Warfarin or dabigatran for treatment of atrial fibrillation.

BACKGROUND: New antithrombotic drugs for prevention and treatment of thromboembolic disorders in AF that are less demanding on local staff and facilities than warfarin should be welcomed if proved successful. OBJECTIVES: The comparative value and possible dangers of substituting the new drug dabigatran as a replacement remain to be established. Its safety and effectiveness must be reviewed and assessed by further study. METHODS: Clinical results of the European Action on Anticoagulation (EAA) computer-assisted dosage study and the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial have been compared. RESULTS: Clinical events were lower in patients on warfarin in the EAA study compared to patients on both warfarin and dabigatran in the RE-LY study. CONCLUSION: Evaluations should recognize optimum requirements for safe and effective administration of both types of drug. In the warfarin arm improvements in effectiveness and safety recently introduced (i.e. the PT/INR line and variance growth analysis) should be included as they have been shown to be successful in improved prediction of bleeding and further thromboembolism. The incidence of bleeding with dabigatran, for which there is no antidote, will require evaluation.

The clinical evaluation of International Normalized Ratio variability and control in conventional oral anticoagulant administration by use of the variance growth rate.

INTRODUCTION: The time in target International Normalized Ratio (INR) range (TIR) is used to assess the control and intensity of oral anticoagulation, but it does not measure variation in the INR. OBJECTIVES: The value of assessing INR variability by use of the variance growth rate (VGR) as a predictor of events was investigated in patients treated with warfarin. METHODS: Three different methods of VGR determination (A, B1, and B2) together with the TIR were studied. Method A measures both INR variability and control, but methods B1 and B2 measure variability only. The VGR and TIR were determined over three time periods: overall follow-up to an event, and 6 months and 3 months before an event. RESULTS: Six hundred and sixty-one control patients were matched to 158 cases (bleeding, thromboembolism, or death). With all VGR methods, the risk of an event was greater in unstable patients at 6 months before an event than in stable patients. Method A demonstrated the greatest risk 3 months before an event in the unstable VGR group as compared with the stable group (odds ratio 3.3, 95% confidence interval 1.9-5.7, P < 0.005). The risk of an event was 1.9 times greater in patients with a low TIR (< 39%) than in those with a high TIR (> 80%) in the 3-month period (P = 0.02). Risk of bleeding was significantly greater in the 3-month period in patients with unstable VGR, with the greatest risk found with method B2 (P < 0.01). CONCLUSIONS: Patients with unstable anticoagulation have a significantly increased risk of 'clinical events' at 3 and 6 months before an event. The VGR can be incorporated into computer-dosage programs, and may offer additional safety when oral anticoagulation is monitored.

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

BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

The prothrombin time/international normalized ratio (PT/INR) Line: derivation of local INR with commercial thromboplastins and coagulometers--two independent studies.

BACKGROUND: The WHO scheme for prothrombin time (PT) standardization has been limited in application, because of its difficulties in implementation, particularly the need for mandatory manual PT testing and for local provision of thromboplastin international reference preparations (IRP). METHODS: The value of a new simpler procedure to derive international normalized ratio (INR), the PT/INR Line, based on only five European Concerted Action on Anticoagulation (ECAA) calibrant plasmas certified by experienced centres has been assessed in two independent exercises using a range of commercial thromboplastins and coagulometers. INRs were compared with manual certified values with thromboplastin IRP from expert centres and in the second study also with INRs from local ISI calibrations. RESULTS: In the first study with the PT/INR Line, 8.7% deviation from certified INRs was reduced to 1.1% with human reagents, and from 7.0% to 2.6% with rabbit reagents. In the second study, deviation was reduced from 11.2% to 0.4% with human reagents by both local ISI calibration and the PT/INR Line. With rabbit reagents, 10.4% deviation was reduced to 1.1% with both procedures; 4.9% deviation was reduced to 0.5% with bovine/combined reagents with local ISI calibrations and to 2.9% with the PT/INR Line. Mean INR dispersion was reduced with all thromboplastins and automated systems using the PT/INR Line. CONCLUSIONS: The procedure using the PT/INR Line provides reliable INR derivation without the need for WHO ISI calibration across the range of locally used commercial thromboplastins and automated PT systems included in two independent international studies.

The cost-effectiveness of computer-assisted anticoagulant dosage: results from the European Action on Anticoagulation (EAA) multicentre study.

BACKGROUND: Increased demand for oral anticoagulation has resulted in wider adoption of computer-assisted dosing in anticoagulant clinics. An economic evaluation has been performed to investigate the cost-effectiveness of computer-assisted dosing in comparison with manual dosing in patients on oral anticoagulant therapy. METHODS: A trial-based cost-effectiveness analysis was conducted as part of the EAA randomized study of computer-assisted dosage vs. manual dosing. The 4.5-year multinational trial was conducted in 32 centres with 13 219 anticoagulation patients randomized to manual or computer-assisted dosage. The main outcome measures were total health care costs, clinical event rates and cost-saving per clinical event prevented by computer dosing compared with manual dosing. RESULTS: Mean dosing costs per patient were lower (difference: euro47) for computer-assisted dosing, but with little difference in clinical event costs. Total overall costs were euro51 lower in the computer-assisted dosing arm. There were a larger number of clinical events in the manual dosing arm. The overall difference between trial arms was not significant (difference in clinical events, -0.003; 95% CI, -0.010-0.004) but there was a significant reduction in events with DVT/PE, suggesting computer-assisted dosage with the two study programs (dawn ac or parma 5) was at least as effective clinically as manual dosage. The cost-effectiveness analysis indicated that computer-assisted dosing is less costly than manual dosing. CONCLUSIONS: Results indicate that computer-assisted dosage with the two programs (dawn ac and parma 5) is cheaper than manual dosage and is at least as effective clinically, indicating that investment in this technology represents value for money.

An international multicenter randomized study of computer-assisted oral anticoagulant dosage vs. medical staff dosage.

BACKGROUND: Increased demand for oral anticoagulants is overwhelming facilities worldwide, resulting in increasing use of computer assistance. A multicenter clinical endpoint study has been performed to compare the safety and effectiveness of computer-assisted dosage with dosage by experienced medical staff at the same centers. METHODS: A randomized study of dosage of two commercial computer-assisted dosage programs (PARMA 5 and DAWN AC) vs. manual dosage at 32 centers with an established interest in oral anticoagulation in 13 countries. The aim was to recruit a minimum of 16,000 patient-years randomized to medical staff or computer-assisted dosage. In total, 13,219 patients participated, 6503 patients being randomized to medical staff and 6716 to computer-assisted dosage. The safety and effectiveness of computer-assisted dosage were compared with those of medical staff dosage. RESULTS: In total, 13,052 patients were recruited (18,617 patient-years). International Normalized Ratio (INR) tests numbered 193 890 with manual dosage and 193,424 with computer-assisted dosage. The number of clinical events with computer-assisted dosage was lower (P = 0.1), but in the 3209 patients with deep vein thrombosis/pulmonary embolism, they were reduced by 37 (24%, P = 0.001). Time in target INR range was significantly improved by computer assistance as compared with medical staff dosage at the majority of centers (P < 0.001). CONCLUSIONS: The safety and effectiveness of computer-assisted dosage has been demonstrated using two different marketed programs in comparison with experienced medical staff dosage at the centers with established interest in anticoagulation. Significant prevention of clinical events in patients with deep vein thrombosis/pulmonary embolism and the achievement of target INR in all clinical groups has been observed. The reliability and safety of other marketed computer-assisted dosage programs need to be established.

Comparison of local International Sensitivity Index calibration and 'Direct INR' methods in correction of locally reported International Normalized Ratios: an international study.

BACKGROUND: It is no longer feasible to check local International Normalized Ratios (INR) by the World Health Organization International Sensitivity Index (ISI) calibrations because the necessary manual prothrombin time technique required has generally been discarded. OBJECTIVES: An international collaborative study at 77 centers has compared local INR correction using the two alternative methods recommended in the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis guidelines: local ISI calibration and 'Direct INR'. METHODS: Success of INR correction by local ISI calibration and with Direct INR was assessed with a set of 27 certified lyophilized plasmas (20 from patients on warfarin and seven from normals). RESULTS: At 49 centers using human thromboplastins, 3.0% initial average local INR deviation from certified INR was reduced by local ISI calibration to 0.7%, and at 25 centers using rabbit reagents, from 15.9% to 7.5%. With a minority of commercial thromboplastins, mainly 'combined' rabbit reagents, INR correction was not achieved by local ISI calibration. However, when rabbit combined reagents were excluded the overall mean INR deviation after correction was reduced further to 3.9%. In contrast, with Direct INR, mean deviation using human thromboplastins increased from 3.0% to 6.6%, but there was some reduction with rabbit reagents from 15.9% to 10% (12.3% with combined reagents excluded). CONCLUSIONS: Local ISI calibration gave INR correction for the majority of PT systems but failed at the small number using combined rabbit reagents suggesting a need for a combined reference thromboplastin. Direct INR correction was disappointing but better than local ISI calibration with combined rabbit reagents. Interlaboratory variability was improved by both procedures with human reagents only.

European Concerted Action on Anticoagulation. A multicentre calibration study of WHO international reference preparations for thromboplastin, rabbit (RBT/90) and human (rTF/95).

A 10 centre calibration was performed after six years to determine the international sensitivity index (ISI) of rTF/95 relative to RBT/90, and to assess any international normalised ratio (INR) bias compared with the original multicentre calibration. After exclusion of one outlying centre, the follow up calibration gave a mean ISI for rTF/95 of 0.99, which although a small difference, is significantly greater than the mean ISI of 0.94 obtained previously. The change in ISI for international reference preparation (IRP) rTF/95 relative to RBT/90 would lead to a slight bias in INR for human compared with rabbit thromboplastins. At a theoretical INR of 3.0, the INR bias is 6.0%, and this is below the accepted 10% level of clinical relevance. Ongoing stability monitoring of World Health Organisation thromboplastin IRP is advised.

Guidelines on preparation, certification, and use of certified plasmas for ISI calibration and INR determination.

Reliable international normalized ratio (INR) determination depends on accurate values for international sensitivity index (ISI) and mean normal prothrombin time (MNPT). Local ISI calibration can be performed to obtain reliable INR. Alternatively, the laboratory may determine INR directly from a line relating local log(prothrombin time [PT]) to log(INR). This can be done by means of lyophilized or frozen plasmas to which certified values of PT or INR have been assigned. Currently there is one procedure for local calibration with certified plasmas which is a modification of the WHO method of ISI determination. In the other procedure, named 'direct' INR determination, certified plasmas are used to calculate a line relating log(PT) to log(INR). The number of certified plasmas for each procedure depends on the method of preparation and type of plasma. Lyophilization of plasma may induce variable effects on the INR, the magnitude of which depends on the type of thromboplastin used. Consequently, the manufacturer or supplier of certified plasmas must assign the values for different (reference) thromboplastins and validate the procedure for reliable ISI calibration or 'direct' INR determination. Certification of plasmas should be performed by at least three laboratories. Multiple values should be assigned if the differences between thromboplastin systems are greater than 10%. Testing of certified plasmas for ISI calibration may be performed in quadruplicate in the same working session. It is recommended to repeat the measurements on three sessions or days to control day-to-day variation. Testing of certified plasmas for 'direct' INR determination should be performed in at least three sessions or days. Correlation lines for ISI calibration and for 'direct' INR determination should be calculated by means of orthogonal regression. Quality assessment of the INR with certified plasmas should be performed regularly and should be repeated whenever there is a change in reagent batch or in instrument. Discrepant results obtained by users of certified plasmas should be reported to manufacturers or suppliers.

European Concerted Action on Anticoagulation (ECAA): an assessment of a method for ISI calibration of two whole blood point-of-care PT monitor systems based on lyophilized plasmas using whole blood equivalent PT.

Previously, the attempt to simplify the International Sensitivity Index (ISI) calibration of the CoaguChek Mini whole blood point-of-care test prothrombin time (PT) monitor system was successful using lyophilized plasmas from coumarin-treated patients but not with lyophilized artificially depleted plasmas. With the TAS PT-NC monitor system, both types of plasma failed to provide reliable calibrations. The present study assesses a procedure for the ISI calibration of a TAS PT-NC and CoaguChek Mini whole blood point-of-care test PT monitor systems using lyophilized plasmas. Using lyophilized artificially depleted and coumarin plasma calibrations, we have evaluated a correction for the monitor displayed PT. This was based on a 'line of equivalence' derived from the relationship between whole blood and fresh plasma PT with both types of monitor system. With the TAS PT-NC, the use of this 'line of equivalence' resulted in reliable ISI with both lyophilized coumarin and artificially depleted plasmas. There was no significant difference between mean monitor and mean reference International Normalized Ratio (INR) with the artificially depleted plasmas. With the lyophilized coumarin plasma calibrations there was only a small INR difference. Correction with the 'line of equivalence' therefore facilitates calibration of the TAS PT-NC with lyophilized plasmas. With the CoaguChek Mini, the correction based on the 'line of equivalence' did not improve results but was not required with this system.

European Concerted Action on Anticoagulation (ECAA). An assessment of lyophilised plasmas for ISI calibration of CoaguChek and TAS whole blood prothrombin time monitors.

AIMS: The recommended method for the international sensitivity index (ISI) calibration of whole blood point of care testing (POCT) prothrombin time (PT) systems was originally described by Tripodi et al in 1993 but is too complex and demanding. The present European Concerted Action on Anticoagulation (ECAA) study aimed to assess the reliability of simpler ISI calibration using lyophilised plasma samples. METHODS: ISI calibrations using three different types of ECAA lyophilised plasma samples (artificially depleted, individual, and pooled coumarin) were compared with whole blood calibrations on CoaguChek Mini and TAS PT-NC POCT monitors at 10 centres. RESULTS: With CoaguChek Mini systems, lyophilised coumarin plasma samples (both single donation and pooled) gave ISI and international normalised ratio (INR) values comparable to whole blood. With artificially depleted plasma, ISI and INR values were too high. With TAS PT-NC systems, all three types of lyophilised plasma samples gave inaccurate ISI and unreliable INR results, similar to previous ECAA findings with fresh plasma calibrations. CONCLUSIONS: With CoaguChek Mini systems, ISI calibration can be simplified by the use of ECAA lyophilised plasma samples from coumarin treated patients. Further study is needed to devise a simpler calibration method for the TAS PT-NC system.

European Concerted Action on Anticoagulation (ECAA). Minimum number of centres for reliable International Sensitivity Index calibration of CoaguChek and TAS point-of-care whole blood monitors.

INTRODUCTION: Prothrombin time (PT) test systems require multicentre calibration for reliable International Sensitivity Index (ISI). Multicentre calibration of CoaguChek Mini and TAS PT-NC point-of-care test (POCT) systems is less precise than conventional PT testing. The aim of the present study was to determine the number of centres required to give reliable ISI and International Normalised Ratio (INR) with these two POCT whole blood PT monitors. MATERIALS AND METHODS: A simulation study, based on results of a 10-centre calibration exercise, was performed to assess reliability of ISI and INR when the number of centres was reduced from 10 to 2. RESULTS AND CONCLUSIONS: With both systems, the range of ISI and INR deviation increased as the number of centres was reduced. For the CoaguChek Mini, at least five centres were needed for satisfactory INR deviation in 95% of calibrations. With the TAS PT-NC, three centres gave satisfactory INR at this level. The number of centres required for multicentre calibration of these two POCT PT systems is greater than the two proposed by World Health Organisation (WHO) Guidelines for conventional PT testing.