Fixed-dose versus adjusted-dose low molecular weight heparin for the initial treatment of patients with deep venous thrombosis Job Harenberg, MD

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1 Fixed-dose versus adjusted-dose low molecular weight heparin for the initial treatment of patients with deep venous thrombosis Job Harenberg, MD Patients with acute deep vein thrombosis (DVT) were treated with a body-weight independent dosage of axa IU low-molecular-weight heparin (LMWH) Certoparin. After the subcutaneous administration of 8000 IU Certoparin, pharmacodynamic parameters did not differ between patients and healthy volunteers, and the AUC of the anticoagulant effects were not related to body weight. Two clinical trials demonstrated a greater regression of thrombi and a lower occurrence of recurrent venous thromboembolism (VTE), major bleeding, and mortality within 14 days of initial therapy compared with intravenous heparin. D-dimer decreased, and anti-xa activity increased in those patients with a regression of thrombosis. The benefit of the reduced occurrence of recurrent VTE, major bleeding, and mortality was maintained up to 6 months. Major bleeding was not related to the body weight in either treatment group. Treatment of acute DVT in adults with fixed dose of axa IU LMWH Certoparin is more effective and safer than heparin. Curr Opin Pulm Med 2002, 8: Lippincott Williams & Wilkins, Inc. 4 th Department of Medicine, University Hospital Mannheim, Ruprecht-Karls University Heidelberg, Mannheim, Germany. Correspondence to Job Harenberg, MD, Professor of Medicine, 4 th Department of Medicine, University Hospital Mannheim, Ruprecht-Karls University Heidelberg, Theodor-Kutzer-Ufer 1, D Mannheim, Germany; j-harenberg@t-online.de Current Opinion in Pulmonary Medicine 2002, 8: Abbreviations DVT deep-vein thrombosis INR International Normalized Ratio LMWH low-molecular-weight heparin RRR relative risk reduction UFH unfractionated heparin VTE venous thromboembolism ISSN Lippincott Williams & Wilkins, Inc. DOI: /01.MCP E1 Many studies have proven an almost equal efficacy and safety of subcutaneous low-molecular-weight heparins (LMWH) as intravenous unfractionated heparin (UFH) for the initial treatment of patients with acute deep-vein thrombosis (DVT) [1 3]. It is suggested, that this is based on improved pharmacologic properties, including higher anti-xa-activity compared with anti-iia-activity, less binding to plasma proteins [4], prolongation of halflife, and high relative bioavailability of the subcutaneous administration [5,6], resulting in a more predictable anticoagulant response [7]. Low molecular weight heparins are usually administered in body-weight-adjusted doses twice per day subcutaneously [8]. However, it is unclear from a pharmacokinetic and clinical point of view, whether body-weight adjustments of LMWH are really necessary for the treatment of patients with acute DVT. The anticoagulant effect of LMWH is more predictable than that of UFH, and consequently, monitoring is not mandatory for prophylaxis or treatment of patients with venous thromboembolism (VTE) [9]. Nevertheless, pharmacodynamic or pharmacokinetic studies of therapeutic doses of LMWHs in humans are required, because laboratory monitoring should be available for some patients. This is of special importance for the treatment of patients with DVT with a fixed, body-weight-independent dose of the LMWH Certoparin. A higher reduction of the thrombus size was observed in patients with DVT treated with LMWH compared with UFH [10 ]. An objective of the present analysis is to question the efficacy and safety of one LMWH based on the results of the Marder score from repeated ascending venography at entry [11 ]. We have focused on the question, whether D-dimer may be relevant in relation to the regression of thrombus size after treatment of DVT with aptt-adjusted intravenous UFH or fixed-dose, body-weight-independent LMWH Certoparin. We were interested specifically to whether differences of D- dimer and of other coagulation markers can be found after patients were treated with LMWH compared with UFH [12 ]. Meta-analyses demonstrated a reduced occurrence of recurrent VTE and of mortality 3 6 months after patients were initially treated with LMWHs compared with UFH 383

2 384 Disorders of pulmonary circulation [10,13,14]. However, pooling of data from clinical studies may encounter difficulties such as homogeneity of patients and comparability of LMWHs [15]. A beneficial long-term clinical outcome has not yet been demonstrated for one LMWH alone based on three independent clinical trials after initial therapy of DVT. The availability of such studies would avoid the bias caused by differences of study designs, study population, treatment regimens, and origins of the LMWH preparations, pooling the data of clinical trials [16,17]. The studies aimed to demonstrate an improved outcome over at least 6 months for patients with acute DVT initially treated with LMWH. Materials and methods Pharmacodynamics of fixed dose low-molecular-weight heparin in healthy volunteers and patients Eighteen male healthy volunteers aged years participated in the single-dose, randomized, two-period crossover studies to receive 8000 IU of the LMWH Certoparin (Novartis Pharma GmbH, Nuremberg, Germany) subcutaneously [18 ]. Four female and nine male patients with acute proximal DVT were enrolled in the study. They received 8000 axa IU Certoparin (Monoembolex; Novartis Pharma GmbH, Germany) bid for the management of acute DVT for 12 days followed by oral anticoagulation over 6 months [19 ]. Anti-Xa activities of Certoparin were measured with the chromogenic substrate S2222 and purified bovine factor Xa (normal range < 0.01 IU/mL) [20]. Regression of thrombi during initial therapy The two studies [16,21 ] included patients 30 years of age with acute symptomatic proximal DVT (ie, thrombosis in the popliteal or more proximal vein) documented by ascending venography according to Rabinov and Paulin [22 ]. Patients were randomly assigned to therapy with 8000 international anti-factor Xa units (axa IU) Certoparin bid subcutaneously or UFH with an initial bolus of 5000 IU followed by a continuous intravenous infusion at an initial rate of 20 IU/kg/h. The dose of UFH was subsequently adjusted to a target-activated partial thromboplastin time (aptt) of two- to threefold the reference value. Oral anticoagulation (vitamin K antagonists) was started before day 10 and was continued for up to 6 months. Treatment with LMWH or UFH was stopped as soon as the International Normalized Ratio (INR) was above 2.0 for 2 consecutive days. Patients underwent a second ascending venography of the affected leg between days 7 and 15, unless clinical symptoms prompted an earlier test. Two independent radiologists quantitatively assessed the thrombosed veins according to the scoring system of Marder et al. [11 ]. In the original studies, the primary outcome measure was defined as a relevant reduction of the Marder score of 30% on the second venography as compared with the one obtained at entry [16]. Regression of thrombi and coagulation markers The results of the coagulation markers were divided into the following groups: patients with improvement or no improvement of the Marder score in the second phlebography as compared with that at entry and treated with LMWH or UFH [12 ]. Plasma samples were collected at days 1 and 12 (or at the end of heparin treatment, whatever came first) at 8 a.m. D-dimer assay (normal range: < 500 µg/l) was performed with commercially available reagents (Gold EIA; Agen Biomedical Limited, Acacia Ridge, Australia). Factor Xa inhibition was measured using the chromogenic substrate S 2222 (normal range < 0.01 heparin units/ml [20]). Heptest clotting assay was performed as described earlier [20]. Normal values ranged from 13 to 20 seconds. Thrombin inhibition was analyzed by the chromogenic S2238 substrate assay. Normal values were below 0.03 IU heparin/ml plasma [20]. Outcome measures after 6 months The results of the two independent large studies [16,17] were combined for this analysis. An independent endpoint committee blinded for treatment groups evaluated all events evaluated recurrent thromboembolism, major hemorrhage, and mortality. The secondary outcome measure of the study was the composite outcome of recurrent VTE, major bleeding, and death during the 6-month follow-up period. Results Pharmacodynamic parameters in healthy volunteers and patients with deep-vein thrombosis The pharmacodynamic parameters are given in Table 1 after the s.c. administration of 8000 IU Certoparin in healthy persons and in patients with acute DVT. Minor, if any, differences can be seen between the groups (Table 1). The body weight did not correlate with the area under the activity time curve of the anti-xa activity (Fig. 1) [18,19 ]. Regression of thrombi during initial therapy Of the 797 patients, 393 were randomized to LMWH and 404 to UFH. No differences in the baseline characteristics of the two treatment groups could be detected. The dosage of LMWH was 8000 axa IU bid subcutaneously throughout the treatment period and of UFH 31,700 IU

3 Fixed-dose vs adjusted-dose LMWH for DVT Harenberg 385 Table 1. Pharmacodynamic parameters after the subcutaneous administration of 8000 IU Certoparin in healthy individuals and in patients with acute deep vein thrombosis Parameter Anti Xa Anti IIa Mean SD Mean SD T max min healthy patients C max IU/mL healthy patients AUC IU/mL h healthy (0 24 h) patients (0 12 h) T 1/2 h healthy patients at day 1 and 35,800 IU at day 10 by continuous intravenous infusion. The duration of treatment was comparable for LMWH (12.5 ± 3.4 days) and UFH (11.4 ± 3.1 days). Venographies at baseline and at the end of the initial treatment period were available in 596 of 797 patients (LMWH group n = 299 [76.1%] and UFH group n=297 [73.5%] patients). The absolute values of the Marder Score were 23.2 ± 8.4 and 23.9 ± 8.9 at entry for LMWH and UFH, respectively (Ps = 0.23). At the end of the initial treatment, the values were 18.9 ± 9.7 and 20.5 ± 9.9 for LMWH and UFH, respectively (Ps = 0.04) in favor of the LMWH treated group [23]. Regression of thrombi and coagulation markers Coagulation markers have been investigated in a subgroup of patients [16]. Plasma samples were taken at entry and after the 12 days heparin treatment period. Forty-eight and 41 patients were randomized to LMWH and UFH. Of these patients, 42 and 29 had an improvement, and 6 and 12 had no improvement of the Marder score at the end of therapy with LMWH and UFH, respectively. The dose of UFH was 30,885 ± 8074 IU/d at day 1 and was adjusted by determinations of the activated partial thromboplastin time during the treatment period (two- to three-fold prolongation of the aptt), leading to 33,974 ± 10,572 IU/d at day 12. Patients with an improved Marder score at day 12 showed lower D-dimer levels in both treatment groups (P < 0.001) and higher values of factor-xa inhibition (P < 0.002) and of Heptest (P < 0.03) and lower thrombin inhibition (P < 0.002) in the LMWH group. It can be seen from the results that these coagulation markers showed lower values in those patients in whom the Marder score did not improve at the second phlebography. There was no correlation between the changes of the Marder scores and the changes of the coagulation markers [12 ]. Clinical outcome after patients were initially treated with fixed-dose low molecular weight heparin Three hundred and ninety-three patients allocated to LMWH and 404 patients allocated to UFH were evaluated. Recurrent VTE, death, or major bleeding was observed during the initial treatment period in five (1.3%) patients receiving LMWH and in 20 (5.0%) patients receiving UFH (Ps = 0.004). The analysis produced a statistically significant pooled RR of 0.26 (95% confidence interval [CI], ) in favor of LMWH or a 74% reduction in risk of combined outcome for LMWH versus UFH. Major bleeding complication was the only item that was significantly less frequently occurring in patients randomized to LMWH compared with those randomized to UFH [23]. Combined analysis of two studies on the clinical outcome at 6 months The results of the [16] two trials [17] could be combined due to the almost identical trial design to analyze the combined outcome of recurrent venous thromboembolism, major bleeding, and mortality at 6 months [24]. Of 1758 patients, 893 were assigned to receive LMWH and 865 to UFH. No differences in the baseline characteristics of the two treatment groups were detected. The mean (± SD) duration of anticoagulant treatment was 11.8 ± 2.8 days with LMWH and 10.7 ± 2.7 days with UFH, respectively (not significant). The doses of UFH were 1352 ± 340 IU per hour at day 1 and 1427 ± 476 IU per hour at day 10. Oral anticoagulation was started at day 8.2 ± 2.4 in patients on LMWH and at day 7.9 ± 2.1 in patients on UFH (not significant). Venous thromboembolism re-occurred in 3.1% and 5.1% of patients initially allocated to LMWH and UFH, re- Figure 1. Area under the activity time curve of the axa activity following a fixed dose Certoparin in healthy and DVT persons in relation to body weight The area under the activity time curve (AUC) of the antifactor Xa activity are depicted versus the body weight of the healthy persons (open circles) and of patients with acute deep vein thrombosis (DVT) (closed circles). No dependence of the AUC of the axa activity can be detected from the body weight using the fixed dose of 8000 axa IU Certoparin.

4 386 Disorders of pulmonary circulation Figure 2. Relative risk of events between 3 and 6 months in patients with DVT treated initially with body weight adjusted LMWH Figure 4. Relation of major hemorrhage during 6 months to the body weight by initial treatment Results show the combined analysis [15] of recurrent venous thromboembolism, major bleeding complications, and mortality for low-molecular-weight heparins (LMWH) and unfractionated heparin (UFH). spectively (relative risk reduction [RRR] 0.62, CI , Ps = 0.04). Major bleeding complications occurred in 2.0% and 3.5% in patients initially allocated to LMWH and UFH, respectively (RRR 0.58, CI , Ps = 0.08). The mortality was 2.1% and 3.6% in patients initially randomized to LMWH and UFH, respectively (RRR 0.59, CI , Ps = 0.08) [24]. Figure 2 shows the results from patients treated with body-weight-adjusted s.c. LMWH [25 ]. Figure 3 shows the RRR of the treatment of patients with DVT using body-weight-independent, fixed-dose Certoparin. All The number of major bleeding depicted in relation to the body weight of patients observed during the 6-month follow-up period after the initial treatment with Certoparin (closed circles) or unfractionated heparin (UFH) (open circles) [24]. No dependence of bleeding complications can be seen using the fixed dose of axa IU Certoparin or APTT-adjusted UFH. data give the incidences including the follow-up periods of 3 6 months (Fig. 2) and 6 months (Fig. 3). Data in Figure 2 were obtained with different LMWHs and different study design. Data for Figure 3 were from studies with the same LMWH, same dosage of the heparins, and the same study designs. Figure 5. Relative risk of hemorrhage and recurrent VTE during therapy and follow-up Figure 3. Relative risk of events at 6 months in patients with DVT treated initially with fixed, body weight independent Certoparin The relative risk of developing recurrent venous thromboembolism (VTE), major bleeding, or mortality during the initial treatment with Certoparin followed by 6 months oral anticoagulation is depicted [24]. These data were obtained with low-molecular-weight heparin (LMWH) alone, in contrast to the data in Figure 2. All incidences are in favor of LMWH used for the initial treatment of patients with acute deep-vein thrombosis. The pooled relative risk of developing major hemorrhage (y-axis) and of developing recurrent venous thromboembolism (x-axis) is depicted, including the follow-up period of individual studies. Data with Certoparin were obtained from the two clinical studies [16,17] and for the other low-molecular-weight heparins (LMWHs), according to the literature [25 ]. Minus values represent results in favor of LMWH. Most studies show lower incidences of major hemorrhages and of recurrent venous thromboembolism during the initial and follow-up period for the various LMWH preparations compared with heparin.

5 Fixed-dose vs adjusted-dose LMWH for DVT Harenberg 387 Relation of major hemorrhage and body weight The dose of the heparins and the body weight of patients did not correlate to incidences of major bleeding complications in patients allocated to LMWH and UFH during the initial treatment and follow-up period (Fig. 4) [24]. Comparison of relative risk of major bleeding and recurrent venous thromboembolism of body-weight-adjusted and fixed-dose low-molecular-weight heparins The data for the different LMWHs have been published earlier [25 ]. The data were included in Figure 5, which were obtained with Certoparin in the two studies. All data represent the incidences from individual studies. They were calculated as the RRR in favor of LMWH, positive values representing a favor for UFH (Fig. 5). Discussion A comparison of the pharmacokinetic studies in healthy volunteers and patients with acute DVT demonstrated an equivalence of anticoagulant effects of subcutaneous fixed, high-dose LMWH Certoparin in both groups. The pharmacokinetic and pharmacodynamic analysis included a number of parameters not described so far for LMWH during the treatment of patients with DVT. The half-life of Certoparin was 5 hours in healthy volunteers as well as in the patients with DVT as determined by the anti-xa assay. Thus, increased plasma levels of heparin-binding proteins [4] do not influence the pharmacokinetic of the LMWH Certoparin in contrast to UFH [26]. This indicates only minor, if any, influence of alterations of plasma proteins during the acute phase of DVT on the pharmacodynamics of LMWH. Regression of thrombosis may still be regarded as a surrogate parameter, which is independent from the clinical outcome. The pooled analysis of the two studies presented here used the same LMWH, thus, avoiding a bias caused by possible differences of the LMWH compounds. In the present analysis, the results of the Marder score values of these two trials were pooled and showed a significant difference of the score after the initial treatment period in favor of LMWH. The analysis of the two studies shows that the thrombus size regressed more, and the composite outcome of recurrent VTE, mortality, and major bleeding was observed less frequently after the initial treatment of patients with acute proximal DVT with fixed-dose, body-weight-independent LMWH compared with UFH. Measurement of D-dimer, a specific fibrin degradation product, demonstrated a decrease during heparin therapy. Lower D-dimer levels at day 5 were associated with an improved venographic outcome after 6 months [27]. D-dimer levels decreased in 10% of patients within 1 3 days, followed by a continuous and slow decline towards the normal range [28]. A relation was demonstrated in the present study of a reduction of the size thrombi and D-dimer levels. The decrease of D-dimer occurred only in those patients who had a reduced Marder score at the end of therapy indicating the profibrinolytic potency of UFH and LMWH. Decreased D- dimer levels and increased axa activities were related to a reduction of the Marder score during treatment with fixed, body-weight-independent dosage of LMWH for the treatment of patients with VTE. Based on these data it may be reconsidered that coagulation parameters should be monitored to improve the treatment strategy with LMWH. The data of the pooled analysis of these two independent studies demonstrates that the initial treatment of patients with acute VTE with the LMWH Certoparin reduces the re-occurrence of VTE during the initial treatment period compared with UFH. This effect is maintained at least for the 6-month follow-up during oral anticoagulant therapy. The present analysis demonstrates the reduced incidences of clinical endpoints during therapy with one LMWH preparation alone compared with other analyses pooling data of trials with different LMWHs. The present overview demonstrates the improved efficacy and safety of a single LMWH for the treatment of patients with acute DVT compared with UFH using a fixed, body-weight-independent dosage of Certoparin. This regimen offers an alternative to body-weightadjusted dosage of LMWHs for the initial treatment of patients with acute DVT. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: Of special interest Of outstanding interest 1 Levine M, Gent M, Hirsh J, et al.: A comparison of low-molecular-weight heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996, 334: This is the first study, demonstrating with sufficient power the equal efficacy and safety of subcutaneous body-weight-adjusted low-molecular-weight heparin compared with intravenous unfractionated, aptt-controlled heparin for the initial treatment of patients with deep vein thrombosis. Main endpoint was 3 months after study incidence of recurrent venous thromboembolism. 2 Koopman MMW, Prandoni P, Piovella F, et al.: Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med 1996, 334: In the same issue of the New England Journal of Medicine is reference 1 (Levine et al., N Engl J Med 1996, 334:677 81). A second study with a different LMWheparin appeared, demonstrating the equal efficacy and safety of body-weightadjusted subcutaneous LMWH as compared with intravenous unfractionated heparin for the treatment of patients with acute deep venous thrombosis. The main endpoint was the recurrent rate of thromboembolism 6 months after the initial event. 3 Breddin HK, Hach-Wunderle V, Nakov R, et al.: Effects of a low-molecularweight heparin on thrombus regression and recurrent thromboembolism in patients with deep-vein thrombosis. N Engl J Med 2001, 344: The study was important to demonstrate the improved reduction of thrombus size during LMWH compared to UFH in patients with deep vein thrombosis. Recurrent thromboembolism after 3 months was related to the reduction of thrombus size after the initial heparin treatment.

6 388 Disorders of pulmonary circulation 4 Young E, Wells P, Holloway S, et al.: Ex-vivo and in-vitro evidence that low molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin. Thromb Haemost 1994, 71: Harenberg J, Stehle G, Augustin J, et al.: Comparative human pharmacology of low molecular weight heparins. Semin Thromb Haemost 1989, 15: Weitz JI: Low Molecular Weight Heparins. N Engl J Med 1997, 337: Hirsh J, Warkentin TE, Shaughnessy SG, et al.: Heparin and low-molecularweight heparin. Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001, 119: Merli G, Spiro TE, Olsson CG, et al.: Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med 2001, 134: The paper describes the equal efficacy and safety of once daily subcutaneous LMWH compared with twice daily subcutaneous LMWH used in body-weightadjusted dosage. 9 Boneu B: Low molecular weight heparin therapy: is monitoring needed? Thromb Haemost 1994, 72: Leizorovicz A, Simonneau G, Decousus H, et al.: Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis. BMJ 1994, 309: Offers meta-analysis demonstrated the equal efficacy and safety of LMWH compared with UFH for the initial treatment of patients with deep venous thrombosis. 11 Marder VJ, Soulen RL, Atichartakarn V, et al.: Quantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and hep- arin therapy. J Lab Clin Med 1977, 89: Standard vengraphic assessment of deep venous thrombosis for a quantification of the thrombus size. 12 Harenberg J, Merx K, Hoffmann U, et al.: Association of changes in D-dimer and other coagulation markers with changes in Marder Score after treatment of acute venous thrombosis. Br J Haematol, submitted. Application demonstrating association of changes of D-dimer with changes inthe Marder score after patients with acute deep venous thrombosis were treated with fixed-dose subcutaneous LMWH. 13 Lensing AW, Prins M, Davidson BL, et al.: Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis. Arch Intern Med 1995, 155: Siragusa S, Cosmi B, Piovella F, et al.: Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med 1996, 100: Dolovich LR, Ginsberg JS, Douketis JD, et al.: A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000, 160: Harenberg J, Schmidt JA, Koppenhagen K, et al.: Fixed-dose, body weightindependent subcutaneous LMW heparin versus adjusted dose unfraction- ated intravenous heparin in the initial treatment of proximal venous thrombosis. EASTERN Investigators. Thromb Haemost 2000, 83: Clinical study showing the proven efficacy and safety profile of fixed-dose bodyweight-independent subcutaneous LMWH for the treatment of patients with acute DVT compared with intravenous unfractionated heparin. First study design using a combined clinical endpoint consisting of the current thromboembolism, majorbleeding complications, and mortality 6 months after the initial event. 17 Riess, H, Koppenhagen K, Tolle AR, et al.: Fixed-dose body weightindependent subcutaneous LMW-heparin (LMWH) Certoparin is equally effective to adjusted-dose intravenous UF-heparin (UFH) for the initial treatment of proximal deep venous thrombosis (DVT). Thromb Haemost 2001, (suppl):oc Clinical study comparing the fixed body-weight-independent subcutaneous dosage of LMWH to intravenous unfractionated heparin on the incidence of recurrent thromboembolism 6 months after the initial treatment. 18 Hoffmann U, Harenberg J, Bauer K, et al.: Bioequivalence of subcutaneous and intravenous body-weight-independent high-dose low-molecular-weight heparin Certoparin on anti-xa, Heptest, and tissue factor pathway inhibitor activity in volunteers. Blood Coagul Fibrinol 2002, 13:1 8. Study in volunteers using fixed-dose subcutaneous body-weight-independent LMWH demonstrating the bioequivalence compared with intravenous demonstration. 19 Bauer K, Hoffmann U, Piazolo L, et al.: Does high-dose LMW-heparin accumulate over 9 days in patients with acute deep venous thrombosis [abstract]. Thromb Haemost 2001, (suppl):p2320. Clinical study in DVT patients demonstrating the lack of dependence of fixed-dose LMWH from the body weight for determination of the area under the activity time curve of the anti-factor Xa activity. 20 Harenberg J, Giese Ch, Knödler A, et al.: Comparative study on a new onestage clotting assay for heparin and its low molecular weight derivatives. Haemostasis 1989, 19: Kirchmaier CM, Wolf H, Schäfer H, et al.: Efficacy of a low molecular weight heparin administered intravenously or subcutaneously in comparison with intravenous unfractionated heparin in the treatment of deep venous thrombosis. Int Angiol 1998, 17: Clinical study comparing intravenous and subcutaneous LMWH for treatment of patients with acute DVT. 22 Rabinov K, Paulin S: Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972, 104: Standard method for radiologic examination of DVT using ascending phlebography. 23 Harenberg J, Huisman MV, Tolle AR, et al.: Reduction in thrombus extension and clinical endpoints in patients after initial treatment for deep vein thrombosis with the fixed-dose body weight-independent low molecular weight heparin certoparin. Semin Thromb Hemost 2001, 27: Analysis of two studies demonstrating a significant higher reduction of thrombus size using fixed-dose subcutaneous LMWH for the initial treatment of patients with DVT compared with intravenous UFH. 24 Harenberg J, Riess H, Brom J, et al.: Reduced re-occurrence of venous thromboembolism over 6 months in patients with deep-vein thrombosis treated initially with subcutaneous body-weight independent low-molecular-weight heparin Certoparin [abstract]. Blood 2001, 98:1120. This is the first analysis of the combined results of two independent studies with only one LMWH demonstrating the long term benefit of an initial therapy of DVT with LMWH. 25 van der Heijden JF, Prins MH, Büller HR: For the initial treatment of venous thromboembolism: are all low-molecular-weight heparin compounds the same? Thromb Res 2000, 100:V Comparison of an improved efficacy and safety of low-molecular-weight heparins in the treatment of patients with acute DVT. The conclusion is the comparability of the different LMWHs. However, differences between the LMWHs can also be observed. 26 Kandrotas RJ: Heparin pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 1992, 22: Holmstrom M, Lindmarker P, Granqvist S, et al.: A 6-month venographic follow-up in 164 patients with acute deep vein thrombosis. Thromb Haemost 1997, 78: Sie P, Cadroy Y, Elias A, et al.: D-Dimer levels in patients with long-term antecedents of deep venous thrombosis. Thromb Haemost 1994, 72: