L. Poller

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.

Fixed minidose warfarin: a new approach to prophylaxis against venous thrombosis after major surgery.

A prospective study was carried out to see whether a small fixed dose of warfarin (1 mg daily) given before operation (mean 20 days) would prevent deep vein thrombosis in patients having major gynaecological surgery. One hundred and four patients were randomised into three groups: fixed minidose warfarin; full dose oral anticoagulation; and no treatment (controls). There was a significantly lower incidence of deep vein thrombosis in the minidose warfarin and full dose anticoagulant treatment groups (9% (3/32) and 3% (1/35) respectively) than in the controls (30%; 11/37) but no significant difference between the two anticoagulant treatment groups. Prothrombin time and the activated partial thromboplastin time were normal on the day of surgery in the warfarin treatment group, whereas times were prolonged in the group given full dose anticoagulation. Mean haemoglobin concentrations fell in all three groups after operation but the fall was significantly less in the minidose warfarin treatment group than after full dose anticoagulation. The benefit from full dose oral anticoagulant prophylaxis, based on a preoperative international normalised ratio of 1.5-2.5 with rabbit brain Manchester reagent, was similar to the protection achieved in an oral anticoagulant treatment group controlled with human brain Manchester comparative reagent at a similar level of anticoagulation. The lack of disturbance of normal haemostasis at the time of operation together with a significant reduction in deep vein thrombosis may encourage surgeons to introduce minidose prophylaxis with warfarin.

Oral anticoagulants controlled by the British comparative thromboplastin versus low-dose heparin in prophylaxis of deep vein thrombosis.

The British comparative thromboplastin (BCT) was used to monitor the effectiveness of oral anticoagulants in preventing deep vein thrombosis (DVT) in patients undergoing major gynaecological surgery. All patients were screened for DVT with the use of the 125I-fibrinogen scan. One hundred and forty-five patients aged 40 years or more were randomised into three groups. Group 1 received oral anticoagulant (nicoumalone) treatment, stabilised over five days before surgery and continuing into the second postoperative week. The other patients served as two contrast groups and were managed on a double-blind basis. Group 2 received a subcutaneous low-dose regimen of heparin calcium. Group 3 received subcutaneous saline. Eleven of 48 patients in the saline group, three of 49 patients in the heparin group, and three of 48 patients in the oral anticoagulant group developed DVT as judged by 125I-fibrinogen scanning. The incidences in groups 1 and 2 were significantly lower than in the saline group. The falls in haemoglobin concentration and incidence of haemorrhage were similar in all three groups. The study showed that oral anticoagulant prophylaxis stabilised preoperatively and low-dose heparin were equally effective in preventing deep vein thrombosis in a moderate-risk group. Immediate preoperative prothrombin ratios of 2·0-2·5 and postoperative ratios of 2·0-4·0 with the BCT gave adequate protection without increased haemorrhagic risk.

Prospective comparative study of computer programs used for management of warfarin.

AIMS--To compare the effectiveness of three computerised systems that are currently used for assisting warfarin control in outpatients with the customary dosing method used by experienced medical staff. METHODS--A pilot randomised study of three systems with a follow up independently randomised study of two of these was made on 186 patients receiving long term treatment or who had recently started warfarin treatment and had been discharged from hospital. RESULTS--All three computerised systems seemed to give satisfactory control compared with the traditional dosing method. For patients receiving more intensive treatment with an assigned target range of 3.0-4.5 computerised dosage programs achieved significantly better control; the medical staff undertreated such patients almost 50% of the time. CONCLUSION--Computer based programs can assist outpatient anticoagulant control with warfarin during both early and long term treatment. For most patients the control achieved is as good as that obtained by the customary method of dosing, by experienced clinic doctors, although the latter tend to be too conservative when dosing patients within the intense target range of 3.0 to 4.5 International Normalised Ratio (INR). The computers were significantly more successful in this higher range.

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.

International Normalized Ratios (INR): the first 20 years.

Adoptionof INRby theWorldHealthOrganization (WHO) [1] 20 years ago has resulted in greater safety and effectiveness of oral anticoagulant treatment with warfarin and related drugs. Massive increase in demand for oral anticoagulation has followed with increased recognition of the benefit in many clinical states including atrial fibrillation where previously treatment risks outweighed advantages. INR are derived from the international sensitivity index (ISI), a quantitative measurement of the responsiveness of individual thromboplastin reagents and prothrombin time (PT) test systems. This is obtained from the comparison of the local PT results with those of a WHO thromboplastin international reference preparation (IRP). The 20 years’ experience of INR has proved their value and also the need for additional steps, centrally and locally, to ensure reliable INR.

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.

Abnormal fibrin polymerization in liver disease.

Summary. Although there have been isolated reports of an acquired abnormal fibrinogen in patients with liver disease, its frequency and clinical significance is not known. In this study 121 consecutive patients with a wide spectrum of hepatic disorders were screened for abnormal fibrin polymerization. A simple colorimetric method using Reptilase was employed. Of 32 patients with proven cirrhosis, 16 (50%) showed abnormal fibrin polymerization. The incidence in decompensated alcoholic cirrhosis was particularly high. The abnormality was also detected in all patients with acute liver failure and seven of 15 with chronic active liver disease. Clinical improvement often correlated with its disappearance. Two patients with primary liver cell tumours demonstrated the abnormal polymerization. In patients with bleeding oesophageal varices the detection of abnormal fibrin polymerization was associated with a poor prognosis. None of the patients with surgical obstructive jaundice (26) or miscellaneous liver disorders (37) had abnormal fibrin polymerization. The occurrence of abnormal fibrin polymerization in liver disease is more frequent than previously suspected and usually signifies severe primary hepatocellular dysfunction. Evidence is presented to support the presence of a primary abnormality of fibrinogen as the cause of impaired fibrin monomer polymerization.

Clotting Factors during Oral Contraception: Further Report

Coagulation studies were performed on 97 women taking a variety of oral contraceptives (OCs) 100 normal control women and 76 pregnant women (13 in the first trimester 26 in the second and 37 in the third). Prothrombin activity cephaline time and factor 7 8 and 10 assays were performed before the start and after 1 2 and 3 months then between 3-6 months 7-12 months and between 1-2 years. Prothrombin activity showed only slight variation throughout. There was little difference in cephalin time between the OC and the normal group. In contrast the pregnant patients showed progressively shorter cephalin times which became shortened during the second trimester the most marked acceleration occurring postpartum. There was little change in factor 7 during the first trimester of pregnancy but from the second trimester on a rise was recorded. A rise in factor 7 and 10 levels was seen from the third month on with the maximum in those patients who had been on OCs for more than 2 years. A broader spectrum of clotting tests appeared to be accelerated during normal pregnancy than during OC therapy and both factor 7 and 10 were higher when comparing trimesters of pregnancy with a similar period on OCs. After a 2 year course the rise in factor 7 levels was of the same order. It was concluded that it is important to determine whether factor 7 goes on increasing with more prolonged courses of oral contraception.

Comparison of prothrombin complex concentrate and vitamin K1 in oral anticoagulant reversal.

A randomised clinical trial was undertaken to compare the value of a factor II, IX, and X concentrate (Prothromplex) with intravenous vitamin K1 (2-5 mg) in reversing an overdose of oral anticoagulants. Rapid partial correction of the prothrombin time, partial thromboplastin time, and the clotting factor assays were observed with the concentrate, but these changes were not always sustained. In contrast vitamin K1 did not show any great effect at two hours but at 24 hours there was always over-correction despite the conservative dosage, prothrombin times being shorter than the therapeutic range. The prothrombin complex concentrate provides a quicker, more controlled but less sustained method of reversing the coumarin defect than vitamin K1. But there remains a significant risk of hepatitis even with a preparation for which strenuous efforts have been made to minimise this risk by screening for hepatitis B virus. The risk should be carefully considered before such concentrates are infused in non-urgent conditions.