Caroline Shiach

Multicentre randomised study of computerised anticoagulant dosage

Summary Background The demand for anticoagulant treatment is increasing. We compared the benefits of computer-generated anticoagulant dosing with traditional dosing decided by experienced medical staff in achieving target international normalised ratios (INRs). Methods In five European centres we randomly assigned 285 patients in the stabilisation period and stabilised patients to the computer-generated-dose group (n=137) or traditional-dose group (n=148). Centres had a specialist interest in oral anticoagulation but no previous experience with computer-generated dosing. The computer program calculated doses and times to next visit. Our main endpoint was time spent in target INR range (Rosendaal method). Findings For all patients combined, computer-generated dosing was significantly beneficial overall in achieving target INR (p=0·004). The mean time within target INR range for all patients and all ranges was 63·3% (SD 28·0) of days in the computer-generated-dose group compared with 53·2% (27·7) in the traditional-dose group. For the stabilisation patients alone, computer-generated doses led to a non-significant benefit in all INR ranges (p=0·06), whereas in the stable patients the benefit was significant (p=0·02). Interpretation The computer program gave better INR control than the experienced medical staff and at least similar standards to the specialised centres should be generally available. Clinical outcome and cost effectiveness remain to be assessed.

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.

Increased bleeding associated with protease inhibitor therapy in HIV‐positive patients with bleeding disorders

The use of protease inhibitor (PI) drugs in treatment regimens for HIV‐infected patients with hereditary bleeding disorders has been associated with an increased bleeding tendency. To characterize the nature of this bleeding tendency, a retrospective case record analysis was performed on 67 HIV‐positive patients with hereditary bleeding disorders who had been treated with PI therapy. 34 patients (51%) developed an increased bleeding tendency on PI therapy, usually within the first few weeks of treatment. As well as an increase in usual joint bleeds, patients developed spontaneous atypical small joint, soft tissue and muscle bleeds. Haematuria was also common. Bleeding episodes tended to respond suboptimally to factor concentrate replacement. Ritonavir was most likely to be associated with bleeding. Nine patients switched first‐line PI therapy as a direct consequence of bleeding and seven had no further bleeding problem on their second PI. Factor concentrate usage was significantly increased during the first 6 months of PI therapy compared to the 6 months preceeding treatment. PI therapy is frequently associated with increased bleeding in patients with hereditary bleeding disorders. The mechanism of the bleeding tendency remains to be elucidated.

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.

Antithrombin alfa in hereditary antithrombin deficient patients: A phase 3 study of prophylactic intravenous administration in high risk situations

During surgery and childbirth, patients with hereditary antithrombin (AT) deficiency are at high risk for thrombosis, and heparin prophylaxis may not be sufficiently efficacious. In these patients, exogenous AT may be used in association with heparin. A recombinant human AT (generic name: antithrombin alfa) has been developed. This multi-center study assessed the efficacy and safety of prophylactic intravenous administration of antithrombin alfa to hereditary AT deficient patients in high risk situations, including elective surgery, childbirth, or cesarean section. Antithrombin alfa was administered prior to and during the high risk period for restoration and maintenance of AT activity at 100% of normal. Heparin, low-molecular-weight heparin, and/or vitamin K antagonists were used according to standard of care. The primary efficacy endpoint was the incidence of acute deep vein thrombosis (DVT) from baseline up to day 30 post dosing as assessed by independent central review of duplex ultrasonograms and/or venograms. Safety was assessed based on adverse events (AEs) and laboratory evaluations. Five surgical and nine obstetrical hereditary AT deficiency patients received antithrombin alfa for a mean period of seven days. No clinically overt DVT occurred. Central review of ultrasonograms identified signs of acute DVT in two out of 13 evaluable patients. No antithrombin alfa-related AEs were reported. No patient developed anti-antithrombin alfa antibodies. In conclusion, this study suggests that antithrombin alfa is a safe and effective alternative to human plasma-derived AT for treating hereditary AT deficiency patients at high risk for thromboembolic events.

Detection of mutations in ectopic factor VIII transcripts from nine haemophilia A patients and the correlation with phenotype

Haemophilia A is a common X-linked recessive disorder of bleeding caused by deleterious mutations in the gene for clotting factor VIII. The large size of the factor VIII gene, the high frequency of de novo mutations and its tissue-specific expression complicate the detection of mutations. We have used a combination of reverse transcription/polymerase chain reaction (RT-PCR) of ectopic factor VIII transcripts and PCR of genomic DNA to amplify the entire essential sequence of the factor VIII gene. Chemical mismatch cleavage analysis and direct sequencing have then be empolyed in order to facilitate a comprehensive search for mutations. In this report, we describe the characterisation of nine potentially pathogenic mutations, six of which are novel. The mutations include six single base substitutions (five missense, viz. D56E, V162M, G701D, A1834T and R18691, and one nonsense, viz. R5X), a single base deletion (5697delC), a gross deletion of exon 16 and one mRNA abnormality characteristic of the common intron-22-embedded F8A-mediated DNA inversion. In each case, a correlation of the genotype with the observed phenotype is presented. In order to evaluate the pathogenicity of the five missense mutations, we have analysed them for evolutionary sequence conservation and for their involvement with sequence motifs catalogued in the PROSITE database of protein sites and patterns. Analysis of the sequences in the immediate vicinity of the mutations has revealed sequence features that may have had a possible role in mutagenesis.

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.