-treatment within-subject variation" (CV) of 10.1%. Results are presented in difference plots with therapeutic intervals and critical differences. If the in-treatment setpoint is mid-interval (INR = 2.5), only 5% of simulated INR values fall outside the therapeutic interval. Setpoints deviating from the mid-interval and increases in the in-treatment within-subject variation considerably increase the number of observations outside the therapeutic interval and the critical differences. In conclusion, random variation, biological or analytical, and setpoints (targets) deviating from mid-interval explain a substantial number of the INR values outside therapeutic intervals observed in clinical studies. Analytical imprecision should be kept < 5% and analytical bias < +/- 0.2 INR.

International normalized ratio for prothrombin times in patients taking oral anticoagulants: critical difference and probability of significant change in consecutive measurements

To determine when a change in serial measurements of prothrombin time in patients receiving oral anticoagulant therapy (ACT) is a statistically significant biological change necessitating dose adjustment, one must know the size of the "critical difference" in statistical terms (i.e., probabilities). In a cohort of 32 ACT patients at pharmacological steady-state, we studied the within-subject total variation of prothrombin time, expressed as International Normalized Ratio (INR), over 6 months. The total within-subject variation (CV) of INR was 10.1%. The corresponding critical differences required for significance of change in serial INR results was 0.7 at a therapeutic target of 2.5 INR and 1.0 at a therapeutic target of 3.5 INR. The data presented allow generation of objective criteria for monitoring ACT patients and deciding dose adjustments. We recommend that estimations of critical differences for significant change of INR in ACT patients should be based on results obtained in the specific clinic investigated to mirror the routine total variation of INR measurements they obtain.

Use of lyophilized calibration plasmas and control blood for international normalized ratio calculation in external quality assessment of the prothrombin time.

In the Netherlands, most anticoagulant clinics (thrombosis centers) use the reagent Thrombotest with citrated venous blood for laboratory control of oral anticoagulant therapy. In a national external quality assessment scheme, artificial control blood samples were mailed to 160 participants. Each participant returned prothrombin times and international normalized ratio (INR) values for these blood samples. The author investigated whether local calibration with lyophilized plasmas could reduce the interlaboratory variation of the INR. Five lyophilized plasmas were mailed along with the control blood samples. Using a local calibration line determined with the lyophilized plasmas, the interlaboratory variation of INRs determined routinely could be reduced slightly from 5.8% to 7% coefficient of variation (CV) to 5.3% to 6.5% CV. In contrast, when a local calibration line was determined with four similar control blood samples, the interlaboratory variation of the INR was reduced substantially to 2.5% CV.