The pharmacokinetics of subcutaneous enoxaparin in end-stage renal disease

STUDY OBJECTIVE: To evaluate the pharmacokinetics of enoxaparin in end-stage renal disease (ESRD), and determine if dosage reduction is necessary to maintain antifactor Xa activity concentrations within the therapeutic range. DESIGN: Prospective, single-dose pharmacokinetic study. SETTING: University-affiliated general clinical research center. PATIENTS: Eight nonthrombosed patients with ESRD requiring hemodialysis. INTERVENTION: All subjects received a single dose of enoxaparin sodium 1 mg/kg subcutaneously and had serial plasma antifactor Xa activity concentrations measured over 24 hours. MEASUREMENTS and MAIN RESULTS: The pharmacokinetics of enoxaparin were determined from plasma antifactor Xa activity concentrations, and various multiple-dose regimens were simulated. After administration of the drug, total body clearance was 14.6 ml/minute and there was a 2-fold prolongation in antifactor Xa activity half-life compared with values reported in healthy subjects. All other pharmacokinetic parameters were similar to those in healthy subjects and patients with chronic renal insufficiency. An accumulation ratio of 1.6 was estimated for a dosing interval of every 12 hours based on single-dose pharmacokinetics. When various therapeutic regimens were simulated to predict average steady-state antifactor Xa activity, standard enoxaparin dosages of 1 mg/kg subcutaneously every 12 hours and 1.5 mg/kg every 24 hours resulted in average steady-state concentrations within the therapeutic range. CONCLUSIONS: Based on antifactor Xa activity, ESRD has little effect on the pharmacokinetics of enoxaparin, and dosing adjustments are unnecessary.     

Correlation of antifactor Xa concentrations with renal function in patients on enoxaparin

Enoxaparin is a low molecular weight heparin (LMWH) that has been shown to be effective in deep vein thrombosis, pulmonary embolism, and unstable angina. Because renal function plays an important role in the clearance of LMWH, the authors sought to investigate the effect of renal function on enoxaparin. This prospective multiple-dose study evaluated 18 patients with varying degrees of renal function initiated on enoxaparin 1 mg/kg subcutaneously every 12 hours. Peak blood levels of anti-Xa concentrations were obtained 4 +/- 0.5 hours postdose after receiving at least three doses of enoxaparin. The median antifactor Xa levels were higher in patients with creatinine clearance (CLCr) < or = 30 mL/min compared to CLCr > or = 31 mL/min (1.34 IU/mL vs. 0.91 IU/mL, respectively, p < 0.05). A linear correlation was established between creatinine clearance and anti-Xa concentrations (p < 0.0005). On the basis of the data, the authors believe that a dose adjustment is necessary in patients receiving repeated doses of enoxaparin with CLCr < or = 30 mL/min.     

Enoxaparin dosage adjustment in patients with severe renal failure: antifactor xa concentrations and safety

STUDY OBJECTIVE: To evaluate the safety and efficacy, by measuring antifactor Xa levels, of enoxaparin 1 mg/kg subcutaneously once every 24 hours in patients with severe renal failure. DESIGN: Prospective study. SETTING: Emergency, internal medicine, geriatrics, and cardiology departments of a medical center in Israel. PATIENTS: Nineteen patients with stage 4 or 5 chronic kidney disease who required full anticoagulation. INTERVENTION: Patients received enoxaparin 1 mg/kg subcutaneously every 24 hours for 2 or more days, as determined by a treating physician. MEASUREMENTS AND MAIN RESULTS: Data on patients' demographic and clinical characteristics were collected. Blood samples for peak and trough antifactor Xa levels were obtained during the enoxaparin treatment period. Of the 19 study patients, 14 (74%) had peak antifactor Xa levels within the recommended range for full anticoagulation of 0.5-1.0 U/ml after their first enoxaparin dose; no concentration exceeded 1.0 U/ml. The mean peak antifactor Xa level was not significantly different after the first enoxaparin dose compared with the second and third doses. The mean +/- SD trough antifactor Xa level, thought to be an indicator of drug accumulation, was 0.12 +/- 0.12 U/ml; its clinical significance and target range are still unknown. No major bleeding events were noted. CONCLUSION: Enoxaparin 1 mg/kg once every 24 hours in patients with stage 4 or 5 chronic kidney disease who required full anticoagulation was safe, and this dose did not exceed recommended concentrations. The significance of enoxaparin trough levels remains unclear and should be investigated in future studies. Other dosing regimens of enoxaparin for specific patient populations should also be assessed for safety and efficacy.     

Development of an efficient sampling strategy to predict enoxaparin pharmacokinetics in stage 5 chronic kidney disease

Patients with renal dysfunction are at greater risk for hemorrhagic events than patients with normal renal function. The objective of this study was to develop an efficient sampling strategy that optimally predicts anti-Xa activity exposure after enoxaparin administration in patients with chronic kidney disease to optimize enoxaparin therapy. The antifactor Xa activity data of 8 anuric patients who were administered 1 mg/kg enoxaparin immediately after hemodialysis were used for the development of the optimal sampling strategies. Maximum A Posteriori Bayesian (MAPB) priors were developed by pharmacokinetic analysis. The 2, 3, and 4 D-optimal sampling designs were determined and Monte Carlo simulations using the MAPB estimator were performed. The original model with the estimator was used to determine the predictive power of the sampling schemes. The most efficient sampling scheme (OSS-2) was accurate and precise in predicting apparent enoxaparin clearance (-3.2% bias, 6.5% precision). The addition of a third sampling time at 30 minutes (OSS-3) was more accurate (P < 0.01) and precise (P < 0.01) than OSS-2 at predicting the rate of absorption (ka) but did not improve the accuracy (P > 0.05) or precision (P = 0.20) of the CLs/F estimate. The determination of antifactor Xa activity at 5 and 24 hours, along with the Bayesian estimators generated from this study, accurately and precisely predict the apparent clearance of antifactor Xa activity. This sampling strategy may be used for therapeutic drug monitoring of enoxaparin and for future clinical trials in patients with chronic kidney disease.     

Peak antifactor xa activity produced by dalteparin treatment in patients with renal impairment compared with controls

STUDY OBJECTIVE: To evaluate the relationship between impaired renal function and antifactor Xa activity in patients receiving dalteparin. DESIGN: Open-label prospective study. SETTING: Inpatient and outpatient units of a large teaching hospital. SUBJECTS: Eleven patients with renal impairment and 11 control subjects with normal renal function. INTERVENTION: Subjects were administered dalteparin at a dosage of approximately 100 U/kg subcutaneously every 12 hours. MEASUREMENTS AND MAIN RESULTS: Peak steady-state antifactor Xa levels were compared between the groups. Mean +/- SD levels were similar for patients with and without renal impairment: 0.47 +/- 0.25 and 0.55 +/- 0.20 U/ml, respectively. A test of equivalency showed statistical significance (p=0.0001). CONCLUSION: No meaningful difference in peak antifactor Xa activity was found between patients with renal impairment and control subjects. To the extent that peak antifactor Xa levels can be used as markers for adjusting doses of dalteparin, these data suggest that such adjustments are not necessary for patients with renal impairment who are not receiving dialysis.     

Tinzaparin in the treatment of venous thromboembolism

Low molecular weight heparin (LMWH) has been widely used for the initial treatment of patients presenting with venous thromboembolism. The LMWH, tinzaparin, has been shown in randomised clinical trials to be as effective and safe as unfractionated heparin for the initial treatment of venous thromboembolism and in clinical trials, it has been used in place of warfarin for the long-term treatment of deep vein thrombosis. Tinzaparin can safely be given to patients with significant renal impairment (creatinine clearance of > or = 20 ml/min) and the dose of tinzaparin does not need to be altered in patients with a body mass index of > 25.     

Tinzaparin sodium: a review of its pharmacology and clinical use in the prophylaxis and treatment of thromboembolic disease

Tinzaparin sodium (tinzaparin; innohep) is a low molecular weight heparin (LMWH) formed by the enzymatic degradation of porcine unfractionated heparin (UFH).In clinical trials, once-daily subcutaneous (SC) tinzaparin was effective and generally well tolerated in the prophylaxis and treatment of thromboembolic disease. SC tinzaparin 75 anti-Xa IU/kg/day showed similar thromboprophylactic efficacy to adjusted-dosage oral warfarin in patients undergoing total hip arthroplasty; in patients undergoing knee replacement, the incidence of deep vein thrombosis (DVT) was significantly lower with tinzaparin. The drug had similar efficacy to equivalent-dosage SC enoxaparin sodium in orthopaedic surgery. In patients undergoing general surgery, SC tinzaparin 3500 anti-Xa IU/day was of equivalent thromboprophylactic efficacy to SC UFH 5000IU twice daily. Encouraging preliminary results have been obtained with tinzaparin in the prevention of DVT in patients with complete motor paralysis. In the initial treatment of acute proximal DVT and pulmonary embolism, SC tinzaparin 175 anti-Xa IU/kg/day was at least as effective as adjusted-dosage intravenous (IV) UFH. In the outpatient treatment of venous thromboembolism, tinzaparin has demonstrated similar efficacy to dalteparin sodium (dalteparin) and warfarin. Tinzaparin was effective in preventing clotting in haemodialysis circuits; the anticoagulant efficacy of tinzaparin in patients undergoing haemodialysis was similar to that of SC dalteparin and similar to or less than (although in this case the tinzaparin dose was too low for sufficient anticoagulant efficacy) that of IV UFH. Advantages of tinzaparin over UFH and warfarin include ease of administration and lack of need for laboratory monitoring. Tinzaparin is more cost effective than UFH in the treatment of established thromboembolic disease, and home-based treatment with tinzaparin may offer greater cost benefits than hospital-based therapy. Tinzaparin is well tolerated, including in elderly patients and those with renal impairment receiving long-term treatment. Incidences of major bleeding complications were low and reports of heparin-induced thrombocytopenia were infrequent in clinical studies. In conclusion, tinzaparin is a valuable LMWH in the prophylaxis and management of thromboembolic disease.     

Antifactor Xa levels in four patients with burn injuries who received enoxaparin to prevent venous thromboembolism

Four patients with severe burn injuries received enoxaparin 40 mg twice/day subcutaneously for the prophylaxis of venous thromboembolism (VTE). Peak antifactor Xa levels were measured 4 hours after administration of a dose, and trough antifactor Xa levels were measured 30 minutes before the next scheduled dose. Ultrasonography was performed once/week to assess the presence of VTE. Any occurrence of major bleeding was documented in the patients' charts. All patients had trough antifactor Xa levels below 0.1 U/ml. Enoxaparin dosages were subsequently adjusted to achieve trough antifactor Xa levels of 0.1-0.2 U/ml. This required dosages higher than those typically recommended for VTE prophylaxis (40 mg every 24 hrs or 30 mg every 12 hrs). One patient needed more than 60 mg every 12 hours. No patient had a venous thromboembolic event or major bleeding. The low antifactor Xa levels that were observed suggest that a reduced dose-response relationship may exist between subcutaneously administered enoxaparin and antifactor Xa activity in patients with severe burn injuries. Prospective studies should be performed to further investigate this relationship.     

Tinzaparin in the treatment of venous thromboembolism

Low molecular weight heparin (LMWH) has been widely used for the initial treatment of patients presenting with venous thromboembolism. The LMWH, tinzaparin, has been shown in randomised clinical trials to be as effective and safe as unfractionated heparin for the initial treatment of venous thromboembolism and in clinical trials, it has been used in place of warfarin for the long-term treatment of deep vein thrombosis. Tinzaparin can safely be given to patients with significant renal impairment (creatinine clearance of ≥ 20 ml/min) and the dose of tinzaparin does not need to be altered in patients with a body mass index of > 25.     

Anti-factor Xa activity of enoxaparin administered at prophylactic dosage to patients over 75 years old

AIMS: Major bleeding complications with low-molecular-weight heparin (LMWH) treatment have been reported both in clinical studies and during postmarketing surveillance. Monitoring of antifactor Xa (anti-Xa) activities is therefore recommended in special populations often predisposed to renal impairment. The PROPHRE.75 study was conducted to estimate the distribution parameters of anti-Xa activity in the elderly. METHODS: PROPHRE.75 was a prospective study of a cohort of consecutive patients aged >75 years and treated with 4000 IU of enoxaparin once daily for venous thromboembolism prophylaxis. Dosing history and measurements of anti-Xa activity in sparse samples were recorded throughout treatment. The covariates included weight, gender, age, renal function, medical history and concomitant medication. Population parameters and interindividual variability were estimated using NONMEM V software. RESULTS: Anti-Xa activity was studied in 189 patients (mean age 82 +/- 5 years, 22% weighing <50 kg, 50% presenting renal impairment according to the Cockcroft and Gault formula). A first-order input two-compartment model best fitted the data. Clearance was significantly related to body weight and creatinine clearance based on the simplified Modification of Diet in Renal Disease formula, central volume being related to body weight. According to individual Bayesian estimations, 4% of patients presented with a peak anti-Xa activity >1.0 IU ml(-1), but this group did not include the sole patient experiencing a major bleed (0.53%). CONCLUSIONS: Systematic monitoring of anti-Xa activity in elderly patients treated with enoxaparin at prophylactic doses does not seem to be necessary to prevent the occurrence of major bleeding.     

Population pharmacokinetics and pharmacodynamics of enoxaparin in unstable angina and non-ST-segment elevation myocardial infarction

AIMS: A major concern with any antithrombotic therapy is an increase in the risk of haemorrhage. The aim of this study was to analyse population pharmacokinetics and pharmacokinetic/pharmacodynamic (PK/PD) relationships for enoxaparin in patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI), which may help predict risk of haemorrhage. METHODS: Anti-factor Xa (anti-Xa) activity was measured as marker of enoxaparin concentration in 448 patients receiving the drug as a single 30-mg intravenous bolus followed by 1.0 or 1.25 mg kg(-1) subcutaneously twice a day. A population pharmacokinetic analysis was conducted and individual estimates of enoxaparin clearance and area under the curve were tested as prognostic factors for the occurrence of haemorrhagic episodes. RESULTS: Basic population PK parameters were an enoxaparin clearance of 0.733 l h(-1)[95% confidence interval (CI) 0.698, 0.738], a distribution volume of 5.24 l (95% CI 4.20, 6.28) and an elimination half-life of 5.0 h. Enoxaparin clearance was significantly related to patient weight and creatinine clearance, and was the only independent predictor of experiencing both all (10.7%, P = 0.0013) and major (2.2%, P = 0.0004) haemorrhagic events. A creatinine clearance of 30 ml min(-1) was associated with a decrease in enoxaparin clearance of 27% compared with that in a patient with a median creatinine clearance of 88 ml min-1, and was related to a 1.5- and 3.8-fold increase in the risk of 'all' and 'major' haemorrhagic episodes, respectively. CONCLUSIONS: Enoxaparin clearance depends on body weight, and, therefore, weight-adjusted dosing is recommended to minimize interpatient variability in drug exposure and the risk of haemorrhage. The importance of an increased risk of haemorrhage with decreasing renal function must be weighed against the benefit of treatment with enoxaparin in patients with UA and NSTEMI.     

Safety profile of tinzaparin administered once daily at a standard curative dose in two hundred very elderly patients.

OBJECTIVES: Too few very elderly patients with an age-related renal impairment are included in clinical trials. We conducted a study in order to evaluate the safety profile of tinzaparin, a low molecular weight heparin (LMWH), given at a curative dose (175 IU/kg once daily) in very elderly patients treated for up to 30 days. SETTING: An 800-bed geriatric hospital. DESIGN: A 1-year prescribing study. PATIENTS: Consecutive in-patients older than age 70, whose creatinine clearance was above 20 ml/min, and requiring full anticoagulation with LMWH were included. MEASUREMENTS: Safety parameters (major bleeding/heparin-induced thrombocytopenia/death) were recorded. Plasma anti-Xa activity levels were regularly measured throughout the treatment period. RESULTS: Two-hundred in-patients, mean age 85.2 +/- 6.9 years (70 to 102), mean creatinine clearance 51.2 +/- 22.9 ml/min, were given tinzaparin. Six patients died during the treatment period: only one could be related to the anticoagulation treatment. Three major bleeding episodes (1.5%) were reported. Antithrombotic drug interactions likely contributed to the bleeding event in two of them. Heparin-induced thrombocytopenia was confirmed in two patients (1%). No correlation was found between anti-Xa activity and creatinine clearance or age. CONCLUSIONS: Tinzaparin can be used safely at a curative dose in very elderly patients as long as (i) the accurate bodyweight-adjusted dose is given; (ii) platelet counts and anti-Xa levels are regularly monitored and; (iii) the interaction with other antithrombotic drugs is correctly managed.     

Evaluation of the pharmacokinetics of dalteparin in patients with renal insufficiency

The pharmacokinetics of the low-molecular weight heparin (LMWH), dalteparin, was evaluated after a single intravenous bolus injection of 50 IU anti-Xa/kg in 8 healthy volunteers, 8 patients with moderate/severe renal failure (Cl(crea) 13.1-56.5 ml/min) and 8 hemodialysis patients. Venous blood samples were taken over a 1-day period to determine anti-Xa activity, anti-IIa activity and plasma levels of free tissue factor pathway inhibitor (free TFPI). Plasma anti-Xa and anti-IIa activities were measured using chromogenic assays and free TFPI levels using an ELISA technique. The anti-Xa clearance was significantly decreased (p < 0.05) in both groups with renal insufficiency when compared with healthy volunteers. There was a positive correlation between creatinine clearance and anti-Xa clearance in the healthy volunteers and patients with moderate/severe renal failure. The anti-Ila activity was characterized by 3- to 4-fold lower plasma concentrations and faster elimination compared with the anti-Xa activity. In patients with moderate/severe renal failure the elimination of anti-lla was only slightly decreased, whereas in hemodialysis patients anti-Ila clearance was significantly decreased (p < 0.01). There was no correlation between creatinine clearance and anti-IIa clearance. The baseline mean free TFPI plasma levels in the two groups with renal insufficiency were significantly higher (p < 0.01) than in healthy volunteers. Dalteparin administration induced a transient, 6.0- to 8.1-fold increase in the free TFPI values in the three study groups. Dalteparin induced an increase in C(max) and AUC(0 - infinity) values of free TFPI in the two groups with renal insufficiency that was higher than in healthy volunteers. No bleeding complications occurred during the study. In conclusion, this is the first report showing retarded elimination of dalteparin and enhanced free TFPI plasma levels induced by a LMWH in patients with renal insufficiency.     

Enoxaparin use in the neonatal intensive care unit: experience over 8 years

STUDY OBJECTIVE: To evaluate the effectiveness and safety of enoxaparin therapy in a neonatal intensive care unit (NICU). DESIGN: Retrospective chart review. SETTING: Level III NICU in a Canadian academic center. PATIENTS: All neonates treated with enoxaparin while in the NICU between January 1, 1998, and June 1, 2006. MEASUREMENTS AND MAIN RESULTS: Data abstracted included patient demographics, diagnosis of thrombosis and its progression, enoxaparin dosages with corresponding antifactor Xa levels, and adverse events. Sixteen neonates (four term, 12 preterm) were treated with enoxaparin at a mean +/- SD initial subcutaneous dose of 1.41 +/- 0.15 mg/kg every 12 hours. The target therapeutic range (antifactor Xa level 0.5-1.0 U/ml) was achieved by 12 infants at a mean +/- SD dose of 1.92 +/- 0.43 mg/kg every 12 hours, after a mean of 5.6 days (range 1-15 days). Preterm infants required a higher dose (per kilogram) compared with term infants to maintain therapeutic antifactor Xa levels (mean +/- SD 1.94 +/- 0.39 vs 1.65 +/- 0.14 mg/kg every 12 hrs, p<0.001). Enoxaparin doses were more strongly correlated to antifactor Xa levels in term infants (r(2)=0.51, p<0.001) compared with preterm infants (r(2)=0.20, p<0.001). Ten (71%) of 14 thromboembolic events resolved, either partially or completely, at a mean of 39 days (range 8-61 days) of enoxaparin therapy. Nine infants (56%) experienced minor local adverse effects at the site of the indwelling subcutaneous catheter (induration, bruises, hematomas, or leakage). Systemic adverse events that were possibly related to enoxaparin therapy included osteopenia (one infant), scleral hemorrhage (one), and minor gastrointestinal tract bleeding (three) found in gastric feeding tubes. No adverse effects were associated with antifactor Xa levels greater than 1.0 U/ml. CONCLUSION: Enoxaparin may be effective in the treatment of neonatal thrombosis. An initial dosage of 1.5 mg/kg every 12 hours is likely inadequate to obtain therapeutic antifactor Xa levels rapidly and differs for term and preterm neonates. Therapeutic levels in preterm infants may be more variable, and the pharmacokinetics of this drug in preterm infants requires further evaluation. Future studies in neonates should prospectively evaluate a higher starting dose of enoxaparin to document effectiveness, acceptance, compliance with treatment guidelines, and adverse effects.     

Dosing low molecular weight heparins in kidney disease

The low molecular weigh heparins (LMWHs) are primarily eliminated renally, and current literature indicates that there is a reduction in clearance and an increase in half-life of LMWHs in patients with severe chronic kidney disease (CKD) associated with elevated anti-Xa levels and an increased risk of bleeding. It therefore becomes clinically prudent to evaluate dosing adjustments in CKD. The American College of Chest Physicians (ACCP), in its 2008 consensus statement, recommends 5 possible approaches to dosing LMWH in patients with severe CKD. In evaluating the individual compounds, enoxaparin, dalteparin, and tinzaparin, this article attempts to address the preferred dosing strategies.     

Safety, efficacy, and dosing requirements of bivalirudin in patients with heparin-induced thrombocytopenia

STUDY OBJECTIVE: To evaluate the safety, efficacy, and dosing requirements of bivalirudin in patients with heparin-induced thrombocytopenia (HIT). DESIGN: Retrospective cohort study. SETTING: University-affiliated hospital. PATIENTS: Thirty-seven adults with a diagnosis or history of HIT who were treated with bivalirudin between January 1, 2004, and March 31, 2007. MEASUREMENTS AND MAIN RESULTS: Patients had a mean +/- SD age of 50 +/- 16 years and weighed 80 +/- 20 kg; 62% were male, 73% were Caucasian, and 95% were treated in the intensive care unit. Patients were divided into three renal function groups for assessment of bivalirudin dosing requirements: creatinine clearance (Cl(cr)) greater than 60 ml/minute (12 patients, group 1); Cl(cr) 30-60 ml/minute (11 patients, group 2); and Cl(cr) lower than 30 ml/minute or receiving continuous renal replacement therapy ([RRT] 14 patients, group 3). Except for renal function, baseline demographic characteristics were similar among groups. A total of 19 (51%) of the 37 patients achieved goal activated partial thromboplastin time (aPTT) with initial mean +/- SD bivalirudin doses of 0.14 +/- 0.04 (median 0.15), 0.1 +/- 0.07 (median 0.08), and 0.05 +/- 0.05 (median 0.05) mg/kg/hour in groups 1, 2, and 3, respectively. Doses remained similar over the study period and were 0.13 +/- 0.04 (median 0.15), 0.1 +/- 0.06 (median 0.1), and 0.04 +/- 0.02 (median 0.03) mg/kg/hour for groups 1, 2, and 3, respectively. The mean +/- SD aPTT value after achieving goal range was 64 +/- 9 seconds (all patients). Bivalirudin dosing requirements correlated with Cl(cr) (r(2) = 0.37, p<0.0001). Therapy duration was a mean +/- SD of 11 +/- 13 days (median 7 days). Systemic thrombosis and bleeding while receiving bivalirudin were also evaluated. Thrombosis occurred in one patient; clinically significant bleeding occurred in two patients. CONCLUSION: Bivalirudin dosing requirements correlated with renal function; therefore, dosage reduction is required in patients with moderate or severe renal dysfunction. Starting bivalirudin at 0.15 mg/kg/hour in patients with Cl(cr) greater than 60 ml/minute, 0.08-0.1 mg/kg/hour in patients with Cl(cr) 30-60 ml/minute, and 0.03-0.05 mg/kg/hour in patients with Cl(cr) below 30 ml/minute or receiving continuous RRT is effective at achieving goal aPTT values in most patients.     

Review of bemiparin sodium--a new second-generation low molecular weight heparin and its applications in venous thromboembolism

Bemiparin sodium (Hibor, Ivor, Zivor, Badyket, Laboratorios Farmaceuticos Rovi SA) is a new second-generation low molecular weight heparin (LMWH). Bemiparin has the lowest mean molecular weight (3600 Da), the longest half-life (5.3 h) and the largest antifactor Xa:antifactor IIa ratio (8:1) of all LMWHs. Bemiparin promotes a greater release of tissue factor pathway inhibitor than unfractionated heparin (UFH) or dalteparin. These properties could result in a more favourable efficacy:safety ratio than the currently marketed LMWHs. Bemiparin 2500 IU/day was as effective as UFH for preventing venous thromboembolism (VTE) in moderate risk abdominal surgery. Bemiparin 3500 IU/day significantly reduced VTE compared to UFH in high-risk hip replacement surgery. Bemiparin 3500 IU/day started postoperatively was as effective as enoxaparin 4000 IU/day started preoperatively in total knee arthroplasty, with a trend towards a lower rate of proximal deep vein thrombosis (DVT), pulmonary embolism and symptomatic VTE. In patients with acute DVT, bemiparin was more effective than UFH in thrombus mass reduction and at least as effective as UFH for the prevention of clinical recurrence. Bemiparin was as effective as UFH for clot prevention during haemodialysis. The use of bemiparin was associated with a lower incidence of major and minor bleeding as compared to UFH in abdominal surgery. When compared with enoxaparin in orthopaedic surgery, a lower rate of complications at injection site was observed.     

Dalteparin: new indication. Prophylaxis in medical patients: no advance

(1) Heparin prophylaxis for medical inpatients who are confined to bed is controversial, because there are no reliable comparative data. Prophylaxis only seems justified for some patients at high risk of pulmonary embolism who have no risk factors for bleeding. (2) The licence of dalteparin, a low-molecular-weight heparin (LMWH), has been extended in France to cover prophylaxis of deep venous thrombosis in patients confined to bed for heart failure, acute respiratory failure, acute infections or acute rheumatological conditions who have at least one other risk factor for venous thromboembolism. (3) Evaluation data in this setting include a placebo-controlled trial but no trials versus unfractionated heparin or enoxaparin (another LMWH already available for this use). (4) The PREVENT trial included 3681 patients matching the characteristics described in the licence. They were randomised to receive (double-blind) daily subcutaneous injections of dalteparin (5000 IU) or placebo for 14 days. There was no difference between the groups in the following outcomes: death, pulmonary embolism and venous thrombosis (incidence below 1% in the placebo group). The results based on an endpoint combining clinical outcomes and phlebographic abnormalities favoured dalteparin. (5) Few data are available on the adverse events occurring in this trial. In other clinical situations, dalteparin has the same adverse effects as other LMWH (thrombocytopenia, hyperkalemia, etc.). (6) In practice, for medical inpatients who are confined to bed, where the thromboembolic risk is low, dalteparin offers no tangible advantages over unfractionated heparin or enoxaparin. The optimal dose for preventing symptomatic thromboembolism and minimising the bleeding risk is unknown.     

Successful Long-term Anticoagulation with Enoxaparin in a Patient with a Mechanical Heart Valve

Thromboembolism related to a mechanical heart valve (MHV) is a major complication after surgical valve replacement. Warfarin remains as guideline-endorsed thromboprophylaxis in patients with MHVs. Alternative anticoagulation therapy for patients who do not tolerate or who fail warfarin is not adequately covered in the current guidelines. We report a case of successful long-term anticoagulation with enoxaparin in a patient with a mechanical aortic valve who had a contraindication to warfarin. The patient developed a left thigh hematoma requiring surgical evacuation 1 month after initiation of weight-based dosing of enoxaparin. His dose was then titrated based on peak anti-factor Xa levels (goal 0.6–1.0 IU/ml). He remained free of signs and symptoms of thromboembolic events, valve dysfunction, bleeding complications, or major adverse effects from long-term enoxaparin use for the next 13 years. Our case provides promising evidence of the potential role of enoxaparin in patients with MHVs in whom warfarin thromboprophylaxis is not possible. Meticulous monitoring of anti-factor Xa levels and dosage adjustments are crucial to treatment success.     

Therapeutic levels of intravenous procainamide in neonates: a retrospective assessment

STUDY OBJECTIVES: To evaluate dosing and pharmacokinetic parameters of intravenous continuous-infusion procainamide in neonates, and to identify dosage regimens and factors leading to therapeutic procainamide levels and minimal adverse events. DESIGN: Retrospective, observational study. SETTING: Pediatric hospital. PATIENTS:. Twenty-one patients (seven preterm, 14 full term) younger than 30 days who received continuous-infusion procainamide therapy for more than 15 hours or had two consecutive therapeutic procainamide levels obtained while receiving therapy between June 1, 2002, and December 31, 2005. MEASUREMENTS AND MAIN RESULTS: Data on demographics, dosing, drug levels, and adverse effects were collected. Doses that achieved therapeutic levels were documented, and procainamide clearance was calculated and evaluated with regard to renal function and gestational age in patients who were at steady state. Mean clearance and mean N-acetylprocainamide (NAPA):procainamide ratios were compared between preterm and term neonates. No patients experienced hemodynamic instability or other adverse effects due to procainamide. Procainamide was given as a mean +/- SD 9.6 +/- 1.5-mg/kg bolus in 20 of 21 patients before continuous infusion. The mean +/- SD dose at which two therapeutic levels were achieved was 37.56 +/- 13.52 microg/kg/minute. Procainamide clearance was 6.36 +/- 8.85 ml/kg/minute and correlated with creatinine clearance (r=0.78, p<0.00001) and age at day of sampling (r=0.49, p<0.00001). The NAPA:procainamide ratio at steady state was 0.84 +/- 0.53; two patients were determined to be fast acetylators (ratio > 1). Preterm infants had lower mean clearance rates (p<0.001) but higher NAPA:procainamide ratios (p<0.01) than those of term infants. Five patients experienced seven supratherapeutic levels while receiving therapy; four of these patients were preterm, and all had creatinine clearances less than 30 ml/minute/1.73 m(2). Three patients had four pairs of levels obtained after discontinuation of procainamide, and elimination rate constant and half-life were calculated. CONCLUSION: Procainamide can be safely used in neonates, with no short-term adverse effects. The dosage regimen for intravenous procainamide required to achieve therapeutic levels in neonates is similar to that of older infants and children. Doses may need to be reduced in premature infants and in those with renal dysfunction.