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Biomedical subjects

P Mismetti

Publications and source records attributed to P Mismetti.

At least 19 recordsLinked to original sources
PubMed2007

Influence of age on the prescription of vitamin K antagonists in outpatients with permanent atrial fibrillation in France.

PURPOSE: The aim of the study was to describe the current rate and determinants of the prescription of antithrombotics in outpatients with permanent atrial fibrillation, with a pre-specified emphasis on the influence of age on the prescription of vitamin K antagonists. METHODS: This was a prospective observational survey in France among 5893 consecutive outpatients with documented permanent atrial fibrillation being seen by 770 physicians from August to December 2002. We recruited physicians from two random lists of general practitioners and cardiologists, respectively, stratified according to their administrative region, from the list of all French private general practitioners and cardiologists. RESULTS: The mean age of patients was 75.8 years. Mean duration since diagnosis of atrial fibrillation was 5.0 years; 31.7% of patients had valvular heart disease and 60.3% hypertension. An antithrombotic was prescribed to 95.5% of patients at the time of consultation. The percentage of patients treated with vitamin K antagonists was 76.4%; it decreased from 86.0% in patients aged 60-70 years to 63.5% in patients aged 80 years or above. On multivariate analysis, high age was a significant predictor (p = 0.001) for the non-prescription of vitamin K antagonists. In patients above 70 years currently receiving an antithrombotic, the probability of prescription of vitamin K antagonists decreased on average by 9.6% per year. CONCLUSIONS: Vitamin K antagonists are administered to most outpatients with permanent atrial fibrillation at high thromboembolic risk seen by French physicians in private practice. However, their use decreases with age.

Age Factors↗
PubMed2006

A randomized study comparing the efficacy and safety of nadroparin 2850 IU (0.3 mL) vs. enoxaparin 4000 IU (40 mg) in the prevention of venous thromboembolism after colorectal surgery for cancer.

BACKGROUND: The optimal thromboprophylactic dosage regimen of low-molecular-weight heparins in high-risk general surgery remains debatable. OBJECTIVES: We performed a randomized, double-blind study to compare the efficacy and safety of nadroparin 2850 IU (0.3 mL) and enoxaparin 4000 IU (40 mg) in the prevention of venous thromboembolism (VTE) after colorectal surgery for cancer. PATIENTS AND METHODS: Patients undergoing resection of colorectal adenocarcinoma were randomized to receive once daily either 2850 IU nadroparin or 4000 IU enoxaparin s.c. for 9 +/- 2 days. The primary efficacy outcome was the composite of deep vein thrombosis (DVT) detected by bilateral venography or documented symptomatic DVT or pulmonary embolism up to day 12. The main safety outcome was major bleeding. A blinded independent committee adjudicated all outcomes. RESULTS: Out of 1288 patients analyzed, efficacy was evaluable in 950 (73.8%) patients. The VTE rate was 15.9% (74/464) in nadroparin-treated patients and 12.6% (61/486) in enoxaparin-treated patients, a relative risk of 1.27 (95% confidence interval; CI: 0.93-1.74) that did not met the criterion for non-inferiority of nadroparin. The rate of proximal DVT was comparable in the two groups (3.2% vs. 2.9%, respectively), but that of symptomatic VTE was lower in nadroparin-treated patients (0.2% vs. 1.4%). There was significantly (P = 0.012) less major bleeding in nadroparin- than in enoxaparin-treated patients (7.3% vs. 11.5%, respectively). CONCLUSION: Compared with those receiving enoxaparin 4000 IU, patients treated with nadroparin 2850 IU showed a higher incidence of asymptomatic distal DVT, but a lower incidence of symptomatic VTE. Nadroparin treatment was safer in terms of bleeding risk.

Adult↗
PubMed2006

Venous thromboembolism prevention in surgery and obstetrics: clinical practice guidelines.

BACKGROUND AND OBJECTIVE: To produce up-to-date clinical practice guidelines on the prevention of venous thromboembolism in surgery and obstetrics. METHODS: A Steering Committee defined the scope of the topic, the questions to be answered, and the assessment criteria. Eight multidisciplinary working groups (total of 70 experts) performed a critical appraisal of the literature in the following disciplines: pharmacology of antithrombotic agents, orthopaedics; general surgery (gastrointestinal (GI) and varicose vein surgery); urology; gynaecology and obstetrics; thoracic, cardiac and vascular surgery; surgery of the head, neck and spine; and surgery of burns patients. The resultant reports and guidelines were submitted for comment and completion of the Appraisal of Guidelines Research & Evaluation questionnaire to a total of 150 peer reviewers, before producing definite guidelines. RESULTS: The report answers the following questions for each type of surgery: (i) What is the venous thromboembolism incidence according to clinical and/or paraclinical criteria in the absence of prophylaxis? (with stratification of venous thromboembolism risk into low, moderate and high categories); (ii) What is the efficacy and safety of the prophylactic measures used? (iii) When should prophylaxis be introduced and how long should it last? (iv) Does ambulatory surgery affect efficacy and safety of prophylaxis? CONCLUSIONS: Apart from answering the above questions, the guidelines provide a summary table for each discipline. This table stratifies types of surgery into the three risk categories, specifies the recommended prophylaxis for venous thromboembolism (pharmacological and/or mechanical) and grades each recommendation. In addition, whenever appropriate, the recommended prophylaxis is adjusted to low- and high-risk patients.

Anticoagulants↗
PubMed2005

[Thromboprohylaxis in orthopedic surgery and traumatology].

Orthopaedic and trauma surgery are classified according 3 groups of venous thromboembolic risk. Elective total hip replacement (THR) or total knee replacement (TKR), hip fracture surgery or trauma patients are at high risk. Isolated lower extremity injury with fracture is at moderate risk whereas this risk is low without fracture as well as with knee arthroscopy. In THR and TKR, low molecular weight heparin (LMWH), fondaparinux or melagatran-ximelagatran are strongly recommended. The routine use of other anticoagulants, in particular vitamin K antagonist are not recommended. In patients at high risk of venous thromboembolism as for example trauma patients, optimal use of intermittent pneumatic compression is an alternative option in case of contra-indication to anticoagulant prophylaxis. Graduated compression stockings enhance the efficacy of pharmacological methods. In schedule surgery, initiation of prophylaxis with LMWH may be started postoperatively. To reduce the haemorrhagic risk of anticoagulants, timing of first postoperative dose is essential and is proper to each drug. Duration of prophylaxis depends on the surgical and the individual patients' risk. Extended prophylaxis in THR for up to 42 days with LMWH and up to 35 days with fondaparinux in hip fracture surgery is recommended. However extended prophylaxis after 14 days in TKR has not demonstrated a higher efficacy and should only be considered for patients with additional risk factors. In patients with isolated lower extremity injury or undergoing knee arthroscopy, LMWH should not be routinely used according to a low or a moderate risk and/or the duration of prophylaxis required. But LMWH has to be considered for patients with additional risk factors. Prophylaxis in other orthopedic procedures has not been assessed and will be extrapolated from the above recommendations.

Animals↗
PubMed2004

Prevention of venous thromboembolism in orthopedic surgery with vitamin K antagonists: a meta-analysis.

BACKGROUND: The benefit-to-risk ratio of vitamin K antagonists (VKA), relative to active comparators, especially low-molecular-weight heparins (LMWH), for preventing venous thromboembolism in patients undergoing major orthopedic surgery is debated. OBJECTIVES: We performed a meta-analysis of all randomized trials in orthopedic surgery comparing adjusted doses of VKA to control treatments. PATIENTS AND METHODS: An exhaustive literature search, both manual and computer-assisted, was performed. Studies were selected on the basis of randomization procedure (VKA vs. a control group). At least one of the following outcome measures was to be evaluated: deep vein thrombosis (DVT), pulmonary embolism (PE), death, major hemorrhage or wound hematoma. Four reviewers assessed each article to determine eligibility for inclusion and outcome measures. RESULTS: VKAs were more effective than placebo or no treatment in reducing DVT [567 patients, relative risk (RR) = 0.56, 95% confidence interval (CI) 0.37, 0.84, P < 0.01] and clinical PE (651 patients, RR = 0.23, 95% CI 0.09, 0.59, P < 0.01). These results were obtained at the cost of a higher rate of wound hematoma (162 patients, RR = 2.91, 95% CI 1.09, 7.75, P = 0.03). VKAs were also more effective than intermittent pneumatic compression (534 patients, RR = 0.46, 95% CI 0.25, 0.82, P = 0.009) in preventing proximal DVT. In contrast, VKAs were less effective than LMWH in preventing total DVT and proximal DVT (9822 patients, RR = 1.51, 95% CI 1.27, 1.79, P < 0.001; and 6131 patients, RR = 1.51, 95% CI 1.04, 2.17, P = 0.028, respectively). The differences between VKA and LMWH in major hemorrhage and wound hematoma were not significant. CONCLUSIONS: In patients undergoing major orthopedic surgery, VKAs are less effective than LMWH, without any significant difference in the bleeding risk.

Fibrinolytic Agents↗
PubMed2003

Poor anticoagulant response to tissue factor pathway inhibitor in patients with venous thrombosis.

Tissue factor pathway inhibitor (TFPI) is of major importance in regulating the coagulation triggering effects of tissue factor. An association between TFPI deficiency and thrombosis has still not been clearly demonstrated. We evaluated the anticoagulant activity of exogenous TFPI added either to the plasma of patients with venous thrombosis (n = 118) or to the plasma of healthy controls similar in terms of mean age and sex ratio (n = 107). A poor anticoagulant response to TFPI, defined as TFPI resistance, was observed in 4.7% of controls and in 11.0% of patients. TFPI resistance was associated with an almost threefold increase in the risk of thrombosis and could therefore represent a novel hemostatic risk factor for venous thrombosis.

Adult↗
PubMed2002

Perioperative pharmacokinetics of factor VII concentrate during liver surgery in a patient with congenital factor VII deficiency: an individual mathematical model.

A patient with congenital factor VII deficiency (baseline activity, 7%) underwent surgery for hepatocellular carcinoma. No literature reference was found concerning the management of this coagulation defect in patients requiring liver surgery. We report one such case, with special reference to the peri-operative management of factor VII replacement therapy and the pharmacokinetic behavior of factor VII. As a result of accidental suprahepatic vein lesion, a bleeding episode occurred. This was associated with an increase in factor VII clearance and volume of distribution values from 1.30 to 3.85 l/h, and from 6.51 to 13.2 l, respectively. After surgery, the patient continued to receive the concentrate every 8 h during the first nine post-operative days. No post-operative bleeding or thrombotic event was observed. The patient was discharged in good condition.

Aged↗
PubMed2001

Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery.

BACKGROUND: Low molecular weight heparins (LMWHs) have become routine thromboprophylaxis in general surgery. However, their actual clinical effect, its magnitude relative to that of unfractionated heparin (UFH), and the optimal dose are still debated. METHODS: A meta-analysis was performed of all available randomized trials in general surgery comparing LMWH with placebo or no treatment, or with UFH. RESULTS: Comparison versus placebo or no treatment confirmed that the significant reduction in asymptomatic deep vein thrombosis (DVT) obtained with LMWH (n = 513; relative risk (RR) 0.28 (95 per cent confidence interval 0.14-0.54)) was associated with a significant reduction in clinical pulmonary embolism (n = 5456; RR 0.25 (0.08-0.79)) and clinical venous thromboembolism (VTE) (n = 4890; RR 0.29 (0.11-0.73)), and a trend towards a reduction in overall mortality rate. Comparison versus UFH showed a trend in favour of LMWH, with a significant reduction in clinical VTE (P = 0.049), a trend also found for cancer surgery. LMWH at doses below 3400 anti-Xa units seemed to be as effective as, and safer than, UFH, while higher doses yielded slightly superior efficacy but increased haemorrhagic risk, including that of major haemorrhage. CONCLUSION: Asymptomatic DVT may be regarded as a reliable surrogate endpoint for clinical outcome in studies investigating thromboprophylaxis in general surgery. LMWH seems to be as effective and safe as UFH. Determination of the optimal dose regimen of LMWH for this indication requires further investigation.

Anticoagulants↗
PubMed2000

Inter-study variability in population pharmacokinetic meta-analysis: when and how to estimate it?

Population pharmacokinetic analysis is being increasingly applied to individual data collected in different studies and pooled in a single database. However, individual pharmacokinetic parameters may change randomly from one study to another. In this article, we show by simulation that neglecting inter-study variability (ISV) does not introduce any bias for the fixed parameters or for the residual variability but may result in an overestimation of inter-individual (IIV) variability, depending on the magnitude of the ISV. Two random study-effect (RSE) estimation methods were investigated: (i) estimation, in a single step, of the three-nested random effects (inter-study, inter-individual and residual variability); (ii) estimation of residual variability and a mixture of ISV and IIV in the first step, then separation of ISV from IIV in the second. The one-stage RSE model performed well for population parameter assessment, whereas, the two-stage model yielded good estimates of IIV only with a rich sampling design. Finally, irrespective of the method used, ISV estimates were valid only when a large number of studies was pooled. The analysis of one real data set illustrated the use of an ISV model. It showed that the fixed parameter estimates were not modified, whether an RSE model was used or not, probably because of the homogeneity of the experimental designs of the studies, and suggest no study-effect in this example.

Computer Simulation↗
PubMed2000

Establishing the dose-dependent daily variations of a low molecular weight heparin (Fraxiparine) through a population approach analysis in the rat.

The effects of dose and dosing time on the anticoagulant activity of a low molecular weight heparin (Fraxiparine) were studied in rats. Three doses were administered at four evenly spaced dosing times. Rats were kept under a light-dark cycle of 24h, and all the main external factors were constant. The bleeding time, the anti-Xa activity of the drug, and the activated partial thromboplastin time (APTT) were measured. A population approach analysis to assess daily variations was used. With standard methods, interindividual variability may mask potential time-related effects, while the population approach analysis overcomes this difficulty. Bleeding time was at its peak at 04:00 and at its trough at 22:00, suggesting that platelet activity was time of day dependent. For the pharmacological activity of the drug, we compared several pharmacokinetic models derived from a monocompartmental model. The model that describes the anti-Xa pharmacological activity best is expressed through parameters that depend on animal weight and drug level. The model for APTT is of a sinusoidal type for which the clearance depends on the dosing time. The most inter esting result is that the amplitude of this daily variation is linearly dependent on drug level.

Algorithms↗
PubMed2000

Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials.

BACKGROUND: The prevention of venous thromboembolic disease is less studied in medical patients than in surgery. METHODS: We performed a meta-analysis of randomised trials studying prophylactic unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) in internal medicine, excluding acute myocardial infarction or ischaemic stroke. Deep-vein thrombosis (DVT) systematically detected at the end of the treatment period, clinical pulmonary embolism (PE), death and major bleeding were recorded. RESULTS: Seven trials comparing a prophylactic heparin treatment to a control (15,095 patients) were selected. A significant decrease in DVT and in clinical PE were observed with heparins as compared to control (risk reductions = 56% and 58% respectively, p <0.001 in both cases), without significant difference in the incidence of major bleedings or deaths. Nine trials comparing LMWH to UFH (4,669 patients) were also included. No significant effect was observed on either DVT, clinical PE or mortality. However LMWH reduced by 52% the risk of major haemorrhage (p = 0.049). CONCLUSIONS: This meta-analysis, based on the pooling of data available for several heparins, shows that heparins are beneficial in the prevention of venous thromboembolism in internal medicine.

Anticoagulants↗
PubMed1999

Population pharmacokinetic of nadroparin calcium (Fraxiparine) in children hospitalised for open heart surgery.

Administration of low molecular weight heparin following heart surgery in paediatric patients in order to prevent thromboembolic events results in a large variation in anti-Xa activities. A population study was undertaken to determine pharmacokinetic parameters after nadroparin calcium (Fraxiparine) administration and the effects of potential covariates; this study included 154 children divided into two groups: a model group (124 patients) and a validation group (30 patients). The 432 anti-Xa activities were analysed using NONMEM on the basis of a one-compartment model with three parameters: apparent clearance, apparent volume of distribution and absorption rate. The influence of body weight, age, sex and dose regimen (once or twice daily) were investigated. The best fit corresponds to the formula: apparent clearance (l/min)=0. 541 x weight1.51/(6.151.51 + weight1.51) and apparent volume (l)=0.355 x weight. The inter-individual variability (expressed in coefficient of variation) of these parameters are high, especially with regard to the apparent volume (92%), but no other available covariate was found to explain this variability.

Anticoagulants↗
PubMed1999

Efficacy and safety of danaparoid sodium (ORG 10172) in critically ill patients with heparin-associated thrombocytopenia.

OBJECTIVE: To evaluate the effectiveness and the safety of danaparoid sodium in the treatment of critically ill patients with standard unfractionated heparin-induced thrombocytopenia (HIT) or low-molecular-weight HIT. SETTING: University hospital. PATIENTS AND METHODS: Retrospective analysis of 42 consecutive critically ill patients who were admitted for HIT between October 1992 and February 1997 and were treated either with therapeutic or prophylactic doses of danaparoid sodium. RESULTS: Among the 26 patients treated with therapeutic doses, neither new thrombotic complications nor thrombosis extension was clinically suspected. Two deaths were directly related to lower limb acute arterial thrombosis associated with HIT. Two major hemorrhagic complications were observed when aspirin in addition to danaparoid sodium was administered. When danaparoid sodium was used in prophylactic doses (20 courses of treatment) to prevent either postsurgical or medical thrombotic complications, no thrombotic event was observed. No death related to HIT or danaparoid sodium treatment was observed. One aggravation of a postsurgical cerebral lesion was observed. During danaparoid sodium treatment, a persistence or a recurrence of thrombocytopenia was observed in 6.5% of patients without thrombotic complications. CONCLUSION: Danaparoid sodium appears to be an efficient and safe treatment in critically ill patients with HIT. The concomitant use of aspirin in addition to danaparoid sodium seems to represent an important additional hemorrhagic risk that should be avoided in patient management.

Adult↗
PubMed1998

Pharmacokinetic and pharmacodynamic variations of acenocoumarol orally administrated either once or twice daily in patients with deep venous thrombosis.

The literature suggests that variations in anticoagulant effect occur when acenocoumarol is administrated in a daily dose. We assessed the anticoagulant effects of acenocoumarol with INR, factors VII and X and protein C in 12 randomly selected hospitalised patients with deep-vein thrombosis, six of them receiving a daily dose of acenocoumarol, the other six receiving twice daily doses. When the drug effect had been at a steady-state for at least 72 h, five blood samples were drawn per patient over a period of 24 h. No nycthemeral significant variations were noted for INR, factor X and protein C in the two groups (P > 0.10). Nycthemeral significant variation in factor VII when acenocoumarol was administered once daily was noted (P = 0.02), but the clinical relevance of factor VII variation at steady-state is uncertain. In spite of the short pharmacokinetic half-life of acenocoumarol, a stable nycthemeral pharmacodynamic activity was observed after once daily administration; twice-daily administration of acenocoumarol does not appear to be justified.

Acenocoumarol↗
PubMed1998

Prevalence of factor V Leiden (APCR) and other inherited thrombophilias in young patients with myocardial infarction and normal coronary arteries.

OBJECTIVE: To investigate the role of activated protein C resistance (APCR, factor V Leiden) in coronary artery thrombosis. METHODS: The prevalence of APCR and of congenital deficiencies of antithrombin III, protein C, protein S, plasminogen, and factor XII was investigated in adult patients under 45 years of age with acute myocardial infarction. The results were compared with those of a group of 53 age and sex matched control subjects. RESULTS: Among 75 patients under the age of 45 years who were admitted from November 1994 to April 1996 for acute myocardial infarction, 22 (29.3%) had normal coronary arteriography (group I) and 53 (70.7%) had significant coronary artery disease (group II). Inherited thrombophilia was more often found in group I (4/22, 18.2%) than in group II (4/53, 7.5%) but the difference was not significant (F test: p = 0.22). The prevalence of APCR was 9.1% (2/22) in group I, 3.8% (2/53) in group 2 (p = 0.57), and 3.8% (2/53) in the normal control group (p = 0.57). CONCLUSIONS: The prevalence of congenital thrombophilias, including APCR, does not seem to be increased in young patients with myocardial infarction and normal coronary angiograms, compared with young patients with coronary atherosclerosis and with normal control subjects. However, the statistical power of the study is too low to detect a significant difference and these results are published to allow a meta-analysis of this problem in the future.

Activated Protein C Resistance↗
PubMed1998

Aging and venous thromboembolism influence the pharmacodynamics of the anti-factor Xa and anti-thrombin activities of a low molecular weight heparin (nadroparin).

Venous thromboembolism may be efficiently treated by one single daily administration of a high dose of low molecular weight heparin (LMWH). The present study investigates if the physiological deterioration of renal function associated with normal aging or the presence of an acute venous thromboembolism influences the pharmacodynamic pattern of the anti-factor Xa and anti-thrombin activities. Three groups of 12 subjects were investigated. The first 2 groups were composed of healthy volunteers differing by age (25 +/- 4 and 65 +/- 3 yrs) and creatinine clearance (114 +/- 15 and 62 +/- 6 ml x min(-1)). The third group was composed of patients hospitalized for deep vein thrombosis, having a mean age of 65 +/- 11 yrs and creatinine clearance of 76 +/- 8 ml x min(-1). Nadroparin was administered subcutaneously once daily at the dose of 180 anti-factor Xa IU.kg(-1) for 6 to 10 days. Serial sampling on day 1 and on the last day of administration (day n) allowed the pharmacodynamic parameters of the anti-factor Xa and anti-thrombin activities to be compared at the beginning and at the end of the treatment. The main findings were the following: (1) After repeated administration, a significant accumulation of the anti-factor Xa activity was observed in the healthy elderly and in the patients but not in the healthy young subjects (accumulation factor: 1.3). There was no evidence of accumulation of anti-thrombin activity; (2) There were significant correlations between the clearance of creatinine and the clearance of the anti-factor Xa activity but not with that of the anti-thrombin activity; (3) In the patients, the clearance of the anti-factor Xa and of the anti-thrombin activities were 1.4 and 2 times higher respectively than those calculated in the healthy elderly; (4) The mean ratio of the of anti-factor Xa and anti-thrombin clearances was close to 2 in the healthy subjects but equal to 5.4 in the patients. These results suggest that the mechanisms involved in the clearance of polysaccharide chains which support the anti-thrombin activity are different from those of the anti-factor Xa activity and that the enhanced binding properties of plasma proteins to unfractionated heparin reported in patients presenting an acute venous thromboembolism also exists for LMWH, predominantly for the anti-thrombin activity.

Adult↗