[Assessing post-hospitalization therapeutic ranges in elderly patients treated for atrial fibrillation with vitamin k antagonists]. / Évaluation de l'équilibre des AVK après hospitalisation, chez des sujets âgés, traités pour une fibrillation atriale.

BACKGROUND: In France, anticoagulants are among the most recommended treatments for serious accidents, particularly among the elderly. OBJECTIVES: The purpose of this study was to evaluate the impact of practical and validated tools designed to reduce the negative effects of vitamin K antagonist (VKA) treatments by assessing patients before and after the tools were implemented. METHODS: An exhaustive before and after multi-centric cohort study was performed in the Agen territory. The follow-up period corresponded to the six-month period post-hospitalization. The principal criterion was the time in the therapeutic range (TTR) at values of 2 to 3 according to the Rosendaal method. RESULTS: The overall time spent in the follow-up period before and after the implementation of the tools in 65- and 74-year-old patients was 58% and 64%, respectively (P=0.584). After the treatments, the TTR in the 85- to 90-year-old patients was 71.1%. An increase was observed in the number of subjects with a TTR≥70% after the implementation of the tools according to age, particularly in the 85- to 90-year-old patients (8 vs. 41; [P=0.01]). Prescription help software revealed a tendency of improvement in TTR values from 61% to 68% (P=0.472). In addition, longer therapeutic periods corresponded to longer patient lifespans (r=0.86). CONCLUSION: This study demonstrates the feasibility and advantages of implementing tools to improve the efficacy of VKA treatment in primary care, particularly for patients from 85 to 90 years old. The results should promote the implementation of this type of treatment method at the national level.

[Anticoagulant clinics are they effective in France? Performance evaluation of six anticoagulant clinics concerning the management of vitamin K antagonists]. / Les cliniques d'anticoagulants sont-elles efficaces en France ? Évaluation des performances de six cliniques dans la gestion des traitements par antivitamines K.

PURPOSE: Recent data show that the quality of anticoagulation evaluated in patients receiving vitamin K antagonists (VKA) is not optimal in France. The aim of this retrospective study was to estimate the performances of six French anticoagulant clinics that manage VKA treatments over a 3-year period, from 2009 to 2011. METHODS: All clinics used the same rule based software. We determined the time spent in the therapeutic range (TTR), a surrogate end-point of quality of treatment with VKA. RESULTS: The overall duration of follow-up was 2755 patient-years concerning 2385 patients. The time spent in the therapeutic range 2 to 3 assigned for 89% of the patients, was 73%. On the other hand the time spent in the therapeutic range for the other two INR ranges (2.5-3.5 and 3-4.5) concerning 11% of patients with prosthetic heart valve was lower (63.7% and 68.8% respectively) with an imbalance in favour of the time below the range. In this study, warfarin (Coumadine(®)) and fluindione (Previscan(®)) allowed an equivalent quality of anticoagulation. The 1728 patients of age ranged from 60 to 100 years spent more time in TTR than the 651 younger patients. The percentage of time spent with an INR greater than 5 was extremely reduced which is a guarantee of safety. CONCLUSION: These results prove that anticoagulant clinics in France have the same good performances as their counterparts abroad. It can be assumed that a high TTR contributes to a low incidence of both bleedings and thrombosis.

Diagnosis of congenital toxoplasmosis: prenatal and neonatal evaluation of methods used in Toulouse University Hospital and incidence of congenital toxoplasmosis.

The aim of this study was to determine the incidence of congenital toxoplasmosis (CT) and to assess the performances of prenatal and neonatal diagnoses. From 1994-2005, in Toulouse University Hospital, France, amniocentesis was performed on 352 pregnant women who were infected during pregnancy. All women were treated with spiramycin and pyrimethamine-sulfadoxine when prenatal diagnosis was positive. Among the 275 foetuses with follow-up, 66 (24%) were infected. The transmission rates of Toxoplasma gondii were 7%, 24% and 59% in the first, second and third trimesters, respectively. The sensitivity and specificity of PCR on amniotic fluid (AF) were 91% and 99.5%, respectively. One case was diagnosed by mouse inoculation with AF and six cases were diagnosed by neonatal or postnatal screening. The sensitivity and specificity of PCR on placentas were 52% and 99%, respectively. The sensitivity of tests for the detection of specific IgA and IgM in cord blood was 53% and 64%, respectively, and specificity values were 91% and 92%. In conclusion, PCR performed on AF had the highest levels of sensitivity and specificity for the diagnosis of CT. This permits an early diagnosis of most cases and should be recommended.

In vitro evaluation of the embolic risk of diagnostic and therapeutic intravascular procedures.

BACKGROUND: The purpose of the study was to evaluate the risk of distal embolisation in a silicon model during different endovascular diagnostic and therapeutic procedures. MATERIAL AND METHODS: Endovascular technics, such as guidewire and catheter advancement, metal stent placement and balloon angioplasty were compared. Clots were produced from human blood sample. The transparent silicon model was filled with saline, flow was generated by an hydraulic pump. Stenosis was created by mechanical compression. The size of the circulating particles were measured with a mesh of nylon filters. RESULTS: No loose particles were detected using guidewire, pigtail and straight catheters. Balloon inflation induced embolisation of particles ranging from 100 microns to 10 mm in length. Deployment of self expandable metallic stents did not result in particle migration but secondary angioplasty inside the stent detached particles (ranging from 400 microns to 12 mm in length). Deployment of balloon expandable stent yielded in the stretching of the clot, which became sometimes longer than the stent, resulting in the detachment of the non covered portion. CONCLUSION: The risk of distal embolisation during guide-wires and catheters manipulation is not significant. Balloon catheters and secondary angioplasty after deployment of self-expanding stents caused large particles detachment.

Detection and incidence of drug-induced liver injuries in hospital: a prospective analysis from laboratory signals.

AIMS: Liver damage remains the most frequent type of adverse drug reaction (ADRs) that can lead to the withdrawal of a drug from the market. The abnormal laboratory data identified by computerized hospital information systems can be used in order to improve the detection of ADRs. Our objectives were to assess the detection and incidence of drug-induced liver abnormalities in a university hospital inpatient population and to evaluate the underreporting rate of drug-induced liver injury. METHODS: We conducted a prospective study performed 1 week per month from June to October 1997. We selected patients by a computerized process using biochemistry laboratory data, based on serum enzyme values, alanine aminotransferase (over 2 fold normal) and alkaline phosphatase (over 1.5 fold normal). RESULTS: Among 1976 ALT and 1814 AP assays performed during the period of the study, 156 (7.9%) and 159 (8.8%) tests, respectively, fell into the selected criteria. These concerned 147 patients. Among these patients, 13 (8.8%) cases of drug-induced liver injuries were suspected. Seven cases were asymptomatic. Six cases were classified as serious by these criteria: hospitalization to investigate the cause of health status impairment (4 patients), prolongation of hospitalization (1 patient) and life-threathening (1 patient). Using the hospitalization database, the incidence of drug-induced liver injuries was estimated as 6.6 per 1000 inpatients a week. Only 1 case was reported by physicians in the same period. CONCLUSIONS: Computerization of biochemical data would allow the development of systems to improve detection of drug-induced injury. Moreover, underreporting remains important for such potentially serious ADRs, even in a university hospital.

Evaluation of the Vega haematology analyser in a university hospital setting.

The performance of the ABX Vega haematology analyser was compared with that of the Sysmex NE-8000, with specific attention to flagging performance and ergonomics. Eight hundred routine samples underwent precision and interinstrument variability studies and 168 samples corresponding to various blood disorders were studied meanwhile. Results from the two instruments gave excellent correlation (r > 0.900) for most parameters except MCHC (r = 0.114), basophil and monocyte percentages (r = 0.617 and 0.552, respectively). The reproducibility, repeatability, linearity, carry-over and stability of the Vega were satisfactory; 'flagging' occurred in 31% of routine samples with sensitivity 88.8%, specificity 41.3% and positive predictive value 85.7%. Various flags appeared in 91% (42/46) of cases where blast cells were microscopically identified. In the four remaining cases, CBC anomalies would themselves have justified microscopic examination of a smear. On 'CBC only' mode reagent consumption was significantly reduced. In the laboratory the analyser was best appreciated for its user-friendliness.

Erythrocyte hyperaggregation and thrombogenic dysfibrinogenemia.

Erythrocyte aggregation was measured in 12 patients with congenital dysfibrinogenemia. The results showed hyperaggregation in four patients who had presented a thrombotic disorder, while aggregation was entirely normal in patients with asymptomatic dysfibrinogenemia. None of the four symptomatic patients had any other anomaly of hemostasis, in particular no coagulation inhibitor deficit or anti-phospholipid antibodies. The possible involvement of erythrocyte hyperaggregation in the thrombotic process is discussed.

Pharmacodynamics and tolerance of two nadroparin formulations (10,250 and 20,500 anti Xa IU x ml(-1)) delivered for 10 days at therapeutic dose.

Venous thromboembolism may be efficiently treated by once-a-day (o.d.) administration of a high dose of low molecular weight heparin (LMWH) instead of administration of the same total dose in two injections a day (b.i.d.). To reduce the volume of the subcutaneous (s.c.) injection, a more concentrated form of the drug is advisable. This study was designed to compare the bioavailability of 2 formulations of nadroparin containing 10,250 and 20,500 anti-Xa IU x ml(-1) respectively. This was an open, randomized, cross-over study where 12 healthy volunteers (age 18-35) were enrolled. They received either 90 anti-Xa IU x kg(-1) b.i.d. of the 10,250 IU preparation (treatment A), or 180 anti-Xa IU x kg(-1) o.d. of the 20,500 IU preparation (treatment B) for 10 days. On day 1, the subjects were sampled between 0 and 12 h (treatment A) or between 0 and 24 h (treatment B). On day 10, they were sampled between 0 and 12 h and between 12 and 24 h (treatment A) or between 0 and 24 h (treatment B). Anti-Xa and anti-IIa activities were determined by specific chromogenic assays. The main result of the study was that the bioavailability of the anti-Xa activity of the 2 nadroparin formulations was equivalent, as shown by the comparison of the AUC(0-12 h) plus AUC(12-24 h) (treatment A) and the AUC(0-24 h) (treatment B), calculated on day 10. This study also allowed a number of interesting observations to be made. 1) Between day 1 and day 10, there was an accumulation of the anti-Xa activity for treatment A but not for treatment B (accumulation factors: 1.6 and 1.1 respectively); 2) On day 10, the AUC(0-12 h) were slightly but significantly lower than the AUC(12-24 h) suggesting a circadian effect for anti-Xa and anti-IIa activities; 3) the clearance of the anti-Xa activity was comparable at the 2-dose regimens, while that of the anti-IIa activity was lower in treatment B than in treatment A, indicating a significant dose effect for the pharmacodynamics of the longer heparin chains; 4) On average, the clearance of the anti-IIa activity was twice as high as that of the anti-Xa activity; 5) For treatment B, significant APTT prolongations were noticed at Tmax (prolongation factor: 1.7 +/- 0.25), in relation with the anti-IIa activity (0.3 +/- 0.1 IU x ml(-1)).

The routine determination of the endogenous thrombin potential, first results in different forms of hyper- and hypocoagulability.

The area under the thrombin generation curve (the endogenous thrombin potential; ETP) has been proposed as a parameter for plasma-based hypercoagulability and to monitor anticoagulant treatment. We present an ETP assay for the routine laboratory using a centrifugal analyser. Throughput is 30 samples/h, within and between run imprecision is 4-5.6%. Suitable substrates were developed for the ranges of 10-500% and 2-100% of normal. Independent of tissue factor concentration (if > 4 pM), the normal value of the extrinsic ETP is 384.8 +/- 51.7 nM.min. The intrinsic ETP, triggered by ellagic acid, is 414 +/- 41 nM.min. The ETP is decreased to 15 and 35% of normal by oral anticoagulation (INR 2.5-4.0) and by heparin administration (APTT 1.5-2.5 x control). The ETP is increased in untreated subjects with congenital antithrombin deficiency and in women using oral contraceptives. In deep vein thrombosis (phlebographically confirmed), it is increased by 29.4% (extrinsic) and 53% (intrinsic). In (angiographically assessed) coronary artery disease the increase is by 10% and 17% respectively.

D-dimer test and diagnosis of deep vein thrombosis: a comparative study of 7 assays.

The current D-Dimer ELISA methods provide high sensitivity and negative predictive value for the diagnosis of deep vein thrombosis but these methods are not suitable for emergency or for individual determination. We have evaluated the performance of 3 newly available fast D-Dimer assays (Vidas D-Di, BioMérieux; Instant IA D-Di, Stago; Nycocard D-Dimer, Nycomed) in comparison with 3 classic ELISA methods (Stago, Organon, Behring) and a Latex agglutination technique (Stago). One-hundred-and-seventy-one patients suspected of presenting a first episode of deep vein thrombosis were investigated. A deep vein thrombosis was detected in 75 patients (43.8%) by ultrasonic duplex scanning of the lower limbs; in 11 of them the thrombi were distal and very limited in size (< 2 cm). We compared the performance of the tests by calculating their sensitivity, specificity, positive and negative predictive value for different cut-off levels and by calculating the area under ROC curves. The concordance of the different methods was evaluated by calculating the kappa coefficient. The performances of the 3 classic ELISA and of the Vidas D-Di were comparable and kappa coefficients indicated a good concordance between the results provided by these assays. Their sensitivity slightly declined for detection of the very small thrombi. Instant IA D-Di had a non-significantly lower sensitivity and negative predictive value than the 4 previous assays; however its performance was excellent for out-patients. As expected, the Latex assay had too low a sensitivity and negative predictive value to be recommended. In our hands, Nycocard D-Dimer also exhibited low sensitivity and negative predictive value, which were significantly improved when the plasma samples were tested by the manufacturer. Thus significant progress has been made, allowing clinical studies to be planned to compare the safety and cost-effectiveness of D-Dimer strategy to those of the conventional methods for the diagnosis of venous thrombosis.

A data management software for the Sysmex NE 8000 haematology analyser.

The Sysmex NE 8000 (TOA-Japan) is a haematology analyser that performs blood cells count and leukocyte differential count. For facilitating the work of technical validation, we developed a software adapted to any IBM or compatible PC running under MS-DOS, to manage the analyser. Data are automatically collected via the RS-232 interface from the analyser or keyed in for the other techniques. The software deals with 64 different analyses entirely "user defined". Six technical alarms of the analyser are taken in account for red or white cells and platelets. An "electronic worksheet" presents the results or alarms with 10 patients to a page. This enables the lab technician to assess the coherence of the various data and to perform verifications or complementary tests if necessary. As an option, a blinking asterisk can signal any results out of predetermined range. By moving the cursor through the table, a test result can be deleted, modified or added. A function displays the patient previous files in a window because the data are recorded in long term archives at the end of the day. This long term recording allows a search of previous files to decide additional tests if the patient is unknown. If the patient is known, with additional tests previously performed, this procedure is time saving. A daily archive function classifies and prints the whole day's work in alphabetical order. A protocol of communication allows a connection to a mainframe computer Bayer-Technicon. This program and the user's manual are free of charge, available on request from J. P. Cambus.

Predicting daily maintenance dose of fluindione, an oral anticoagulant drug.

Due to large inter-individual variations, the dose of vitamin K antagonist required to target the desired hypocoagulability is hardly predictible for a given patient, and the time needed to reach therapeutic equilibrium may be excessively long. This work reports on a simple method for predicting the daily maintenance dose of fluindione after the third intake. In a first step, 37 patients were delivered 20 mg of fluindione once a day, at 6 p.m. for 3 consecutive days. On the morning of the 4th day an INR was performed. During the following days the dose was adjusted to target an INR between 2 and 3. There was a good correlation (r = 0.83, p < 0.001) between the INR performed on the morning of day 4 and the daily maintenance dose determined later by successive approximations. This allowed us to write a decisional algorithm to predict the effective maintenance dose of fluindione from the INR performed on day 4. The usefulness and the safety of this approach was tested in a second prospective study on 46 patients receiving fluindione according to the same initial scheme. The predicted dose was compared to the effective dose soon after having reached the equilibrium, then 30 and 90 days after. To within 5 mg (one quarter of a tablet), the predicted dose was the effective dose in 98%, 86% and 81% of the patients at the 3 times respectively. The mean time needed to reach the therapeutic equilibrium was reduced from 13 days in the first study to 6 days in the second study. No hemorrhagic complication occurred. Thus the strategy formerly developed to predict the daily maintenance dose of warfarin from the prothrombin time ratio or the thrombotest performed 3 days after starting the treatment may also be applied to fluindione and the INR measurement.

Automated technical validation--a real time expert system for decision support.

Dealing daily with various machines and various control specimens provides a lot of data that cannot be processed manually. In order to help decision-making we wrote specific software coping with the traditional QC, with patient data (mean of normals, delta check) and with criteria related to the analytical equipment (flags and alarms). Four machines (3 Ektachem 700 and 1 Hitachi 911) analysing 25 common chemical tests are controlled. Every day, three different control specimens and one more once a week (regional survey) are run on the various pieces of equipment. The data are collected on a 486 microcomputer connected to the central computer. For every parameter the standard deviation is compared with the published acceptable limits and the Westgard's rules are computed. The mean of normals is continuously monitored. The final decision induces either an alarm sound and the print-out of the cause of rejection or, if no alarms happen, the daily print-out of recorded data, with or without the Levey Jennings graphs.

A data management program for the Electra 800 automatic analyser.

The Electra 800 automatic coagulation analyser rapidly performs most chronometric coagulation tests with high precision. To facilitate data handling, software, adaptable to any PC running under MS-DOS, was written to manage the analyser. Data are automatically collected via the RS232 interface or can be manually input. The software can handle 64 different analyses, all entirely 'user defined'. An 'electronic worksheet' presents the results in pages of ten patients. This enables the operator to assess the data and to perform verifications or complementary tests if necessary. All results outside a predetermined range can be flagged and results can be deleted, modified or added. A patient's previous files can be recalled as the data are archived at the end of the day. A 120 Mb disk can store approximately 130,000 patient files. A daily archive function can print the day's work in alphabetical order. A communication protocol allows connection to a mainframe computer. This program and the user's manual are available on request, free of charge, from the authors.

Computer program for connection and data management of an automated coagulation system: the KC 10.

In Europe, the KC 10, manufactured by Amelung Germany, is one of the instruments most commonly found in coagulation laboratories. For facilitating the work of technical validation, we wrote a software adapted to any IBM or compatible PC running under MS-DOS, to manage the analyser performance. Data are automatically collected via the BCD interface from the analyser or keyed in for the other techniques. The software deals with 64 different analyses entirely 'user defined'. An 'electronic worksheet' presents the results, by page of ten patients. This enables the laboratory technician to assess the coherence of the various data and to perform verifications or complementary tests if necessary. As an option, a blinking asterisk can signal all results outside predetermined range. By moving the cursor through the table, a test result can be deleted, modified or added. A function displays the patient's previous files in a window because the data are recorded in long-term archives at the end of the day. This long-term recording allows a search of previous files to decide additional tests if the patient is unknown. A daily archive function classifies and prints the whole day's work in alphabetical order. A protocol of communication allows connection to a mainframe Bayer-Technicon computer. This program and the user's manual are free, available on request from address above.

A new chronometric assay to determine plasma antifactor Xa activity which is insensitive to the antithrombin activity of low molecular weight heparins.

Some commercially available chronometric assays are influenced by the residual antithrombin activity of low molecular weight heparins (LMWH) and they underestimate the ex vivo anti Xa activity. We have evaluated a new kit (Staclot-Heparin) highly specific for the anti Xa activity of LMWH. A comparison with the results given by a reference chromogenic method (Stachrom-Heparin) indicates a very good correlation between the 2 assays (r = 0.95, n = 59). This new assay is not influenced by vitamin K antagonist treatments. Clinical biologists now have the possibility of determining the anti Xa activity generated by LMWH easily and accurately, using a chronometric assay.