Lack of effect of a low-molecular-weight heparin (nadroparin) on mortality in bedridden medical in-patients: a prospective randomised double-blind study.

BACKGROUND: Hospitalised medical patients are at significant risk of venous thromboembolic disease through fatal pulmonary embolism; low-molecular-weight heparins have been proved efficient in preventing deep venous thrombosis in surgical and medical patients, but their effect on mortality in bedridden medical patients remains unknown. METHODS: In a multi-centre, randomised, double-blind, placebo-controlled study, 2,474 consecutive patients aged over 40 years admitted to internal medicine departments in the last 24 h and unable to move alone were randomised to receive 0.3 ml nadroparin (7,500 anti-Xa units) or placebo for up to 21 days. The primary end-point was overall mortality at day 21. RESULTS: There were no significant differences between the patients' characteristics. Overall mortality between the two groups was not statistically different [10.08% (124 of 1,230) versus 10.29% (128 of 1,244), respectively, in the nadroparin and in the placebo groups; relative risk reduction 0.02, CI (-0.27, +0.25), P=0.89]. An autopsy was performed in 123 of the 252 patients who died (49%). Pulmonary embolism was discovered at autopsy in 10 of 63 patients in the nadroparin group and in 17 of 60 in the placebo group [relative risk reduction 0.38, CI (-0.27, +0.70), P=0.13]. CONCLUSION: Nadroparin does not have a significant effect on mortality in bedridden medical patients, based on the study results. The study provides no data suggesting that low-molecular-weight heparins might reduce the incidence of thromboembolic in-patients hospitalised for an acute medical disease.

Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis.

BACKGROUND: A high frequency of asymptomatic pulmonary embolism (PE) has been reported in patients with deep venous thrombosis (DVT) in studies of a limited number of patients using varying criteria for lung scan assessment. OBJECTIVES: To estimate the frequency of PE using systematic lung scans in a large group of outpatients with DVT and to compare the results using varying lung scan assessment criteria. METHODS: An international multicenter study comparing 2 different regimens of low-molecular-weight heparin nadroparin in DVT: perfusion lung scans were performed in 622 outpatients with no clinical indication of PE and with proximal DVT confirmed by venography. Three hundred seventy-nine of these patients underwent ventilation lung scans. High-probability (HP) scans for PE were assessed separately using either ventilation scans or chest radiographs to define mismatched perfusion defects. RESULTS: Perfusion scans showed abnormalities in 82% of the patients; 59% had segmental defects and 30% had normal scans or scans with a very low probability of PE. Depending on the criteria used, 32% to 45% had HP scans for PE; these percentages were higher in young patients. No relationship was found between extent of thrombosis and HP scans. The estimated frequency of silent PE was 39.5% to 49.5%. During a 3-month follow-up period during which the patients received therapy, the rate of PE recurrence was low (1.3%) and did not differ between patients with baseline HP scans and those with normal scans. CONCLUSIONS: Regardless of what interpretative criteria are used for assessing lung scans in PE, the frequency of silent PE is 40% to 50% in patients with DVT. A baseline lung scan may easily detect PE in these patients but is not useful for predicting early thromboembolic recurrences that may occur during therapy.

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.

Comparison of a once daily with a twice daily subcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis. FRAXODI group.

BACKGROUND: Clinical trials have been performed to compare with standard heparin a once or a twice daily regimen of low-molecular-weight heparin but no direct comparison has been done between these two low-molecular-weight heparin regimens in terms of efficacy and safety with a long-term clinical evaluation. METHODS: Patients with proximal deep vein thrombosis, confirmed by venography were randomly assigned to either nadroparin (10,250 AXa IU/ml) twice daily or nadroparin (20,500 AXa IU/ml) once daily for at least 5 days. Regimens were adjusted to bodyweight. Oral anticoagulants were started on day 1 or 2 and continued for 3 months. Patients were followed up for 3 months. The composite outcome of venous thromboembolism and death possibly related to pulmonary embolism was the primary measure of efficacy. Major bleeding was the principal measure of safety. The study was designed to show equivalence between the two regimens. RESULTS: Recurrent thromboembolic events or death possibly related to pulmonary embolism were reported in 13 patients in the once daily group (4.1%) and in 24 patients of the twice daily group (7.2%): (absolute difference 3.1% in favor of the once daily regimen; 95% confidence interval -6.6%, +0.5%). Major bleeding episodes during nadroparin treatment occurred in 4 (1.3%) and 4 patients (1.2%) in the once and twice daily groups, respectively. CONCLUSIONS: A nadroparin regimen of one injection per day is at least as effective and safe as the same total daily dose divided over two injections for the treatment of acute deep vein thrombosis.

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)).

Effect of nadroparin, a low-molecular-weight heparin, on clinical and angiographic restenosis after coronary balloon angioplasty: the FACT study. Fraxiparine Angioplastie Coronaire Transluminale.

BACKGROUND: Experimental studies suggest that the antiproliferative effect of heparin after arterial injury is maximized by pretreatment. No previous studies of restenosis have used a pretreatment strategy. We designed this study to determine whether treatment with nadroparin, a low-molecular-weight heparin, started 3 days before the procedure and continued for 3 months, affected angiographic restenosis or clinical outcome after coronary angioplasty. METHODS AND RESULTS: In a prospective multicenter, double-blind, randomized trial, elective coronary angioplasty was performed on 354 patients who were treated with daily subcutaneous nadroparin (0.6 mL of 10,250 anti-Xa IU/mL) or placebo injections started 3 days before angioplasty and continued for 3 months. Angiography was performed just before and immediately after angioplasty and at follow-up. The primary study end point was angiographic restenosis, assessed by quantitative coronary angiography 3 months after balloon angioplasty. Clinical follow-up was continued up to 6 months. Clinical and procedural variables and the occurrence of periprocedural complications did not differ between groups. At angiographic follow-up, the mean minimal lumen diameter and the mean residual stenosis in the nadroparin group (1.37+/-0.66 mm, 51.9+/-21.0%) did not differ from the corresponding values in the control group (1.48+/-0.59 mm, 48.8+/-18.9%). Combined major cardiac-related clinical events (death, myocardial infarction, target lesion revascularization) did not differ between groups (30.3% versus 29.6%). CONCLUSIONS: Pretreatment with the low-molecular-weight heparin nadroparin continued for 3 months after balloon angioplasty had no beneficial effect on angiographic restenosis or on adverse clinical outcomes.

Low molecular weight heparin and compression stockings in the prevention of venous thromboembolism in neurosurgery.

Perioperative anticoagulant prophylaxis for postoperative venous thromboembolism (VTE) in neurosurgical patients has not gained wide acceptance due to the fear of intracranial bleeding. Physical methods give a worthwhile reduction of postoperative VTE but there still remains a substantial residual incidence. In other clinical indications, low molecular weight heparins have proven to be effective for prophylaxis of VTE when administered postoperatively, with the advantage of no bleeding enhancement during surgery. Therefore, we performed a multicentre, randomized, double-blind trial in neurosurgical patients to investigate the efficacy and safety of adding a low molecular weight heparin (LMWH), nadroparin, initiated postoperatively, to graduated compression stockings in the prevention of VTE. Deep-vein thrombosis was detected by mandatory venography. Bleeding was determined according to pre-defined objective criteria for major and minor episodes. An adequate bilateral venogram was obtained in 166 of 241 LMWH patients (68.9%) and 179 of 244 control patients (73.4%). A total of 31 of 166 LMWH patients (18.7%) and 47 of 179 controls patients (26.3) had VTE up to Day 10 postoperatively (p = 0.047). The relative risk reduction (RRR) was 28.9%. The rates for proximal deep-vein thrombosis/pulmonary embolism were 6.9% and 11.5% for the two groups, respectively (RRR: 40.2%; p = 0.065). Secondary analyses involved all VTE up to day 56 post-surgery which was detected in 33 patients of 241 in the LMWH group (13.7%) and 51 of 244 control patients (20.9%; RRR 34.5%; p = 0.018). The corresponding percentages for proximal deep-vein thrombosis/pulmonary embolism were 5.8% and 10.2% for the two groups, respectively, giving a RRR of 43.3%; p = 0.36. Major bleeding complications, during the treatment period, occurred in six low molecular weight heparin treated patients (2.5%) and in two control patients (0.8%); p = 0.87. A higher mortality was observed in the low molecular weight heparin group over the 56-day follow-up period (22 versus 10; p = 0.026). However, none of these deaths was judged by a blinded adjudication committee to be related to the study drug. In conclusion, this study demonstrates that the low molecular weight heparin, nadroparin, added to graduated compression stockings results in a clinically significant decrease in VTE without inducing any significant increase of major bleeding.

Randomized trial of subcutaneous low-molecular-weight heparin CY 216 (Fraxiparine) compared with intravenous unfractionated heparin in the curative treatment of submassive pulmonary embolism. A dose-ranging study.

BACKGROUND: We compared the efficacy and safety of different dosages of a low-molecular-weight heparin, CY 216 D (Fraxiparine), in the treatment of submassive pulmonary embolism with unfractionated heparin in a prospective, randomized, dose-finding study. METHODS AND RESULTS: The primary outcome was the evolution of pulmonary vascular obstruction. We enrolled 101 patients. Four patient groups were formed: standard heparin by continuous intravenous infusion (group 1) and Fraxiparine subcutaneously 400, 600, and 900 anti-Xa Institute Choay units/kg, respectively (groups 2, 3, and 4). Inclusions were stopped prematurely in groups 3 and 4 because of the incidence of major bleedings. At day 8, the improvement of the pulmonary vascular obstruction and the major bleedings were similar in groups 1 and 2. CONCLUSIONS: The Fraxiparine dosage of 400 anti-Xa Institute Choay units/kg is as effective and safe as unfractionated heparin in the treatment of submassive pulmonary embolism.

Influence of thromboembolism prophylaxis by low molecular weight heparin CY 216 (Fraxiparine) on several parameters of haemostasis in patients under dialysis and receiving either unfractionated heparin or CY 216.

The hemorrhagic risk of an association of the low molecular weight (LMWH), Fraxiparine injected intravenously at the dose of 7.500 AXalCU or of unfractionated heparin (UFH) injected intravenously at the usual dose used during hemodialysis (3.750 +/- 1.280 IU + 1.000 IU after 2 hours of dialysis) to the subcutaneous administration once daily of a thromboembolism preventive dose of Fraxiparine (7.500 AXalCU) was evaluated on the modification of the following hemostasis parameters: thrombin time, activated partial thromboplastin time (APTT), anti Xa activity, in 13 uremic patients on hemodialysis. The association of intravenous and subcutaneous Fraxiparine prevented efficiently the clotting of the extracorporeal circulation without inducing a detectable antithrombinic activity. In contrast, the association of I.V. UFH to subcutaneous Fraxiparine induced a significant increase of the thrombin time and of the APTT, so explained by the activity of UFH. It is concluded that subcutaneous Fraxiparine at the thromboembolism preventive dose can be associated as well to I.V. Fraxiparine as to UFH without increasing the potential hemorrhagic risk. Nevertheless the association of SC and IV Fraxiparine 7.500 AXalC u seems preferable to the association of SC Fraxiparine with UFH.

[Use in hemodialysis and hemofiltration of CY 216 (Fraxiparine) administered via intravenous bolus in patients with acute and chronic renal insufficiency with and without hemorrhagic risk]. / Utilisation en hémodialyse et en hémofiltration du CY 216 (Fraxiparine) en bolus intraveineux, chez des patients insuffisants rénaux aigus et chroniques, avec et sans risque hémorragique.

The effectiveness and safety of CY 216 as anticoagulant for extracorporeal circulation were evaluated in 403 haemodialysis of haemofiltration sessions performed in 33 patients with chronic [24] or acute [9] renal failure; 149 of the sessions were carried at risk of haemorrhage. Initially CY 216 was administered as a bolus intravenous injection in doses of 7,500 anti-Xa Institut Choay units (AXa.IC.U) to patients under 50 kg, 15,000 AXa.IC.U to patients weighting between 50 and 80 kg and 22,500 AXa.IC.U to patients over 80 kg. Subsequently dosage was adjusted according to clinical results. With a median dose of 250 AXa.IC.U per kg, no haemorrhage was observed. Blood restitution was satisfactory in 84.6% of the cases, extracorporeal circulation was without clotting of fibrin deposit in 90% of the cases and the incidence of total coagulation was only 0.5%. Using CY 216 seems to be effective in preventing coagulation in the extracorporeal circuit and was well tolerated by all patients whether or not they were carried at risk of haemorrhage.

Pharmacodynamics of CY 216 in healthy volunteers: inter-individual variations.

The pharmacodynamic parameters of a low molecular weight heparin (LMWH, CY 216) and their inter-individual variations were investigated. In a cross over study 100 anti-factor Xa IC U/kg were injected, one week apart, to 12 healthy volunteers by intravenous (IV) or subcutaneous (SC) route. The pharmacological effects were followed by performing activated partial thromboplastin time (APTT), thrombin clotting time (TCT) and a chromogenic anti-factor Xa assay. The main pharmacodynamic parameters were calculated from the anti-factor Xa activity disappearance curves. Five to ten min after IV injection, the APTT ranged between 56 and 98 sec (baseline 40 sec), the TCT between 28 and 99 sec (baseline 19 sec) and the anti-factor Xa activity between 1.58 and 2.28 IC U/ml. The anti-factor Xa activity half-life ranged between 1.5 and 2.9 h. After SC injection, there were no detectable APTT and TCT prolongations; the maximum anti-factor Xa activity ranged between 0.36 and 0.88 IC U/ml and the half life between 1.5 and 6.4 h. These results indicate that, as for standard heparin, there are large inter-individual variations in the anticoagulant responses to a given dose of CY 216 an observation which may have clinical implications.

[Should the pharmaceutical industry play an active part in pharmacosurveillance? (author's transl)]. / L'industrie du médicament a-t-elle une vocation de pharmacovigilance?

The development of new drugs by pharmaceutical firms proceeds through different phases, i. e. pre-clinical studies and stage I, II and III clinical studies, which normally result in authorization to market. Once the drug is on the market, however, further research work is required to perfect its use and complete our knowledge of it. Stage IV clinical trials, which may be termed "pharmacosurveillance", fall as much as the previous ones within the responsibilities of the pharmaceutical industry, since reports on side-effects are collected and these may have practical applications. Thus, clinical research may be shifted towards possible new indications, or new pharmacological studies may be undertaken to elucidate the mechanism of some side-effects, develop them if they are beneficial, or find a way of preventing them if they are indesirable. With these considerations in mind, the authors have developed a protocol of pharmacosurveillance aimed at determining, through a preliminary in vitro study, the origin of some adverse reactions of anaesthetic drugs. Depending on the results of these studies, clinical applications are considered.