Introduction. Patients, Materials and Methods

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1 Original Paper Haemostasis 2001;31:42 48 Received: November 20, 2000 Accepted in revised form: January 2, 2001 Effect of Patient Weight on the Anticoagulant Response to Adjusted Therapeutic Dosage of Low-Molecular- Weight Heparin for the Treatment of Venous Thromboembolism S. Jo-Anne Wilson a Kerry Wilbur d Erica Burton b David R. Anderson c a Faculty of Health Professions, Dalhousie University, and Pharmacy Department, b Data Base Department and c Department of Medicine, Division of Hematology, Queen Elizabeth II Health Sciences Centre, Halifax, N.S., and d Faculty of Pharmaceutical Sciences, University of British Columbia and Vancouver Hospital and Health Sciences Centre, Vancouver, B.C., Canada Key Words Low-molecular-weight heparin W Anti-Xa levels W Venous thromboembolism Abstract Data evaluating the safety of using weightbased dosing of low-molecular-weight heparin (LMWH) in obese patients are limited. Some manufacturers have recommended a maximum daily dose of LMWH not to be exceeded. The purpose of this study was to determine if body weight influenced the anticoagulant response to a weight-based dose of LMWH for the treatment of venous thromboembolism. Patients with serum creatinine levels! 150 Ìmol/l receiving the LMWH, dalteparin 200 anti-xa IU/kg based on actual body weight subcutaneously once daily for the treatment of deep vein thrombosis or pulmonary embolism, were eligible for the study. Patients received a minimum of 5 days LMWH treatment. Patients had peak anti-xa levels (IL Test Chromogenic assay) measured 3 4 h following their day 3 injection and trough anti-xa levels measured immediately prior to injections on day 3 and 5. No dose adjustments were made on the basis of the anti-xa levels. Patients were a priori stratified into three weight classes: (A) within 20% of ideal body weight (IBW) (n = 13); (B) 20 40% of IBW (n = 14), and (C) greater than 40% of IBW (n = 10). The largest patient weighed 190 kg and had a body mass index of 58. Mean daily LMWH doses were 14,030, 17,646 and 23, 565 IU for groups A, B and C, respectively. Mean (SD) trough anti-xa levels on day 3 were 0.12 (0.05) anti-xa IU/ml for ABC Fax karger@karger.ch S. Karger AG, Basel /01/ $17.50/0 Accessible online at: Dr. S. Jo-Anne Wilson, Queen Elizabeth II Health Sciences Centre Pharmacy Department Victoria General, Room 2043 Victoria Halifax, NS B3H 2Y9 (Canada) Tel , Fax RXJSW@qe2-hsc.ns.ca

2 group A, 0.11 (0.03) anti-xa IU/ml for group B and 0.11 (0.03) anti-xa IU/ml for group C (p 1 0.2). Similar trough anti-xa levels were observed on day 5. Mean (SD) peak anti-xa levels on day 3 were 1.01 (0.20) anti-xa IU/ml, 0.97 (0.21) anti-xa IU/ml and 1.12 (0.22) anti- Xa IU/ml for groups A, B and C, respectively (p 1 0.2). No thromboembolic or bleeding complications occurred during LMWH therapy in any patients. These findings suggest that body mass does not appear to have an important effect on the response to LMWH up to a weight of 190 kg in patients with normal or near normal renal function. Introduction Copyright 2001 S. Karger AG, Basel Low-molecular-weight heparins (LMWHs) have become an important class of antithrombotic agents in the treatment of thromboembolic disorders. Clinical trials have demonstrated that LMWHs are safe, effective and cost-effective for the treatment of venous thromboembolism [1 8]. The doses of LMWH used to treat venous thrombosis have usually been adjusted to a patient s body weight. However, data evaluating the safety of using weight-based doses of LMWH in obese patients are limited. In the absence of clinical data, some manufacturers have recommended a maximum daily dose of LMWH not be exceeded due to the uncertainty of their pharmacokinetic response. The manufacturer of the LMWH evaluated in this study, dalteparin, recommend the maximum daily dose be 18,000 anti-xa IU [9]. Since the recommended dose of dalteparin for the treatment of venous thromboembolism is 200 anti-xa IU/kg, patients weighting 190 kg would have their doses capped. If administering a weight-based dose of LMWH is important to achieve a therapeutic antithrombotic effect, there is concern that arbitrarily capping the dose of LMWH may result in insufficient treatment of heavy patients. LMWH has only a moderate prolonging effect on the activated partial thromboplastin time and is therefore not recommended to be used to monitor LMWH therapy [9, 10]. Anti- Xa levels are the recommended method for monitoring the anticoagulant response to LMWH. Although monitoring anti-xa levels is not routinely required for patients receiving LMWH, it has been recommended these levels be followed in obese patients [9, 10]. The purpose of this study was to determine if patient weight influenced the anticoagulant response to LMWH as determined by anti-xa levels. Patients, Materials and Methods Patients and Study Design This prospective cohort study involved patients who received LMWH therapy for the treatment of deep vein thrombosis or pulmonary embolism diagnosed using objective tests. Potentially eligible patients were excluded if they had a major contraindication to anticoagulant therapy, a history of heparin-induced thrombocytopenia, heparin allergy or if their serum creatinine was 1150 Ìmol/l. The study was approved by the Research Ethics Board of the Queen Elizabeth II Health Sciences Centre and informed consent was obtained from all participants. Patients received the LMWH dalteparin (Pharmacia & Upjohn, Mississauga, Ont., Canada) 200 anti-xa IU/kg based on actual body weight subcutaneously once daily. There was no capping of the LMWH dose. The oral anticoagulant, sodium warfarin (Dupont Pharma, Mississauga, Ont., Canada) was started within 24 h of diagnosis and administered according to a standardized nomogram [11]. Dalteparin was discontinued after a minimum of 5 days of therapy once the INR was 11.9 for 2 consecutive days. Patients were a priori stratified into three weight classes: (A) within 20% of ideal body weight (IBW); (B) 20 40% of IBW, and (C) greater than 40% of IBW. IBW was defined as 50 kg plus 2.3 times height in inches over 5 ft in males Effect of Weight on the Anticoagulant Response to Low-Molecular-Weight Heparin Haemostasis 2001;31:

3 and 45.5 kg plus 2.3 times height in inches over 5 ft in females [12]. It was planned that a minimum of 10 patients be selected from each weight group. Peak anti-xa levels were measured 3 4 h following the day 3 LMWH injection and trough anti-xa levels were measured immediately prior to LMWH injections on day 3 and day 5. If day 3 or day 5 fell on a weekend or holiday, anti-xa levels were measured on the nearest working day. No dose adjustments were made on the basis of the anti-xa levels. Patients were followed daily to document the occurrence of hemorrhagic or thromboembolic complications during dalteparin treatment. Patients were also contacted 3 months after their initial diagnosis to determine if any thromboembolic or hemorrhagic complications had occurred. Anti-Factor Xa Assay Anti-Xa blood samples were collected into citrated (3.8%) glass vials. Anti-Xa levels were measured using the IL Test Chromogenic Heparin (Xa) Assay manufactured by Instrumentation Laboratory Co. (Lexington, Mass., USA). Outcomes The primary study outcome was the anti-xa level. Mean trough anti-xa levels on day 3 and day 5 and mean peak anti-xa levels on day 3 were compared among the three groups. Secondary outcome measures included hemorrhagic and recurrent venous thromboembolic complications which were classified according to previously published criteria [13]. Statistical Analysis Quantitative variables were expressed as mean and standard deviation (SD). The primary analysis, comparing anti-xa levels in the three groups, was done by analysis of variance using STATA 6.0 statistic software. Multiple linear regression analysis techniques were performed to determine the effect of patient weight, creatinine clearance, and age on anti-xa levels. Results Patients Thirty-seven patients were enrolled in this study. Thirteen were stratified into group A (within 20% of IBW), 14 into group B (20 40% of IBW) and 10 into group C (greater than 40% of IBW). Twelve were female and 25 were male. Although patients in the largest weight group tended to be younger than patients in the lowest weight strata and creatinine clearance tended to be greater in the higher weight strata, these differences did not achieve statistical significance (table 1). Anti-Factor Xa Levels among Weight Groups Ninety-two percent (34/37) of patients had trough anti-xa levels drawn on day 3, whereas 95% (35/37) had trough and peak anti-xa levels drawn on both day 3 and day 5. All trough levels were within the manufacturer s recommended range of!0.5 anti-xa IU/ml. Mean (SD) trough anti-xa levels on day 3 were 0.12 (0.05) anti-xa IU/ml, 0.11 (0.03) anti-xa IU/ ml, and 0.11 (0.03) anti-xa IU/ml for groups A, B and C, respectively (p 1 0.2). Similar trough anti-xa levels were observed on day 5 (p 1 0.2) (table 2). Mean (SD) peak anti-xa levels on day 3 were 1.01 (0.20) anti-xa IU/ml for group A, 0.97 (0.21) anti-xa IU/ml for group B and 1.12 (0.22) anti-xa IU/ml for group C (p 1 0.2). Regression analysis demonstrated that adjusting for patient age, creatinine clearance, and weight did not influence the trough or peak anticoagulant responses to dalteparin as monitored by anti-xa levels. The timing of peak anti-xa levels (mean B SD) was similar for group A 224 B 47 min, group B 238 B 45 min and group C 226 B 43 min (p 1 0.2). Thromboembolic or Hemorrhagic Complications No thromboembolic or hemorrhagic events occurred during LMWH therapy in any patient. There were also no thromboembolic complications up to 90 days following LMWH therapy. 44 Haemostasis 2001;31:42 48 Wilson/Wilbur/Burton/Anderson

4 Table 1. Patient characteristics Characteristic Group 1 ABW within 20% 1 IBW (n = 13) Group 2 ABW 20 40% 1 IBW (n = 14) Group 3 ABW 1 40% IBW (n = 10) Male/female 10/3 10/4 5/5 Proximal DVT Pulmonary embolism Age, years Mean (SD) 65 (14) 65 (13) 45 (14) Range Weight, kg Mean (SD) 70 (9) 89 (11) 117 (32) Range Dalteparin dose, anti-xa IU Mean (SD) 14,030 (1,902) 17,646 (2,040) 23,565 (6,472) Range 11,200 16,000 15,000 21,200 16,400 38,000 SCr, Ìmol/l Mean (SD) 90 (21) 77 (13) 75 (11) Range Crcl, ml/min Mean (SD) 69 (22) 80 (21) 95 (27) Range Duration of dalteparin, days Mean (SD) 6.3 (1.5) 6.3 (1.2) 6.8 (1.7) Range SD = Standard deviation; SCr = serum creatinine; Crcl = creatinine clearance; ABW = actual body weight; IBW = ideal body weight. Table 2. Anti-Xa activity during dalteparin therapy Group 1 ABW within 20% 1 IBW (n = 13) Group 2 ABW 20 40% 1 IBW (n = 14) Group 3 ABW 1 40% IBW (n = 10) p Mean (SD) day 3 trough, anti-xa U/ml 0.12 (0.05) 0.11 (0.03) 0.11 (0.03) % CI Mean (SD) day 5 trough, anti-xa IU/ml 0.10 (0.02) 0.11 (0.04) 0.12 (0.06) % CI Mean (SD) day 3 peak, anti-xa IU/ml 1.01 (0.20) 0.97 (0.21) 1.12 (0.22) % CI ABW = Actual body weight; IBW = ideal body weight; SD = standard deviation. Effect of Weight on the Anticoagulant Response to Low-Molecular-Weight Heparin Haemostasis 2001;31:

5 Discussion Multiple LMWH preparations have been proven to be safe and effective therapies for the treatment of venous and arterial thrombotic disorders. Most clinical trials have based LMWH dose on patient weight [1 7], however, little data is available regarding the use of LMWH in obese patients. Some manufacturers have recommended capping LMWH dose whereas others do not recommend such a cap. In addition, some manufacturers have recommended that when using LMWH in obese patients, the anticoagulant effect of the drug be monitored using anti-xa levels and that dose adjustments be made if required. Anti-Xa activity assays are recognized to only measure one component of the antithrombotic activity of LMWH. Nevertheless, anti-xa assays are the recommended test to monitor the effect of LMWH in clinical situations in which uncertainty exists in the dose response of the medication. These scenerios include patients with renal dysfunction or who are obese [9, 10, 14]. The target peak and trough anti-xa level therapeutic ranges for LMWH therapy for the treatment of venous thromboembolism are controversial. Furthermore, there have been no studies that have prospectively validated such ranges. For dalteparin, the manufacturer recommends the peak anti-xa level be U/ml and the trough be 10.1 U/ml. However, this range was developed based on twice-daily dosing. According to the 2000 product monograph for dalteparin, the recommended range for once-daily dosing is a trough!0.3 U/ml and a peak!1.7 U/ml [9]. We demonstrated that with once-daily weight-based dosing, the peak effect of LMWH, measured with anti-xa levels, after the day 3 injection, was similar in patients with acute venous thromboembolism in three weight categories: (A) normal body weight (within 20% of IBW); (B) mildly obese (20 40% of IBW), and (C) moderately obese (greater than 40% of IBW). Perhaps of greater significance, we also found that the trough effect of LMWH was very low and similar in all three weight groups when measured on days 3 and 5 of therapy. There was no trend to suggest a cumulative effect of LMWH between days 3 and 5. Thus, our findings would suggest that with the usual recommended 5- day treatment course of LMWH for venous thromboembolism, neither dose capping nor routine anti-xa monitoring are required in the management of moderately obese patients with normal or near normal renal function for the treatment of venous thromboembolism. Clinical study results are conflicting about whether there is correlation between anti-xa activity and patient outcomes in studies evaluating LMWH for the treatment and prevention of venous thromboembolism [15 26]. Interpreting the results of LMWH studies evaluating the clinical significance of anti-xa levels for the prevention or treatment of venous thromboembolism is problematic because of the variability in the timing of anti- Xa measurements, and of the LMWH products and anti-xa assays used [14]. Studies evaluating LMWH for the treatment of venous thromboembolism have primarily used weight-based dosing [1 7]. Alhenc-Gelas et al. [15] reported there was an association between anti-xa levels and resolution of deep vein thrombosis following LMWH as measured by the Marder score. Nieuwenhuis et al. [25] found major bleeding complications were observed more frequently in patients with anti-xa levels 10.8 U/ml. However, other investigators have not reported an association between anti-xa levels and thrombotic or bleeding complications in patients receiving LMWH for the treatment of venous thromboembolism [3, 4]. 46 Haemostasis 2001;31:42 48 Wilson/Wilbur/Burton/Anderson

6 In prophylaxis studies, LMWH has been administered in a fixed dose not adjusted for body weight. Again, clinical trial results are conflicting about whether a relationship exists between anti-xa levels and patient outcome. Levine et al. [24] reported a highly significant association between anti-xa levels and rates of venographically confirmed deep vein thrombosis and wound hematomas with LMWH prophylaxis following total hip arthroplasty. Other investigators have noted weaker associations between anti-xa levels and deep vein thrombosis rates with LMWH prophylaxis following general surgery [19, 22], but not for major orthopedic procedures [16, 21, 23, 26]. There are several limitations of our study. First, sample size was small and may be underpowered to detect statistically significant differences between the three weight groups. Although this is a possibility, based on the similarities in anti-xa levels between weight groups, particularly in the trough levels, it appears unlikely that small significant differences would be clinically important. Second, patients in the highest patient weight groups tended to be younger and had higher creatinine clearance levels than those in the lower weight groups. Although differences in creatinine clearance could have favored more clearance in the highest weight group, our regression analysis did not suggest that weight had any influence on the anti-xa response when the dose of LMWH is weight-based. Third, the highest patient weight in the study was 190 kg and most patients had creatinine clearances that were within normal limits. Therefore, these study results may only be generalizable in patients with normal or near normal renal function and may not apply to patients with weights 1200 kg. Finally, although anti- Xa levels have been recommended as the assay of choice to monitor the anticoagulant effect of LMWH, the evidence to suggest anti- Xa levels correlate with clinically important outcomes has been conflicting. In summary, there is insufficient evidence to suggest that administering LMWH based on a weight-adjusted dose requires modification in obese patients and there is likely limited value in monitoring anti-xa levels in obese patients who receive 5-day courses of LMWH for the treatment of venous thromboembolism. Further research is required to determine if anti-xa levels are of clinical significance in this or other clinical settings. Acknowledgements We would like to thank Ms. Joanne Burdock for her secretarial assistance with the manuscript. References 1 Hull RD, Raskob GE, Pineo GF, Green D, Trowbridge AA, Elliott CG, Lerner RG, Hall J, Sparling T, Brettell HR, Norton J, Carter CJ, George R, Merli G, Ward J, Mayo W, Rosenbloom D, Grant R: Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal vein thrombosis. N Engl J Med 1992;326: Simmonneau G, Sors H, Charbonnoi B, Decousus H, Planchon B, Ninet J, Sie P, Silsiguen M, Combe S: Subcutaneous low-molecularweight heparin compared with continuous intravenous infusion unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med 1993;153: Lindmarker P, Holmstrom M, Granqvist S, Johnsson H, Lockner D: Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost 1994;72: Effect of Weight on the Anticoagulant Response to Low-Molecular-Weight Heparin Haemostasis 2001;31:

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