J. Jespersen

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.

Inflammation, thrombosis and atherosclerosis: results of the Glostrup study.

Summary.  Inflammation and thrombosis are important mechanisms in cardiovascular disease, as illustrated by the consistent association between inflammatory and hemostatic variables and the risk of cardiovascular events in epidemiological studies. However, the relationship between plasma concentrations of inflammatory and hemostatic markers and the severity of atherosclerosis is not yet well studied. We have evaluated 325 men and 370 women of 60 years, participating in the Danish Glostrup study. We diagnosed atherosclerosis by ultrasonographic measurement of intima‐media thickness (IMT) of the right carotid artery and the assessment of plaque occurrence. Plasma samples were analyzed for the concentration of C‐reactive protein (CRP), fibrinogen, d‐dimer, plasminogen activator inhibitor type‐1 (PAI‐1) antigen and activity, tissue‐type plasminogen activator (t‐PA) antigen and activity, factor VII (FVII) antigen, FVII coagulant activity (FVII:C) and activated FVII (FVIIa). DNA variations were determined for fibrinogen, PAI‐1, t‐PA, FVII, factor XIII and methylene tetrahydrofolate reductase (MTHFR). Subjects with high IMT (upper 10% of distribution, n = 63) had higher CRP levels [2.2 mg L−1 (SE 0.3)] than subjects with IMT in the lowest tertile (n = 217) [1.7 mg L−1 (SE 0.1), P = 0.04], whereas there was no association between the hemostatic variables and IMT. There was an association between fibrinogen and d‐dimer concentrations and number of plaques (P < 0.01), whereas there were no associations between CRP and the other hemostatic variables and the number of plaques. Genetic variation in the t‐PA and MTHFR gene was associated with IMT. In conclusion, in the Glostrup population study, thrombosis and inflammation are associated with the severity of atherosclerosis, as reflected by IMT and plaque occurrence.

Genetic influence on thrombotic risk markers in the elderly--a Danish twin study.

Summary.  Objective: Several hemostatic variables are identified as cardiovascular risk markers. In young and middle‐aged individuals, plasma concentrations of these variables are partly determined by genetic factors. The genetic contribution to cardiovascular disease (CVD) decreases with increasing age, and it is therefore important to determine the heritability of hemostasis also in the elderly. Methods: The heritability of plasma levels of factor VII, fibrinogen, tissue factor, tissue factor pathway inhibitor, von Willebrand factor, thrombin activatable fibrinolysis inhibitor (TAFI), and D‐dimer was determined in 130 monozygotic and 155 dizygotic same‐sex twin pairs, aged 73–94 years, who participated in the Longitudinal Study of Aging of Danish Twins. Furthermore, we determined the influence of promoter polymorphisms in corresponding genes on the plasma level variation. Results: Genetic factors accounted for 33% (D‐dimer) to 71% (TAFI) of the variation in plasma levels. Polymorphisms were associated with concentrations of FVII and TAFI in sib‐pair based analyses, but in linkage analyses the polymorphisms did not explain a significant part of the genetic variation for any of the variables. Conclusions: Concentrations of hemostatic variables have a substantial genetic variation in the elderly, but in this study the promoter polymorphisms only explained a minimal part of this variation.

Gender-Related Association Between β-Fibrinogen Genotype and Plasma Fibrinogen Levels and Linkage Disequilibrium at the Fibrinogen Locus in Greenland Inuit

Elevated plasma fibrinogen levels represent an increased risk for cardiovascular disease, but the mechanism explaining this association is still not clear. Genetic differences may play a role, because it has been shown that individuals who carry the rare alleles of polymorphisms in the genes for the B beta-chain (Bcl I and G/A-455) and the A alpha-chain (Taq I) of fibrinogen have higher plasma fibrinogen levels and that patients with peripheral arterial disease have a higher frequency of the rare allele of the Bcl I polymorphism than do healthy control subjects. We studied the Greenland Inuit, a population with a low incidence of ischemic heart disease; polymorphisms of the fibrinogen gene; and their association with plasma fibrinogen level. The group studied had a small age range (30 to 34 years), 97% were smokers, 62 were men, and 71 were women. We observed that in the Inuit, frequencies of the rare alleles of the beta gene and of the common alleles of the alpha gene polymorphisms were lower than those published for other populations (all Caucasian). Accordingly, in the Inuit, these distribution patterns give a higher frequency of alleles that are associated with lower plasma fibrinogen levels. We further observed comparable linkage disequilibrium between alpha and beta gene polymorphisms in Caucasian populations. In Inuit men the rare allele of the Bcl I and G/A-455 fibrinogen polymorphisms was associated with plasma fibrinogen level comparable with the association described in Caucasian populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Increase of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) in plasma after thrombolytic therapy of patients with myocardial infarction. A randomised, placebo-controlled study

Based on recent studies we hypothesised that the marked generation of thrombin in patients who undergo coronary thrombolysis was associated with substantial deviations of endogenous tissue-type plasminogen activator (t-PA) and the plasminogen activator inhibitor type 1 (PAI-1) in plasma. In the present placebo-controlled study we observe in 20 patients treated with recombinant t-PA (rt-PA) a marked increase (p<0.001) of antigen concentrations in plasma of endogenous t-PA and PAI-1 during the first 12h after initiation of treatment. The concentrations of endogenous t-PA and PAI-1 in plasma correlated significantly (p<0.05) with an estimate of generated thrombin in vivo, determined as plasma concentrations of thrombin-antithrombin III complexes. We conclude that the generation of coagulant activity following coronary thrombolysis is associated with an increased synthesis and/or release of endogenous t-PA and PAI-1, which suggests that the procoagulant condition involves an altered functional state of the vascular endothelium.

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 comparison of artificially-depleted, lyophilized coumarin and fresh coumarin plasmas in thromboplastin calibration

Artificially‐depleted lyophilized plasmas and lyophilized coumarin plasmas were prepared and compared with fresh coumarin plasmas to assess their comparative reliability in local thromboplastin calibration using the manual prothrombin time (PT) technique. Their certified PT values were inserted in turn on the vertical axis in place of the PT obtained with fresh coumarin plasmas. PT results were obtained at eight ECAA national laboratories (‘test centres’) and inserted on the horizontal axis. The resulting thromboplastin calibration slopes were compared with conventional fresh coumarin plasma calibration slopes at the same ‘test centres’. When 60 artificially‐depleted plasmas were substituted for 60 fresh plasmas, the mean calibration slopes with the human plain International Reference Preparation (IRP) were 4.2% higher. For comparison with 20 lyophilized coumarins, three sets of 20 artificially‐depleted plasmas were selected in sequential order from the 60. The lyophilized coumarin plasmas gave a mean deviation of 9.6% from the fresh plasma calibration slopes compared with values of 2.0%, 6.1% and 11.7% for the three sets of 20 depleted plasmas.

Positive impact of hormone replacement therapy on the fibrinolytic system: a long‐term randomized controlled study in healthy postmenopausal women

Summary.  Background: The mechanisms by which postmenopausal hormone replacement therapy (HRT) may influence risk of cardiovascular disease are still unclear. Impaired fibrinolytic function is associated with an enhanced risk of cardiovascular disease and therefore the effect of HRT on fibrinolysis may be of importance. Objectives: To investigate the prolonged effect of HRT on the fibrinolytic system and to determine whether two common polymorphisms in the plasminogen activator inhibitor‐1 (PAI‐1) and tissue‐type plasminogen activator (t‐PA) genes modulate this effect. Methods: Healthy postmenopausal women (n = 248) were randomized to HRT (n = 122) or no substitution (n = 126) 5 years prior to investigation. Results: Significantly higher values of t‐PA activity and lower values of PAI‐1 activity and PAI‐1 antigen were found in the HRT group compared with the control group. This effect was independent of smoking and without influence from the two common polymorphisms PAI‐1 −675(4G/5G) and t‐PA intron8ins311. Furthermore, no difference between opposed estrogen (with norethisterone acetate as the gestagen component) and unopposed estrogen therapy was found. Both an intention‐to‐treat and a per‐protocol analysis were performed and similar results were obtained. Conclusions: Long‐term treatment with HRT in healthy postmenopausal women was found to be associated with a beneficial fibrinolytic profile. This effect was found independent of smoking status, opposed and unopposed estrogen therapy had equal effect, and no influence of the two common polymorphisms PAI‐1–675(4G/5G) and t‐PA intron8ins311 was found. This effect of HRT on fibrinolytic capacity may be one of the beneficial effects of HRT in relation to cardiovascular diseases.

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.