M. Keown

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

Summary.  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.

European Concerted Action on Anticoagulation

International sensitivity index (ISI) calibration of whole blood prothrombin time (PT) monitors is too complex. We previously simplified the method by using European Concerted Action on Anticoagulation (ECAA) lyophilized plasma samples with the TAS PT-NC (Bayer AG, Leverkusen, Germany) and the CoaguChek Mini (Roche Diagnostics, Mannheim, Germany) whole blood PT monitoring systems. The TAS PT-NC required a correction derived from the line of equivalence. Monte Carlo bootstrap analysis of reducing numbers of test samples was performed with both systems. Plasma samples from patients receiving coumarin (coumarin samples), healthy subjects (normal samples), and plasma samples artificially depleted of coagulation factors were used. With the TAS PT-NC, 20 coumarin samples or 20 artificially depleted samples with 7 normal samples gave reliable ISI and international normalized ratio and satisfactory precision. With the CoaguChek Mini, 30 coumarin and 10 normal samples were required. Simplification of ISI calibration of the 2 monitoring systems is possible using fewer ECAA lyophilized plasma samples than the 80 required according to the World Health Organization guidelines for conventional PT systems and previously recommended for fresh plasma samples tested on the same 2 monitoring systems.

Reliability of international normalised ratios from two point of care test systems: comparison with conventional methods

Abstract Design Comparison of the INRs from the two systems with a “true” INR on a conventional manual test from the same sample of blood. Setting 10 European Concerted Action on Anticoagulation centres. Participants 600 patients on long term dosage of warfarin. Main outcome measures Comparable results between the different methods. Results The mean displayed INR differed by 21.3% between the two point of care test monitoring systems. The INR on one system was 15.2% higher, on average, than the true INR, but on the other system the INR was 7.1% lower. The percentage difference between the mean displayed INR and the true INR at individual centres varied considerably with both systems. Conclusions Improved international sensitivity index calibration of point of care test monitors by their manufacturers is needed, and better methods of quality control of individual instruments by their users are also needed.

European Concerted Action on Anticoagulation (ECAA): multicentre international sensitivity index calibration of two types of point-of-care prothrombin time monitor systems

Summary. A multicentre modified World Health Organization (WHO)‐type international sensitivity index (ISI) calibration has been performed at 10 European Concerted Action on Anticoagulation (ECAA) national laboratories using non‐citrated whole‐blood on two point‐of‐care test (POCT) prothrombin time (PT) monitor systems, CoaguChek Mini and TAS PT‐NC, using single lots of test cards/strips. The relevant species (human and rabbit) WHO international reference preparations (IRPs) were tested with the manual PT technique on citrated plasma from the same blood donations. The ISI was calculated from the slope of the orthogonal regression line relating log PT (POCT) to log PT (IRP). The mean ISI of the CoaguChek Mini system was 1·75 and 1·13 with the prothrombin time non‐citrated Thrombolytic Assessment System (TAS PT‐NC). With the CoaguChek Mini system, seven out of 10 calibrations exceeded the current 3% WHO recommended limit for the coefficient of variation (CV) of the slope with conventional PT testing, whereas with the TAS PT‐NC system, it was eight out of 10. All the POCT calibrations had a CV of the slope < 5%. It is suggested that this level of precision be adopted as the limit of acceptability of calibration of these monitor systems. In these circumstances, the modified WHO‐type ISI calibration appeared to be satisfactory for the POCT whole‐blood monitors.

A national field study of quality assessment of CoaguChek point-of-care testing prothrombin time monitors.

A system for quality assessment (QA) of the CoaguChek (Roche Diagnostics, Mannheim, Germany) point-of-care testing prothrombin time monitor has been developed by the European Concerted Action on Anticoagulation. Hitherto there has not been an adequate rapid method for CoaguChek QA. Sets of 5 certified international normalized ratio (INR) plasma samples were tested on 539 CoaguChek monitors by experienced staff at 9 Netherlands Thrombosis Centers and results compared with certified INR. A 15% or more deviation has been classified as significant deviation. Overall mean and certified INR values were similar, but 20.3% of participants showed a 15% or more deviation from the certified INR on at least 1 of the 5 QA plasma samples. Statistically significant differences in results with different lots of CoaguChek test strips were found. There is need for large scale QA of CoaguChek monitors. The importance of the 5 CoaguChek certified INR QA plasma samples being tested on a single occasion is demonstrated.

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: €47) for computer‐assisted dosing, but with little difference in clinical event costs. Total overall costs were €51 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.

A multicentre randomised clinical endpoint study of PARMA 5 computer-assisted oral anticoagulant dosage

To meet growing demand for oral anticoagulation worldwide there has been increased dependence on computer‐assistance in dosage although the safety and effectiveness of any of the individual computer‐assisted dosage programs has not previously been established. This randomised multicentre clinical end‐point study assessed a new version of the parma 5 program. It compared parma 5 safety and effectiveness with manual dosage by experienced medical staff at 19 centres with a known interest in oral anticoagulation. Target recruitment was 8000 patient‐years, randomised to medical staff or parma‐5 assisted dosage. Safety and effectiveness of the parma 5 program was compared with manual dosage. A total of 10 421 patients were recruited (15 369 patient‐years) in the 5‐year study. International normalised ratio (INR) tests numbered 167 791 with manual and 160 078 with parma 5 dosage. With parma 5 there was overall a non‐significant reduction in clinical events but in the 2542 patients with deep vein thrombosis/pulmonary embolism, clinical events were significantly reduced (P = 0·005). Success in achieving ‘time in target INR range’ was also significantly greater with parma 5 compared with the dosage by experienced medical staff. This study demonstrated the safety and effectiveness of parma 5‐assisted dosage.

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.

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

Summary.  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.

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

Summary.  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.