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Modified anticoagulant therapy factor and international normalized ratio in patients in an unstable coagulation state with respect to warfarin therapy.

In our pilot study of 1997, an Anticoagulant Therapy Factor (ATF) was formulated, compared to the International Normalized Ratio (INR) and proposed to replace the INR. Statistically, replacement of the INR was reasonable; but many discrepancies occurred when the results of ATFs and INRs were compared for individual patients. The study was based on patients undergoing induction of warfarin anticoagulant therapy, so they were "unstable" with respect to warfarin. A 1998 follow-up study by Carroll and Jackson based on patients "stable" with respect to warfarin, having taken the drug for at least six weeks, was, therefore, undertaken. In this study, the ATF was modified to an MATF by both multiplying the ATF by the prothrombin ratio (PR) and adjusting the INR-ATF linear regression analysis line by analytic geometry, so that the slope was one and the line passed through the origin. These modifications achieved both statistical and individual patient concordance between INRs and ATFs. The purpose of the present paper is to apply the techniques of the 1998 study to the original 1997 pilot study to see if the reprocessed data on the "unstable" patients is, in fact, also concordant with respect to INRs and ATFs.

Blood Coagulation↗

Anti-Xa and anti-IIa drugs alter international normalized ratio measurements: potential problems in the monitoring of oral anticoagulants.

Several of the newly developed anti-Xa and anti-IIa agents have been shown to influence the International Normalized Ratio (INR) values. During phase I trials with normal healthy volunteers and phase II study patients who were given warfarin and concomitant anti-IIa or anti-Xa agents, it has been reported that INR values were falsely elevated. It is of critical importance to know of the effects of these agents on INR to avoid dosage errors. To study the influence of these agents on INR, we used several anti-IIa agents (argatroban, recombinant hirudin, efegatran, and PEG-hirudin) and anti-Xa drugs (pentasaccharides such as fondaparinux and idraparinux, DX-9065a and JTV-803). The anti-IIa drugs were supplemented in citrated plasma at a concentration of 0 to 1 microg/mL level and anti-Xa drugs in the range of 0 to 25 microg/mL. The IC(50) values for each of these agents were calculated. Four different commercially available prothrombin time (PT) reagents were used to perform the PT assays and to calculate the relative INR values. Direct synthetic factor IIa and Xa inhibitors exhibited a concentration-dependent increase in the INR values. Hirudin, efegatran, and PEG-hirudin showed a weaker effect, whereas argatroban showed a much higher elevation of the INR values. Synthetic indirect anti-Xa agents such as the pentasaccharide did not show any effect on the INR values. Furthermore, prothrombin time reagents with high ISI values exhibited disproportionally higher INR values for both the direct anti-Xa and anti-IIa agents. Elevation of INR values has therapeutic implications when non-oral anticoagulant drugs are used in combination with drugs such as warfarin. Because of the false elevation of INR values with some of the non-oral anticoagulant drugs, patients who are on concomitant warfarin therapy should be carefully evaluated for their corresponding INR values for proper dosing. To avoid dosing errors it is best not to use the INR values in the therapeutic monitoring of anti-Xa and anti-IIa agents either in the monotherapeutic or polytherapeutic modalities. These data also warrant the development clinically relevant methods for the monitoring of the concomitant use of newly developed anti-Xa and anti-IIa drugs with oral anticoagulants.

Adult↗

Course of the international Normalized Ratio in response to oral vitamin K1 in patients overanticoagulated with phenprocoumon.

Oral vitamin K1 is used for the treatment of excessive anticoagulation. Detailed information on changes in the International Normalized Ratio (INR) in response to vitamin K1 is not available. We therefore measured the INR for the first 7 d following the oral intake of 1-5 mg of vitamin K1 in 24 patients routinely treated with phenprocoumon who had an INR > or =6.0 at presentation. On the first 2 d after administration of vitamin K1, the mean INR decreased by 40% and 23% respectively. After day 2, the day-to-day proportional change in the mean INR depended on the dose of vitamin K1 and varied from a decrease of 12% to an increase of 21%. On day 7 the mean INR was higher than on day 2 in three out of five treatment groups. Between day 2 and day 7, in general, 32% of the patients had an INR value within the target zone, 25% had an INR value > or =6.0 and 8% had an INR value <2.0. These findings suggest that our routine treatment of overanticoagulation in patients on phenprocoumon should be intensified to improve its efficacy.

Administration, Oral↗

Accuracy of laboratory and portable monitor international normalized ratio determinations. Comparison with a criterion standard.

BACKGROUND: Portable instruments that measure the prothrombin time and automatically calculate the international normalized ratio (INR) with the use of a drop of whole blood have simplified the treatment of patients who are receiving warfarin therapy. The accuracy of these portable monitors has never been determined by comparing INR results with a criterion (gold) standard INR determination. METHODS: Duplicate whole-blood INR determinations were made with two commercially available portable INR monitors. Duplicate frozen-plasma samples were measured with four different thromboplastin reagents, each with a different international sensitivity index. The criterion standard INR was determined by using an international reference thromboplastin and the manual tilt-tube technique. Agreement was evaluated by determining how accurately laboratory and monitor INR determinations matched criterion standard values in designating a sample to be within or outside of currently recommended INR target ranges. RESULTS: Two of the laboratory methods, which used relatively sensitive thromboplastins, showed close agreement with the criterion standard, whereas two laboratory methods that used less sensitive thromboplastin reagents showed poor agreement. Both of the portable monitors fell between these extremes. The two best laboratory methods ere significantly better (P < .003) than both monitors, which in turn were better (P < .003) than the remaining two laboratories. CONCLUSIONS: There is large interlaboratory variation in the accuracy of INR determinations. Laboratory methods that used insensitive (high international sensitivity index) thromboplastins performed poorly. Accuracy of monitor measurements appears satisfactory.

Adult↗

Relationship of international normalized ratio to bleeding and thromboembolism rates in Taiwanese patients receiving vitamin K antagonist after mechanical valve replacement.

BACKGROUND AND PURPOSE: Asians may be less vulnerable to thrombotic disease than Caucasians. Optimum international normalized ratio (INR) anticoagulant therapy guidelines for Asian populations remain to be established. This study investigated the risk factors for major bleeding or thromboembolism (TE) in Taiwanese patients receiving mechanical aortic and/or mitral valve replacement, including INR < or > 2.0. METHODS: The records of 563 Taiwanese patients receiving mechanical aortic and/or mitral valve replacement between 1996 and 2001 were retrospectively studied. Patient follow-up data was divided into several 6-month periods: 6-month increments after surgery if no bleeding or TE occurred and the 6 months preceding the adverse event when an event occurred. Data including warfarin sodium dosage and estimated INR unit for each time period were collected and analyzed. RESULTS: A total of 3,391 records were retrieved for analysis with an average follow-up period of 3.3 +/- 1.4 years. The mean warfarin sodium dose was 2.86 +/- 1.09 mg/day and the INR was 1.86 +/- 0.66. Major bleeding events occurred in 20 patients (1.07% per patient-year) and TE events in 38 patients (2.04% per patient-year), accounting for a 3.11% rate of overall events (bleeding or TE) per patient-year. Multivariate risk analysis revealed follow-up age > 60 years and receiving mitral valve replacement were risk factors for overall events (odds ratio = 1.84, p = 0.021 for follow-up age > 60 years; odds ratio = 1.36, p = 0.019 for receiving mitral valve replacement), while gender, double valve replacement, valve type, INR < 2.0, and atrial fibrillation were not. CONCLUSIONS: Our data suggest that low-intensity anticoagulant therapy (INR < 2.0) in Taiwanese patients was not associated with increased TE and bleeding rates compared to higher intensity anticoagulant therapy. Follow-up age over 60 years and valve replacement at the mitral site were associated with increased rate of overall events.

Anticoagulants↗

Variations in prothrombin time and international normalized ratio over 24 hours in warfarin-treated patients.

STUDY OBJECTIVE: To determine the variation of prothrombin times and international normalized ratio (INR) over 24 hours in humans. DESIGN: Prospective, parallel study. SETTING: University-affiliated general clinical research center. PATIENTS: Six patients receiving long-term warfarin therapy and six sex-matched controls. INTERVENTIONS: Warfarin was administered to the patients at 6:00 P.M. MEASUREMENTS AND MAIN RESULTS: Prothrombin times and INR were determined every 2 hours over 24 hours. Time of study entry, meals, and sleep cycles were controlled. A significant cosinor rhythm for prothrombin times and INR (p < or = 0.03) occurred in warfarin-treated patients, suggesting that diurnal variation occurs. The mean difference between the peak and trough prothrombin times was 1.8 +/- 0.9 seconds (range 0.8-3 sec) with a mean change of 9.3% +/- 3.7%. The peak prothrombin time and INR values occurred between 4:00 A.M. and 8:00 A.M. in five patients, and trough values between 6:00 P.M. and midnight in five. No significant cosinor rhythm was noted for controls (p > 0.5). CONCLUSION: Significant variations in prothrombin time and INR occurred in patients receiving warfarin therapy, with the highest values occurring in the morning and the lowest in the evening. These results may have clinical implications for patients receiving either high- or low-intensity warfarin therapy.

Adult↗

Prothrombin time international normalized ratio monitoring by self-testing.

PURPOSE OF REVIEW: The increasing numbers of patients on oral anticoagulants may challenge the traditional organization of patient monitoring. The availability of portable coagulometers capable of measuring prothrombin time (PT) international normalized ratio (INR) in a drop of capillary blood facilitates decentralization of monitoring by self-testing. This article reviews the literature on use of portable coagulometers. RECENT FINDINGS: Numerous studies have evaluated the reliability of portable coagulometers in testing the PT-INR. This has been assessed by statistically as well as clinically relevant criteria. Other studies have been devoted to developing calibration models fulfilling the criteria recommended by the World Health Organization (WHO) for the calibration of INR measuring systems. Finally, studies have assessed the value of schemes for patient training and for the long-term quality assurance of portable coagulometers. SUMMARY: It can be concluded from the published studies that PT-INR self-testing may be considered as a suitable alternative to conventional laboratory testing. For the PT-INR to be reliable, manufacturers of portable coagulometers should calibrate their devices against international standards for thromboplastin with procedures similar to those recommended by WHO for conventional measuring systems. Training of patients and implementation of appropriate quality assessment schemes are also essential prerequisites for the success of PT-INR self-testing.

Administration, Oral↗

Relationship between prothrombin activation fragment F1.2 and international normalized ratio in patients with atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators.

BACKGROUND AND PURPOSE: The prothrombin time (expressed as the international normalized ratio [INR]) is the standard method of monitoring warfarin therapy in patients with atrial fibrillation. Prothrombin activation fragment F1.2 provides an index of in vivo thrombin generation and might provide a better index of the effective intensity of anticoagulation. We examined the relationship between F1.2 and INR in patients with atrial fibrillation. METHODS: We measured INR and F1.2 levels in 846 patients with atrial fibrillation participating in the Stroke Prevention in Atrial Fibrillation III study. Two hundred nineteen (26%) were taking aspirin alone, 326 (39%) were taking adjusted-dose warfarin, and 301 (36%) were taking a low fixed dose of warfarin (1 to 3 mg) plus aspirin (combination therapy). F1.2 levels were measured with an enzyme-linked immunosorbent assay. RESULTS: Patients receiving adjusted-dose warfarin or combination therapy had significantly higher INR and significantly lower F1.2 values than those on aspirin alone (P < or = .0001 for each of the four comparisons). F1.2 values (nanomolar) were inversely correlated with INR (F1.2 = -0.1 + 2.3[1/INR]; R2 = .37; P < .0001; simple linear regression). However, significant variability remained. Among patients receiving warfarin, older patients had higher F1.2 values than younger patients after adjustment for INR intensity (P < .001) in the model. There was no difference in the relationship between F1.2 and INR between men and women. CONCLUSIONS: Increasing intensity of anticoagulation, as measured by the INR, is associated with decreasing thrombin generation as measured by the F1.2 level, but significant variability exists in this relationship. Older anticoagulated patients have higher F1.2 values than younger patients at equivalent INR values. The clinical significance of these differences is not clear. F1.2 measurement might provide information regarding anticoagulation intensity in addition to that reflected by the INR.

Aged↗

International normalized ratio self-management after mechanical heart valve replacement: is an early start advantageous?

BACKGROUND: Severe thromboembolic and hemorrhagic complications after mechanical heart valve replacement essentially depend on the intensity of oral anticoagulation and the fluctuation of individual international normalized ratio (INR) values. METHODS: After heart valve replacement with Medtronic Hall, St. Jude Medical, and CarboMedics implants, patients were randomly divided into two groups, one controlling INR values at home, the other being monitored by family practitioners. RESULTS: Almost 80% of the INR values recorded by patients at home were within the stipulated therapeutic range, INR 2.5 to 4.5, compared with just 62% of INR values recorded by family practitioners. The overall complication rate (hemorrhages and thromboembolic events) of the self-management group was significantly (p < 0.05) decreased compared with the conventional group. CONCLUSIONS: Through INR self-management, an improvement in the quality of ongoing oral anticoagulation could be shown. Starting this form of therapeutic control early after mechanical heart valve replacement appears to effect a further reduction in anticoagulant-induced complications.

Adult↗

Usefulness of lyophilized calibration plasmas for International Normalized Ratio determination with the bovine combined thromboplastin (Thrombotest): results of a collaborative study.

The logical solution to account for the influence of coagulometers on the International Sensitivity Index (ISI) is local calibration with freeze-dried plasmas. However, because of their unpredictable behavior these plasmas must be validated before large-scale implementation. We report on a collaborative exercise designed to evaluate the suitability of a set of such plasmas used with Thrombotest in combination with a coagulometer provided by the manufacturer to be used with that reagent. This was a two-step study. First, one lot of reagent was calibrated against the international standard OBT/79 in two expert laboratories. The calibrated lot was then used as an intermediate standard to calibrate two additional lots of the same reagent in four field laboratories where the ISI was determined for both plasma and native blood. The International Normalized Ratio (INR) for the patient plasmas tested in each laboratory were calculated using two algorithms: the World Health Organization-recommended ISI mode (gold standard), and the simplified calibration plasma mode. In the latter, the INR was derived from the local calibration curve constructed by plotting the certified INR versus local coagulation times obtained with calibration plasmas. The between-algorithm INR differences indicate that this set of calibration plasmas may be employed for local INR calibration of the investigated reagent/instrument combination, especially when plasma is used for INR determination where the average INR (range) difference is 5% (3-13%) or 2% (3-8%) according to whether the INRs to calibration plasmas were assigned by the manufacturer or by the two expert laboratories. A slight but measurable difference of the INR may be predicted [9% (6-20%) or 6% (8-15%)] if this set of calibration plasmas is used for local calibration when native blood is employed for INR determination. Whether this bias is of practical significance is to be determined.

Animals↗

[International normalized ratio (INR) for optimal anticoagulant therapy].

Optimal therapeutic ranges for an oral anticoagulant therapy has been discussed for many years. Prothrombin time, prothrombin time ratios (PTR) and thrombotest have been employed so far, but, recently, International Normalized Ratio of prothrombin time (PT-INR or INR) has been introduced. We investigated paying special interest to INR, the effectiveness of oral anticoagulant therapy in 170 prosthetic valve patients and in 157 patients with various cardiovascular diseases who received warfarin at two different centers. The thrombotest, prothrombin time and INR were measured at follow-up visits every month. Regarding the 170 patients with prosthetic valves with a mean follow-up period of 2.44 years, 9 thromboembolisms (TE) were reported. The average TT and INR values in TE-free patients among 101 in whom coagulability could be measured, were 21.1% and 1.73 respectively. The average TT and INR values in 5 patients with TE were 26.4% and 1.53 respectively and this was significantly (p < 0.01) higher (smaller) than in TE-free patients. 157 patients (mean age 55 +/- 12 y.o.) with various cardiovascular diseases (Table 2) were followed up for a mean of 4.9 +/- 3.2 years. As is seen in figure 4, mean INR values in TE patients were 1.28, in patients with bleeding complications 4.1, and in event free patients 2.07 respectively. In conclusion, with INR greater than 2.75, no thromboembolic complication occurred, but several hemorrhagic complications occurred at INR greater than 3. Therefore INR therapeutic ranges between 2.0-3.0 are recommendable both for the prevention of TE and bleeding complications.

Administration, Oral↗

A comparison between capillary and venous blood international normalized ratio determinations in a portable prothrombin time device.

The CoaguChek PT system is a portable point-of-care device for prothrombin time testing that can be used with capillary and venous whole blood. This system had been calibrated by the manufacturer in terms of the international normalized ratio (INR) for monitoring oral anticoagulant therapy. The purpose of the present study was to compare capillary blood with venous blood INRs from healthy volunteers and patients treated with oral anticoagulants using the same CoaguChek PT system. Two different CoaguChek PT strip formulations [international sensitivity index (ISI), 1.5 and 1.1] were used in separate test series. The differences between capillary and venous blood INRs were statistically significant (P < 0.001) but the magnitude of the differences was small. The mean relative deviations of the INR were 5.8 and 2.8% for the strips with ISI 1.5 and 1.1, respectively. These deviations are clinically acceptable. It is concluded that capillary blood can be replaced by venous blood for the calibration of the CoaguChek PT system.

Anticoagulants↗

Capillary whole blood testing by a new portable monitor. Comparison with standard determination of the international normalized ratio.

We evaluated a new portable monitor (AvoSure PT PRO, Menarini Diagnostics, Firenze, Italy) developed to test the prothrombin time in capillary blood and plasma by comparing it with the standard laboratory determination. We studied 62 patients receiving acenocoumarol therapy. The international normalized ratio (INR) in capillary blood was analyzed by 2 methods: AvoSure PT PRO and Thrombotrack Nycomed Analyzer (Axis-Shield, Dundee, Scotland). Parallel studies were performed in plasma samples by a reference method using the Behring Coagulation Timer (Behring Diagnostics, Marburg, Germany). Plasma samples also were tested with the AvoSure PT PRO. Correlation was good for INR values for capillary blood and plasma samples by AvoSure PT PRO and our reference method (R2 = 0.8596) and for capillary blood samples tested by the AvoSure PT PRO and Thrombotrack Nycomed Analyzer (R2 = 0.8875). The correlation for INR in capillary blood and plasma samples by AvoSure PT PRO was 0.6939 (P < .0004). Capillary blood determinations are rapid and effective for monitoring oral anticoagulation therapy and have a high correlation to plasma determinations. AvoSure PT PRO is accurate for controlling INR in plasma and capillary blood samples, may be used in outpatient clinics, and has advantages over previous portable monitors.

Acenocoumarol↗

Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects.

Major bleeding is a frequent and hazardous complication associated with thromboprophylaxis using vitamin-K antagonists (VKA). Suggested regimens for control of highly elevated International Normalized Ratio (INR) and hemorrhagic events during VKA treatment include administration of vitamin K, infusion of fresh frozen plasma (FFP) or a prothrombin complex concentrate (PCC). In contrast, this communication present the first report on the efficacious use of recombinant factor VIIa (rFVIIa) as additional therapy in seven patients presenting with central nervous system (CNS) bleeding emergencies. Pre-treatment INRs ranged from 1.7 to 6.6, and 10 min after a single dose of rFVIIa (10-40 microg/kg) all INRs were </= 1.5. Six patients underwent drainage of the CNS hematoma and all patients survived. No untoward biochemical signs of coagulation activation were detected and no incidence of thromboembolism was observed. In ex-vivo experimental studies, profiles of continuous whole blood clot formation were evaluated by thrombelastography in 25 patients on VKA treatment (INR 1.7-4.3), demonstrating a significantly prolonged initiation phase and diminished propagation of clot formation. Ex-vivo supplementation with rFVIIa to blood of six patients returned a distinct reduction of the prolonged initiation but variable changes in the maximum velocity of clot formation. The ex-vivo experiments and our clinical data support recent suggestions that rFVIIa might substitute for infusion of FFP or PCC in acute reversal of VKA treatment.

Adult↗

Point-of-care testing of the international normalized ratio in patients with antiphospholipid antibodies.

Antiphospholipid antibodies can influence the results of clotting tests in a subset of patients, which can be a major obstacle in monitoring warfarin. The aim was to determine if point-of-care testing of the International Normalized Ratio (INR) is influenced by antiphospholipid antibodies. We compared 59 patients receiving warfarin for a diagnosis of antiphospholipid antibody syndrome (APS) to 49 patients receiving warfarin for atrial fibrillation to evaluate the consistency between INR results obtained by different methods. INR results obtained by finger stick (capillary whole-blood) and venipuncture (non-citrated and citrated whole-blood) were compared with our laboratory plasma-based prothrombin time assay. Five patients (8%) with APS and both elevated anti-beta2glycoprotein I levels and positive lupus anticoagulants had non-measurable ProTime INR results and generally higher Hemochron Signature INR results than the plasma-based method, but the corresponding chromogenic factor X results were not supratherapeutic. For the remaining patients, differences between the plasma-based INR and the point-of-care INR results ranged from 0.2 +/- 0.2 to 0.4 +/- 0.3. The differences were similar for patients with APS and atrial fibrillation for all INR comparisons with the exception of the plasma-based method compared with the ProTime, which showed a mean absolute difference of 0.4 +/- 0.3 for APS patients and of 0.2 +/- 0.2 for atrial fibrillation patients (p = 0.02). In a subset ofAPS patients, the ProTime system will not yield an INR result and the HEMochron Signature (citrate and non-citrate whole-blood) INR results will exhibit elevated INR results. For this subset of APS patients, we suggest using an alternative method to monitor warfarin.

Adult↗

Differences in warfarin dosing decisions based on international normalized ratio measurements with two point-of-care testing devices and a reference laboratory measurement.

STUDY OBJECTIVES: To assess the accuracy of warfarin dosing decisions and the degree of numeric bias between two point-of-care devices using a local reference laboratory's international normalized ratio (INR) as the standard measure, and to determine the relationship between dosing decisions and INR values obtained with the point-of-care devices. DESIGN: Prospective study. SETTING: Outpatient anticoagulation clinic. SUBJECTS: Two hundred two patients taking oral warfarin and 10 control subjects. INTERVENTIONS: For the two point-of-care devices, AvoSure and ProTime, the finger-stick method was used to collect capillary blood samples in each subject. At the same visit, one venous blood sample was collected from each subject for the laboratory analysis. MEASUREMENTS AND MAIN RESULTS: Dosing agreement was assessed as the proportion of agreement between each device and the laboratory in terms of maintenance dosage adjustments (increase, decrease, or no change). The level of agreement between each device and the laboratory was evaluated by dosing agreement analysis, bias analysis, and concordance coefficient analysis. In the dosing agreement analysis, 78% of INR values from the AvoSure device would have resulted in the same dosing decision as that with the laboratory INR values compared with 66% from the ProTime device (p < 0.001). The mean bias for the ProTime device (0.5 +/- 0.4 INR units) was significantly higher (p = 0.005) than that for the AvoSure device (0.4 +/- 0.5 INR units). The ProTime device overestimated low INR values to a greater extent than did the AvoSure device. Concordance between the laboratory measurement and each device was similar (rho(c) = 0.82 for ProTime, rho(c) = 0.76 for AvoSure). CONCLUSIONS: Assessing dosing decisions yielded distinct, useful clinical information. The AvoSure device is associated with less systematic bias and a higher degree of clinical agreement with our reference laboratory measurement than those of the ProTime device.

Adult↗

Patient-specific errors in agreement between International Normalized Ratios measured by a whole blood coagulometer and by a routine plasma-based method.

We applied a new statistical method to improve comparisons between systems measuring prothrombin time (PT) by splitting disagreement into systematic errors, which can be eliminated, and random errors, which can not. We found that the disagreement between International Normalized Ratio (INR) measurements based on plasma and whole blood was significantly patient-dependent.

Blood Coagulation Tests↗

Correction of instrument- and reagent-based differences in determination of the International Normalized Ratio (INR) for monitoring anticoagulant therapy.

As recommended by the World Health Organization, standardization of prothrombin time assays involves conversion of prothrombin times into International Normalized Ratios (INR). We investigated the effect of two different methods (Nycomed's Thrombotest, and Instrumentation Laboratory's PT-fibrinogen) and three coagulation instruments (Schnitger & Gross, KC-10, and ACL) on calculations of INR. The INR plots showed considerable scatter of individual values around the regression lines when the two different methods were compared. Systematic differences in the outcome of INR calculation were related to the use of the different coagulation instruments. Prothrombin times obtained with the different instruments were linearly correlated. We used the bias of these lines to correct results for both the patients' samples and the reference samples. This correction yielded INR values from the different instruments that agreed well.

Anticoagulants↗