Venous International Normalized Ratio Research Articles

CoaguChek® XS versus standard laboratory prothrombin time for anticoagulant monitoring in patients with antiphospholipid syndrome.

The standard of care for thrombotic antiphospholipid syndrome (APS) is anticoagulation with vitamin K antagonists (VKAs). Prothrombin time, and its corresponding international normalized ratio (INR), is the laboratory test routinely performed to assess anticoagulation. Self-management of VKA therapy using point-of-care (POC) devices seems to be an attractive option. To evaluate the accuracy of a POC device (CoaguChek XS) in APS patients by comparing it with venous laboratory INR. Furthermore, we analyzed whether other clinical and laboratory features could interfere with the CoaguChek XS results. This is a single-center cross-sectional study with 94 APS patients from a tertiary rheumatology clinic performed from August 2014 to March 2015. The comparison between CoaguChek XS and venous laboratory INR results was evaluated using the coefficient of determination (r) followed by the Bland-Altman test. A paired t-test was also applied. A difference of up to ±0.5 INR unit between the two systems was considered clinically acceptable. The mean CoaguChek-INR was 2.94 ± 1.41 and venous laboratory INR was 2.43±0.86, with a correlation coefficient (r) of 0.95. Categorizing INR values in ranges (INR <2, INR 2-3, INR 3-4, and INR >4), we found that the INR >4 group presented a lower correlation (r = 0.64) compared to the other ranges (p < 0.05). Although both methods were highly correlated, CoaguChek XS showed higher values than the venous laboratory INR, with an increased average of 0.42 ± 0.54. Therefore, we proposed a simple linear regression model to predict the venous laboratory INR values, using results obtained from CoaguChek XS. A difference ≤0.5 INR unit between the two systems was observed in 57.4% of patients, and the aPL profile did not influence the results. Although CoaguChek XS and venous laboratory INR demonstrated a good linear correlation in the group of INR ≤4, extra caution should be taken in APS patients, since a reasonable proportion of patients can present differences in INR results that are not acceptable. We do not recommend routine POC in APS patients.

Generational performance of three point-of-care testing devices compared with standard laboratory measurement of the international normalised ratio across extended ranges

Point-of-care testing (POCT) of the international normalised ratio (INR) is recognised as a rapid and reliable alternative to venous INR measurement for titration and monitoring of patients anticoagulated with vitamin...

Performance of the LumiraDx Platform INR Test in an Anticoagulation Clinic Point-of-Care Setting Compared With an Established Laboratory Reference Method.

Vitamin K antagonists, such as warfarin, have a narrow therapeutic window; patients on these therapies therefore require regular international normalized ratio (INR) monitoring to maintain optimal dosing. This involves periodic checks and laboratory testing using venepuncture, which are often perceived as a burden. This study aimed to determine the accuracy and precision of the LumiraDx INR Test, a new point-of-care in vitro diagnostic platform, in an anticoagulation clinic setting. In this observational, cross-sectional study, precision of the LumiraDx INR Test was assessed using paired replicate samples (n = 366) and 3 test strip lots. Accuracy was determined by comparing capillary blood INR, ascertained by the LumiraDx INR Test, with venous plasma INR, measured by the laboratory reference instrument, the IL ACL ELITE Pro. Furthermore, INR was assessed across a range of hematocrit (25%-55%). In addition, feedback was collected from health-care professionals via a self-completed questionnaire. This trial was registered at ClinicalTrials.gov (NCT03682419). The precision (% coefficient of variation) of the LumiraDx INR Test was <4 when samples were applied by direct application or via a capillary transfer pipette, as well as between test strip lots. Accuracy of the LumiraDx INR Test, across the INR range of 0.8 to 7.5, was confirmed by a strong correlation of 0.965 (95% confidence interval: 0.959-0.970) when compared with the IL ACL ELITE Pro, which was maintained across the hematocrit range. Feedback from health-care professionals indicated that the instructions given by the system were easy to follow. In conclusion, the strong agreement between the LumiraDx Platform INR point-of-care test and the IL ACL ELITE Pro laboratory reference system, as well as between the different application methods and test lots, indicates that it can provide a rapid, accurate, and reliable INR analysis.

The impact of frequency of patient self-testing of prothrombin time on time in target range within VA Cooperative Study #481: The Home INR Study (THINRS), a randomized, controlled trial.

Anticoagulation (AC) is effective in reducing thromboembolic events for individuals with atrial fibrillation (AF) or mechanical heart valve (MHV), but maintaining patients in target range for international normalized ratio (INR) can be difficult. Evidence suggests increasing INR testing frequency can improve time in target range (TTR), but this can be impractical with in-clinic testing. The objective of this study was to test the hypothesis that more frequent patient-self testing (PST) via home monitoring increases TTR. This planned substudy was conducted as part of The Home INR Study, a randomized controlled trial of in-clinic INR testing every 4 weeks versus PST at three different intervals. The setting for this study was 6 VA centers across the United States. 1,029 candidates with AF or MHV were trained and tested for competency using ProTime INR meters; 787 patients were deemed competent and, after second consent, randomized across four arms: high quality AC management (HQACM) in a dedicated clinic, with venous INR testing once every 4 weeks; and telephone monitored PST once every 4 weeks; weekly; and twice weekly. The primary endpoint was TTR at 1-year follow-up. The secondary endpoints were: major bleed, stroke and death, and quality of life. Results showed that TTR increased as testing frequency increased (59.9 ± 16.7 %, 63.3 ± 14.3 %, and 66.8 ± 13.2 % [mean ± SD] for the groups that underwent PST every 4 weeks, weekly and twice weekly, respectively). The proportion of poorly managed patients (i.e., TTR <50 %) was significantly lower for groups that underwent PST versus HQACM, and the proportion decreased as testing frequency increased. Patients and their care providers were unblinded given the nature of PST and HQACM. In conclusion, more frequent PST improved TTR and reduced the proportion of poorly managed patients.

Contribution of 1173C &gt; T polymorphism in the VKORC1 gene to warfarin dose requirements in Han Chinese patients receiving anticoagulation

The objective was to assess 1173C > T polymorphism of the VKORC1 gene and its contribution to warfarin dose requirements in Han Chinese patients. Blood samples were collected from 178 patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range (1.5 - 3.0). Polymorphisms for VKORC1 (1173C > T), CYP2C9, venous INR, and plasma concentration and unbound concentration of warfarin were analyzed. VKORC1 (1173C > T) genotyping showed that 154 patients were homozygous TT, 23 were heterozygous CT, and one was homozygous for the CC genotype. Patients with the VKORC1 (1173CC + CT) genotype required a significantly higher warfarin dose (3.33 ± 1.04 mg/day) than those with 1173TT (1.81 ± 0.63 mg/day; p < 0.001). The multiple linear regression model for warfarin dose indicated significant contributions from the VKORC1 (1173C > T) genotype (r2 = 0.355; p < 0.001), and age, body weight, and CYP2C9 and VKORC1 genotype together (r2 = 0.513; p < 0.001). The two SNPs (-1639 and 1173) were found to be in very strong linkage disequilibrium with estimated D' = 0.96 (95%CI (0.83 - 0.99)). The VKORC1 (1173C > T) polymorphism might be very important, and its contribution can be equally explained by the VKORC1(-1639 G > A) polymorphism for warfarin dose requirements in Han Chinese patients.

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements in an adult Turkish population

In this study, we investigated the contribution of vitamin K epoxide reductase (VKORC1) and cytochrome P450 2C9 (CYP2C9) genotypes, age, and body surface area (BSA) on warfarin dose requirements and in an adult Turkish population. Blood samples were collected from 100 Turkish patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the therapeutic range. Genetic analyses for CYP2C9 genotypes (*2 and *3 alleles) and VKORC1 -1639 G>A polymorphism were performed and venous INR determined. The mean warfarin daily dose requirement was higher in CYP2C9 homozygous wild-type patients, compared to those with the variant *3 allele (P < 0.05), similar to those with the variant *2 allele (P > 0.05) and highest in patients with the VKORC1 -1639 GG genotype compared to those with the GA genotype and the AA genotype (P < 0.01). The time to therapeutic INR was longer in CYP2C9 homozygous wild-type patients compared with those with the variant *2 and *3 alleles (P < 0.01), and longer in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P < 0.01). The multivariate regression model including the variables of age (R (2) = 4.4%), BSA (R (2) = 27.4%), CYP2C9 (R (2) = 8.1%), and VKORC1 genotype (R (2) = 34.1%) produced the best model for estimating warfarin dose (R (2) = 60.4%). VKORC1 genotype and CYP2C9 polymorphism affect daily dose requirements and time to therapeutic INR in Turkish patients receiving warfarin for anticoagulation.

Self-Monitoring of Oral Anticoagulation Therapy in Children

This study aimed to investigate the accuracy of home International Normalized Ratio (INR) self-monitoring in pediatric patients on long-term oral anticoagulation therapy. Statistical and clinical agreement of INR values from capillary whole blood samples measured by 2 different portable prothrombin time monitors (CoaguChek S and XS) and venous blood samples measured by a laboratory coagulation analyzer were evaluated using the Bland-Altman analysis. Eighty-three INR comparisons (56 using the CoaguChek S and 27 using the CoaguChek XS) were obtained from 35 children aged 4 months to 18 years. Mean differences between venous and capillary INR values and their limits of agreement were –0.04 (–0.63 to 0.55) overall, 0.006 (–0.63 to 0.65) for the CoaguChek S and –0.13 (–0.57 to 0.31) for the CoaguChek XS. The Pearson correlation coefficients were 0.88 overall, 0.84 for the CoaguChek S and 0.95 for the CoaguChek XS. Expanded and narrow agreements for all patients were 97.6 and 94%, respectively. In conclusion, home INR self-monitoring is accurate for children requiring long-term oral anticoagulation therapy. Our data suggest that INR self-monitoring with the newer CoaguChek XS is more accurate than with the older CoaguChek S monitor.

Point-of-care monitoring of oral anticoagulation therapy in children

Point-of-care (POC) monitoring of oral anticoagulation has been widely adopted in both paediatric and adult patients. A new POC system, the CoaguChek XS has recently been developed to measure the international normalised ratio (INR) and may offer significant advantages. The CoaguChek XS utilises a new method of electrochemical clot detection based on thrombin generation. This system has not been previously evaluated in children with reference to the laboratory gold standard, the prothrombin time using reference thromboplastin. It was the objective to compare values obtained by the CoaguChek XS system with both the venous INR and the gold standard for anticoagulant monitoring, prothrombin time with reference thromboplastin (rTF/95). To evaluate the impact of testing using the CoaguChek XS on clinical anticoagulant dosing decisions. Fifty paired venous INR and capillary CoaguChek XS results were obtained from 31 children (aged up to 16 years). The laboratory gold standard, a manual prothrombin time with reference thromboplastin (rTF/95) was additionally performed on 26 samples. Correlation between the CoaguChek XS result and the venous INR was r = 0.810. Agreement between the CoaguChek XS result and the reference INR was shown to be higher (r=0.95), in the subset analysed by this method. Correlation between the venous INR and reference INR was r=0.90. Despite changes to the methodology of testing with the CoaguChek XS POC monitoring system, the accuracy of this method when compared with both the venous INR and gold standard reference INR was satisfactory. This resulted in infrequent changes to clinical decision making regarding anticoagulation.

Accuracy of Capillary Whole Blood International Normalized Ratio on the CoaguChek S, CoaguChek XS, and i-STAT 1 Point-of-Care Analyzers

We evaluated the accuracy of capillary whole blood international normalized ratio (INR) on the CoaguChek S (Roche Diagnostics, Indianapolis, IN), CoaguChek XS (Roche Diagnostics), and i-STAT 1 (i-STAT, East Windsor, NJ) point-of-care (POC) analyzers compared with venous plasma INRs determined by a reference laboratory method. Overall agreement between POC and laboratory plasma INR was very good, with median bias between capillary whole blood and laboratory plasma INRs varying from 0.0 to -0.2 INR units on all devices. More than 90% of results on the CoaguChek XS and i-STAT 1 and 88% of CoaguChek S results were within 0.4 INR units of the reference laboratory method. The CoaguChek XS and i-STAT 1 demonstrated greater accuracy than the CoaguChek S as measured by the number of results that differed by more than 0.5 INR units from the reference method. Median bias between CoaguChek S capillary whole blood and laboratory plasma INRs changed over time, demonstrating the need for ongoing quality assurance measures for POC INR programs.

Contribution of age, body weight, and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients

The objective of this study was to assess the contribution of the VKORC1 and CYP2C9 genotypes and age, body size, and weight of the patients to the warfarin dose requirement in a Chinese population. Blood samples were collected from 178 Chinese patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range (1.5-3.0). The polymorphisms for the VKORC1 (-1639GA) and CYP2C9*3 genotypes, venous INR, and plasma concentration and unbound concentration of warfarin were then analyzed. VKORC1 (-1639G>A) genotyping showed that 149 patients were homozygous AA, 28 were heterozygous GA, and one was homozygous for the GG genotype. CYP2C9*3 genotyping showed that 162 patients were *1/*1, and 16 patients were heterozygous *1/*3. Patients with the VKORC1(-1639 GG+GA) (3.32 +/- 1.02 mg/day) and CYP2C9*1/*1 (2.06 +/- 0.82 mg/day) genotypes required a significantly higher warfarin dose than those with the -1639 AA (1.76 +/- 0.57 mg/day; P < 0.001) or CYP2C9*1/*3 (1.60 +/- 1.29 mg/day; P < 0.001), genotype. The multiple linear regression model for warfarin dose indicated significant contributions from age (r (2) = 0.084; P < 0.001), weight (r (2) = 0.063; P < 0.001), VKORC1 genotype (r (2) = 0.494; P < 0.001), and age, weight, and CYP2C9 and VKORC1 genotype together (r (2) = 0.628; P < 0.001). This study shows that age, weight and the VKORC1 and CYP2C9 polymorphism affect warfarin dose requirements in our sample of Chinese patients receiving long-term therapy and showing stable control of anticoagulation. It is anticipated that the use of dosing regimens modified by taking into account the contribution of age, weight, and the CYP2C9 and VKORC1 genotypes has the potential to improve the safety of warfarin therapy.

INR comparison between the CoaguChek® S and a standard laboratory method among patients with self-management of oral anticoagulation

Introduction Portable coagulation monitors have been developed to measure International Normalised Ratio (INR) in orally anticoagulated patients using capillary whole blood from a finger stick. Because of unsatisfactory precision of some of the monitors in comparison with laboratory methods new devices are being developed. In the present study we compared INR determination with the CoaguChek S device with a standard laboratory method among patients with self-management of oral anticoagulation (OAC). Methods Two hundred and forty-two patients performing self-management of OAC were enrolled into this study. Parallel INR measurements were performed within one hour. Capillary INR measurements (INRcap) were done by the patients with the CoaguChek S and venous INR (INRven) by qualified medical staff using a standard laboratory method. Results We found a correlation coefficient ( r S) of 0.85 (95% CI: 0.81–0.88) among the 242 patients between INRven and INRcap. In 84.4% of the INR parallel measurements the difference between the two values was below 0.5 INR units. In only 2 of 242 cases the difference was > 1 INR unit (1.1 and 1.3). The slope of the Passing Bablok regression line was 0.91 (95% CI: 0.83–1.0) and the y-intercept 0.06 (95% CI: − 0.20–0.25). Agreement between both methods was 90.5% (95% CI: 86.8–94.2) and standard-agreement even 97.1% (95% CI: 95–99.2). Conclusions INR measurement with CoaguChek S device by trained patients revealed reliable results in comparison to the values obtained with a standard laboratory method.

Discrepancy between capillary and venous International Normalised Ratio (INR) in a patient on vitamin-K antagonist: Potentially serious clinical consequences

Discrepancy between capillary and venous International Normalised Ratio (INR) in a patient on vitamin-K antagonist: Potentially serious clinical consequences -

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen

AbstractCurrent dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined. The mean warfarin daily dose requirement was highest in CYP2C9 homozygous wild-type patients, compared with those with the variant *2 and *3 alleles (P < .001) and highest in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P < .001). Mean warfarin daily dose requirements fell by 0.5 to 0.7 mg per decade between the ages of 20 to 90 years. Age, height, and CYP2C9 genotype significantly contributed to S-warfarin and total warfarin clearance, whereas only age and body size significantly contributed to R-warfarin clearance. The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%). Based upon the data, a new warfarin dosing regimen has been developed. The validity of the dosing regimen was confirmed in a second cohort of patients on warfarin therapy.

Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin

Our objective was to assess the contribution of CYP2C9 genotype, age, body size, and vitamin K and lipid status to warfarin dose requirements. Patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range of 2.0 to 3.0 were recruited to the study. On arrival at the clinic in the morning, after an overnight fast, a blood sample was taken from each patient for CYP2C9 genotyping and for determination of venous INR and plasma vitamin K, R- and S-warfarin, and triglyceride concentrations. A total of 121 patients were recruited to the study. CYP2C9 genotyping showed that 74 patients were homozygous wild-type (*1/*1), 30 were heterozygous *1/*2, and 15 were heterozygous *1/*3 genotype. One patient was found to have the genotype *2/*3, and another was found to have the genotype *3/*3. The mean warfarin daily dose requirement in milligrams fell from 4.06 +/- 1.72 mg in homozygous wild-type patients to 3.63 +/- 1.78 mg for *1/*2-positive patients and 2.70 +/- 1.36 mg for *1/*3-positive patients. The multiple linear regression model for warfarin dose indicated significant contributions from age (r = 0.41, P <.001), genotype (r = 0.24, P <.005), and age and genotype together (r = 0.45, P <.005). Although there were significant linear correlations between warfarin dose and body surface area (r = 0.21, P =.02), body weight (r = 0.25, P =.005), and plasma vitamin K concentration (r = 0.18, P <.05), none of these variables made a significant contribution to the regression model for warfarin dose. CYP2C9 genotype had a significant effect on S-warfarin clearance (r = 0.34, P <.0001) but none on R-warfarin clearance. This study showed that age and CYP2C9 polymorphism affect warfarin dose requirements in patients receiving long-term therapy and having stable control of anticoagulation. It is anticipated that using dosing regimens modified to take into account the contribution of age and CYP2C9 genotype has the potential to improve the safety of warfarin therapy.

INR comparison between the CoaguChek® Pro PT N and a standard laboratory method

Background: The prothrombin time (PT), also called thromboplastin time (“Quick”), is usually measured using citrated plasma from venous blood. Recently, portable coagulation monitors have been developed, which measure PT using non-anticoagulant capillary whole blood from a finger stick. In the present study, we compared the International Normalized Ratio (INR) of the standard laboratory method (INRven) with the newly developed reagent PT N for the CoaguChek® Pro portable monitor (INRcap) in various patient groups: healthy individuals, patients with oral anticoagulation and patients with a deficiency of coagulation factor V, factor VII or factor X, respectively. Methods: One hundred and fifty-five patients were included in this prospective open comparison study. Capillary PT was measured with the portable coagulation monitor CoaguChek® Pro using the new disposable cartridge PT N (containing rabbit brain thromboplastin). In comparison, PT was measured using citrated venous plasma and the reagent Innovin® on the coagulation analyzer STA-R®. Results: We found a correlation coefficient of 0.85 between capillary and venous INR values among the 100 patients with oral anticoagulation. The slope of the regression line was 1.4 and the y-intercept is −0.65. Agreement between both methods was found to be 80% (95% CI: 72–88%) and the standard-agreement was 85% (95% CI: 78–92%). Among the 30 healthy subjects, the individual differences between INRven and INRcap were in 4 cases 0, in 21 cases 0.1 and in 5 cases 0.2. Conclusion: The new test cartridge PT N was found to be a valuable tool for measuring PT among healthy subjects. However, among patients with oral anticoagulation, agreement between INRcap measured with the new cartridge PT N and INRven was only moderate. Our results show that improvements are necessary for a more valuable measurement of capillary PT with portable coagulation monitors.

The use of vitamin k for reversal of over-warfarinization in children

We have followed the discussion about reversal of warfarin therapy with interest (Pendry et al, 2001; Watson et al, 2001). An increasing number of young children are now receiving long-term warfarin, following surgery for major heart defects. Control of therapy is more difficult than in adults (Streif et al, 1999). Few data are available about warfarin reversal in children; fresh-frozen plasma is not appropriate for non-bleeding patients and may not produce adequate correction in bleeding patients (Makris et al, 1997). Blood products should be avoided in small children because of anxieties concerning possible transmission of infectious agents. Because low-dose vitamin K (0·5–1 mg) produces a lowering of a high International Normalized Ratio (INR) to near or within the therapeutic range in adults (Hung et al, 2000), we decided to extrapolate this to children with high INRs (venous INR > 8). The INR was successfully lowered in six out of seven cases (Fig 1) with a single dose of 30 µg/kg (1/10th of the full dose) given intravenously (doses ranging from 350 to 1000 µg). These six children were well and treated as outpatients. One other sick inpatient with deranged liver function tests required three doses to bring the INR into the therapeutic range. Our weight-adjusted regimen is safer than a universal dosage (0·5–2 mg subcutaneously). Even 0·5 mg (sufficient for many adults) is likely to be too high for most young children (too high for five of our seven children). Seriously ill children with liver dysfunction may require more than a single dose; this is one reason why it is important to confirm adequate correction at a chosen time interval: 4–6 h in those at highest risk or 24 h in milder cases. Low-dose i.v. vitamin K for warfarin reversal in children. Oral or subcutaneous vitamin K is effective in adults (Raj et al, 1999), but the INR fall is slower than i.v. injection. Our preferred route is therefore i.v., but in a child with poor venous access, the subcutaneous or oral route may be used, particularly if the INR is 6–10. A paediatric protocol should include specific advice that vitamin K should not be given intramuscularly to children on anticoagulants because of the risk of intramuscular haemorrhage. Paediatricians are more used to giving Vitamin K i.m., as this is standard practice for neonatal prophylaxis.