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Previous Volume 344:626-631 March 1, 2001 Number 9 Next

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ABSTRACT

Background Low-molecular-weight heparins are frequently used to treat venous thromboembolism, but optimal dosing regimens and clinical outcomes need further definition.

Methods In this multicenter, open-label study with blinded adjudication of end points, we randomly assigned patients with acute deep-vein thrombosis to one of three treatment regimens: intravenous administration of unfractionated heparin; subcutaneous administration of a low-molecular-weight heparin, reviparin, twice a day for one week; or subcutaneous administration of reviparin once a day for four weeks. The primary end point was evidence of regression of the thrombus on venography on day 21; secondary end points were recurrent venous thromboembolism, major bleeding within 90 days after enrollment, and death.

Results Of the patients receiving unfractionated heparin, 40.2 percent (129 of 321) had thrombus regression, as compared with 53.4 percent (175 of 328) of the patients receiving reviparin twice daily and 53.5 percent (167 of 312) of the patients receiving reviparin once daily. With regard to thrombus regression, reviparin administered twice daily was significantly more effective than unfractionated heparin (relative likelihood of thrombus regression, 1.28; 97.5 percent confidence interval, 1.08 to 1.52), as was reviparin administered once daily (relative likelihood, 1.29; 97.5 percent confidence interval, 1.08 to 1.53). Mortality and the frequency of episodes of major bleeding were similar in the three groups.

Conclusions In acute deep-vein thrombosis, reviparin regimens are more effective than unfractionated heparin in reducing the size of the thrombus. Reviparin is also more effective than unfractionated heparin for the prevention of recurrent thromboembolism and equally safe.

Because of their greater bioavailability, low-molecular-weight heparins can be administered subcutaneously without the need for laboratory monitoring. Randomized, controlled trials of treatment for acute deep-vein thrombosis^{5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20} or pulmonary embolism²¹ have demonstrated that low-molecular-weight heparins are at least as effective and safe as unfractionated heparin. In addition to the assessments of clinical outcome, repeated venography has revealed a tendency for the thrombus to regress in the groups receiving a low-molecular-weight heparin.^5,10,11,14 Although these studies did not have the statistical power to show the superiority of low-molecular-weight heparins over unfractionated heparin for improving venous patency, meta-analyses concluded that treatment with a low-molecular-weight heparin increased the frequency of thrombus regression.^22,23,24

A definition of a response to therapy on venography (a reduction of at least 30 percent in the Marder score²⁵) was used recently to compare the efficacy of a low-molecular-weight heparin with that of unfractionated heparin.²⁶ A correlation between the clinical rate of recurrence and the rate of thrombus regression was not achieved.

Therefore, we conducted a study comparing two regimens of the low-molecular-weight heparin reviparin with a regimen of unfractionated heparin, using both clinical recurrence of venous thromboembolism and thrombus regression, as assessed by venography, as outcome measures. Instances of major bleeding and deaths from any cause were recorded throughout the study.

Methods

Study Design

In a multicenter, randomized, controlled, open-label trial with blinded assessment of outcomes, the intravenous administration of unfractionated heparin for 5 to 7 days was compared with the subcutaneous administration of reviparin twice a day for 5 to 7 days or once a day for 28±2 days. All the patients received vitamin K antagonists until the end of the 90-day observation period. A total of 104 centers in 10 countries participated in the study (see the Appendix). The protocol was approved by the local institutional review boards and was conducted in accordance with national and international regulations.

Patients

Patients who were at least 18 years of age and had acute deep-vein thrombosis of the legs, confirmed by venography, and who had had symptoms for no more than 14 days were eligible for enrollment. All patients gave written informed consent. Criteria for exclusion from the study were the presence of thrombi only in isolated calf veins or isolated muscle veins; clinically symptomatic pulmonary embolism; treatment with unfractionated heparin, a low-molecular-weight heparin, or a vitamin K antagonist for 24 hours or more before enrollment; uncontrolled hypertension; stroke within three weeks before enrollment; cerebral vascular aneurysm or active gastroduodenal ulcer; bacterial endocarditis; thrombocytopenia (less than 100,000 platelets per cubic millimeter); severe liver or renal insufficiency; receipt of spinal or epidural anesthesia or lumbar puncture in the five days before enrollment; surgery in the five days before enrollment; concomitant treatment with fibrinolytic agents or platelet-function inhibitors; a body weight of less than 35 kg; pregnancy; and known drug abuse.

Treatments

Patients were randomly assigned to one of three groups, stratified according to site. The first group received an intravenous bolus of 5000 IU of unfractionated heparin, followed by a continuous intravenous infusion of 1250 IU per hour. The second group received the low-molecular-weight heparin reviparin (Clivarin, Knoll, Ludwigshafen, Germany) twice a day for five to seven days. In both these groups, a vitamin K antagonist was given from day 1 to day 90. The third group received reviparin once a day for 28 days and a vitamin K antagonist from day 21 to day 90. The dose of reviparin, given as one injection every 12 hours or as one injection every 24 hours, was based on the patient's weight (7000 anti-Xa units for a weight of 35 to 45 kg, 8400 anti-Xa units for 46 to 60 kg, and 12,600 anti-Xa units for more than 60 kg).

The intravenous infusion of unfractionated heparin was adjusted according to daily measurements of the activated partial-thromboplastin time to achieve a value 1.5 to 2.5 times the base-line level. Heparin treatment was continued until an international normalized ratio of more than 2 was reached, and this ratio was subsequently maintained.

End Points

The primary outcome variable with respect to efficacy was a change in the venographically determined thrombus size between base line and day 21 (±2 days), assessed with the use of the Marder score.²⁵ This score allocates points to each of the involved deep venous segments of the lower limb. If all the veins in one leg are occluded, the total score is 40 (6 for iliac, 4 for common femoral, 10 for superficial femoral, 4 for popliteal, 4 for anterior tibial, 6 for peroneal, and 6 for posterior tibial veins). Partially occluded veins are given a lower score, depending on the extent of the thrombus. Patients were considered to have a response when their scores decreased by at least 30 percent; all other patients were classified as having no response, including those in whom new, confirmed symptomatic venous thromboembolism developed. This reduction in the Marder score was selected because it has been shown to represent partial treatment success accurately. The venograms were assessed by two members of an independent committee who were unaware of the patients' treatment assignments and of whether the venograms were obtained before or after treatment. Discrepancies were resolved by a joint evaluation. The number of patients whose Marder scores decreased was also assessed. Symptomatic deep-vein thrombosis and pulmonary embolism were documented by objective methods during the 90-day observation period; these clinical variables and death were selected as secondary end points, and events were also reviewed by an adjudication committee whose members were unaware of the patients' treatment assignments.

Assessment of Clinical Outcomes

Immediate venography or scintigraphy was requested if clinical symptoms of recurrent deep-vein thrombosis or pulmonary embolism developed, according to predefined criteria. The criteria for the verification of symptomatic deep-vein thrombosis were an extension of an intraluminal filling defect visible on a venogram, a new intraluminal filling defect, or an extension of the area of nonvisualization of proximal veins plus a sudden cutoff defect visible on a venogram in at least two projections.

The criteria for the diagnosis of symptomatic pulmonary embolism were a ventilation–perfusion mismatch of at least 75 percent of the segmental size, positive results on pulmonary angiography, or a finding of pulmonary embolism at autopsy. If no adequate objective tests were available, the adjudication committee based its final decision on the clinical information provided.

Adverse Events

Bleeding complications and other adverse events were evaluated by an independent safety committee whose members were unaware of the patients' treatment assignments. Bleeding was defined as major if it was clinically overt and associated with a fall in the hemoglobin level of at least 2.0 g per deciliter, if it required the transfusion of two or more units of red cells, if it was retroperitoneal or intracranial, or if it warranted the permanent discontinuation of treatment. For patients who died, the cause of death was classified as pulmonary embolism, hemorrhage, cancer, or other.

Laboratory Tests

Deep-frozen, platelet-poor plasma was analyzed at a central laboratory. Each center monitored the dosage of unfractionated heparin with use of the local reagent used for determining the activated partial-thromboplastin time. Anti–factor Xa activity was measured centrally with the use of an amidolytic assay.

Complete blood counts were obtained before enrollment; platelet counts were performed on days 4, 8, 14, and 21.

Statistical Analysis

Well-documented methods of determining sample size²⁷ were used to ensure that the study would have at least 80 percent statistical power for the two major objectives: to show that reviparin administered twice daily for one week is not inferior to unfractionated heparin and that reviparin administered once daily for four weeks is superior to unfractionated heparin for the treatment of deep-vein thrombosis. Assuming a 30 percent rate of refusal to undergo follow-up venography or other major violations of the protocol, a total of 1134 patients (378 per group) were needed.

The Mantel–Haenszel statistic was used according to the method of Yanagawa²⁸ to compare reviparin administered twice daily with unfractionated heparin and reviparin administered once daily with unfractionated heparin. To ensure an overall alpha level of 0.05, a closed testing procedure was used; in the first step, the hypothesis that twice-daily reviparin is not inferior to unfractionated heparin was tested at the 0.025 level (the noninferiority test).

With regard to recurrent venous thromboembolism, the limit of noninferiority of twice-daily reviparin was defined by an incidence rate no more than 3 percentage points higher than that in the group receiving unfractionated heparin. This hypothesis of noninferiority was tested according to the method of Blackwelder.²⁹ The superiority of once-daily reviparin over unfractionated heparin was determined by the Mantel–Haenszel test. The same procedure was used to ensure an overall alpha level of 0.05. Except for those calculated by the noninferiority test, all reported P values are two-sided. All treatment effects were described as differences in incidence and estimates of relative risk with two-sided 97.5 percent confidence intervals.

Results

Base-Line Characteristics

The study was carried out between July 1996 and November 1998. A total of 2607 consecutive patients with symptomatic acute deep-vein thrombosis of the leg, confirmed by venography, were screened, and 1148 were enrolled. Eleven enrolled patients never received study medication and were not included in the analysis; thus, the study population consisted of 1137 patients. A total of 375 patients were assigned to receive unfractionated heparin, 388 to receive reviparin twice daily, and 374 to receive reviparin once daily; of these, 961 had two venograms that could be evaluated (321, 328, and 312 patients, respectively). There were no significant differences between the treatment groups with regard to base-line characteristics (Table 1).

View this table: [in this window] [in a new window]   Table 1. Base-Line Characteristics of the Patients.

 
Efficacy

The proportions of patients who responded to treatment according to the venographic criteria were 40.2 percent (129 of 321) in the group receiving unfractionated heparin, 53.4 percent (175 of 328) in the group receiving reviparin twice daily, and 53.5 percent (167 of 312) in the group receiving reviparin once daily. The superiority of reviparin administered twice daily (P<0.001) and the superiority of reviparin administered once daily (P<0.001), as compared with unfractionated heparin, were demonstrated. Reviparin administered twice daily was significantly superior to unfractionated heparin (relative likelihood of regression of thrombus, 1.28; 97.5 percent confidence interval, 1.08 to 1.52), as was reviparin administered once daily (relative likelihood, 1.29; 97.5 percent confidence interval, 1.08 to 1.53) (Table 2).

View this table: [in this window] [in a new window]   Table 2. Venographic Assessment of the Three Treatment Groups.

 
Recurrent thromboembolic events occurred in 7 of 388 patients (1.8 percent) receiving reviparin twice daily (relative risk of recurrence, 0.28; 97.5 percent confidence interval, 0.11 to 0.74) and in 13 of 374 patients (3.5 percent) receiving reviparin once daily (relative risk, 0.55; 97.5 percent confidence interval, 0.24 to 1.16), as compared with 24 of 375 patients (6.4 percent) receiving unfractionated heparin (Table 3). Since the upper limit of the 97.5 percent confidence interval for the difference was less than 0, reviparin administered twice daily was significantly more effective than unfractionated heparin. Reviparin administered once daily and unfractionated heparin did not differ significantly with regard to recurrent thromboembolic events (P=0.07).

View this table: [in this window] [in a new window]   Table 3. Clinical End Points.

 
There was a high degree of statistical correlation (P<0.001) between venographic results and clinical recurrence. Among 490 patients classified as having no response on venography, 34 (7.0 percent) had a recurrent venous thromboembolic event, whereas only 5 (1.0 percent) of 476 patients classified as having a response had such an event. A plot of the time to a recurrent event in the three treatment groups is shown in Figure 1.

View larger version (14K): [in this window] [in a new window]   Figure 1. Kaplan–Meier Analysis of the Time to the Recurrence of Thromboembolic Events over a Period of 90 Days in the Three Treatment Groups. I bars represent 95 percent confidence intervals at 20 and 80 days.

 
The target range for the activated partial-thromboplastin time was reached in 67 percent of the patients treated with unfractionated heparin within 24 to 48 hours. The international normalized ratio reached the therapeutic range on day 5 in the group receiving unfractionated heparin and in the group receiving reviparin twice daily. In the group receiving reviparin once daily, oral anticoagulant therapy was initiated on day 22 and reached therapeutic levels on day 30.

Safety

Major hemorrhagic complications occurred during the first 21 days in two patients receiving unfractionated heparin, in one patient receiving reviparin twice daily, and in one patient receiving reviparin once daily (Table 4). During the observation period from day 22 to day 90, two patients receiving reviparin twice daily and one patient receiving reviparin once daily had major bleeding. There were minor bleeding episodes during the first 21 days in 16 patients receiving unfractionated heparin, 13 patients receiving reviparin twice daily, and 15 patients receiving reviparin once daily. During days 22 to 90, there were 10 episodes of minor bleeding among patients receiving unfractionated heparin, 11 among those receiving reviparin twice daily, and 9 among those receiving reviparin once daily. The incidence of bleeding was similar in the three treatment groups (Table 4).

View this table: [in this window] [in a new window]   Table 4. Adverse Events.

 
During the 90-day study period, 11 patients receiving unfractionated heparin died, as did 9 receiving reviparin twice daily and 15 receiving reviparin once daily. A total of 6 of 42, 5 of 41, and 9 of 54 patients with cancer died in the groups receiving unfractionated heparin, reviparin twice daily, and reviparin once daily, respectively (Table 4). Two patients receiving unfractionated heparin, none receiving reviparin twice daily, and two receiving reviparin once daily had heparin-associated thrombocytopenia, defined as a platelet count below 100,000 per cubic millimeter or a drop of more than 50 percent in the platelet count during administration of the drug. Pulmonary embolism developed in one of the patients who had thrombocytopenia two days after the discontinuation of unfractionated heparin; by this time, his platelet count had returned to normal.

Discussion

Our study demonstrates that two regimens of a low-molecular-weight heparin, reviparin, are more effective than a regimen of unfractionated heparin for the initial treatment of deep-vein thrombosis, as assessed by a greater reduction in thrombus size on sequential venography. The clinical end points, recurrent deep-vein thrombosis and new pulmonary embolism, were also less frequent in the two groups receiving reviparin, and this reduction in clinical events was significantly correlated with the venographic results.

The clinical and venographic results were similar in the groups receiving reviparin twice daily and once daily; once-daily reviparin was given without a vitamin K antagonist for the first 21 days and thus could be a safe and effective alternative for patients with a contraindication to oral anticoagulant therapy.

The primary objective of anticoagulant therapy for deep-vein thrombosis is the prevention of fatal pulmonary embolism. However, the use of this end point in clinical trials is impractical because of the large number of patients who would need to be enrolled, and symptomatic recurrences of deep-vein thrombosis or nonfatal symptomatic pulmonary embolism are therefore frequently used to compare treatment effects. Clinically detected new symptomatic thromboses are encountered less frequently than recurrent thrombosis, which is detected by venography, after initial treatment, as is well demonstrated in trials of prevention of thrombosis in patients at high risk.^30,31,32 This discrepancy is even more pronounced with regard to pulmonary embolism. Up to 50 percent of patients with an acute deep-vein thrombosis have asymptomatic pulmonary embolism at presentation.^26,33 Subsequent symptoms of pulmonary embolism during treatment may be due to a preexisting pulmonary embolism rather than to new disease. It is thus inappropriate to rely on clinical end points alone to assess the efficacy of therapy for deep-vein thrombosis.

The venographic assessment of the change in thrombus size over time is a surrogate marker for regression, but it permits the evaluation of treatment effects in every patient with two venograms. The use of a venographic score,²⁵ which allows for definitions of regression, progression, and unchanged thrombosis, ensures an objective evaluation. The definition of response to therapy (a reduction of at least 30 percent in the Marder score) has been used in previous studies and has thus been validated.^26,34 Our study revealed a correlation between clinical outcome and change in thrombus size. The rate of venographically determined response can therefore be used confidently as a more objective way of assessing the efficacy of antithrombotic agents than reliance on clinical symptoms. Our data also reveal that patients without a venographically evident response to therapy are at higher risk for symptomatic deep-vein thrombosis and pulmonary embolism.

The degree of regression of the thrombus may depend on the duration of treatment.^26,34 In a trial in which venography was performed after 14 days,²⁶ the response rate was 33 percent in the group assigned to unfractionated heparin and 42 percent in the group assigned to low-molecular-weight heparin. In the present trial, in which the venograms were obtained on day 21, the response rate was 40.2 percent in the group receiving unfractionated heparin and 53.4 percent in the group receiving reviparin twice daily.

In the Columbus Study,¹⁶ reviparin was as effective as unfractionated heparin for the prevention of recurrent venous thromboembolism. The better efficacy of reviparin in the present study may be explained by the fact that in the patients in the Columbus Study there was a longer interval between the occurrence of symptoms and the initiation of treatment. Prolonged treatment with reviparin administered once daily without initial treatment with a vitamin K antagonist did not lead to an increased rate of recanalization of occluded veins, but it can be regarded as a safe and effective alternative to a regimen of reviparin administered twice daily with vitamin K antagonists for the early treatment of deep-vein thrombosis.

Supported by a grant from Knoll, Ludwigshafen, Germany.

^* Other members of the CORTES (Clivarin: Assessment of Regression of Thrombosis, Efficacy, and Safety) study group are listed in the Appendix.

Source Information

From the International Institute of Thrombosis and Vascular Diseases, Frankfurt, Germany.

Address reprint requests to Dr. Breddin at the International Institute of Thrombosis and Vascular Diseases, Ferdinand-Schrey-Weg 6, D-60598 Frankfurt, Germany, or at breddin{at}em.uni-frankfurt.de.

References

1. Salzman EW, Deykin D, Shapiro RM, Rosenberg R. Management of heparin therapy: controlled prospective trial. N Engl J Med 1975;292:1046-1050. [Abstract]
2. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990;322:1260-1264. [Abstract]
3. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986;315:1109-1114. [Abstract]
4. Bernardi E, Piccioli A, Oliboni G, Zuin R, Girolami A, Prandoni P. Nomograms for the administration of unfractionated heparin in the initial treatment of acute thromboembolism -- an overview. Thromb Haemost 2000;84:22-26. [ISI][Medline]
5. Albada J, Nieuwenhuis HK, Sixma JJ. Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin): results of a double-blind randomized study. Circulation 1989;80:935-940. [Free Full Text]
6. A randomised trial of subcutaneous low molecular weight heparin (CY 216) compared with intravenous unfractionated heparin in the treatment of deep vein thrombosis: a collaborative European multicentre study. Thromb Haemost 1991;65:251-256. [ISI][Medline]
7. Holmström MC, Berglund MC, Granquist BS, Bratt G, Törnebohm E, Lockner D. Fragmin once or twice daily subcutaneously in the treatment of deep venous thrombosis of the leg. Thromb Res 1992;67:49-55. [CrossRef][ISI][Medline]
8. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992;326:975-982. [Abstract]
9. Lindmarker P, Holmström 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;72:186-190. [ISI][Medline]
10. Prandoni P, Lensing AWA, Büller HR, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992;339:441-445. [CrossRef][ISI][Medline]
11. Lopaciuk S, Meissner AJ, Filipecki S, et al. Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial. Thromb Haemost 1992;68:14-18. [ISI][Medline]
12. Simonneau G, Charbonnier B, Decousus H, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med 1993;153:1541-1546. [Abstract]
13. Pini M, Aiello S, Manotti C, et al. Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thromb Haemost 1994;72:191-197. [ISI][Medline]
14. Fiessinger JN, Lopez-Fernandez M, Gatterer E, et al. Once-daily subcutaneous dalteparin, a low molecular weight heparin, for the initial treatment of acute deep vein thrombosis. Thromb Haemost 1996;76:195-199. [ISI][Medline]
15. Partsch H, Kechavarz B, Mostbeck A, Kohn H, Lipp C. Frequency of pulmonary embolism in patients who have iliofemoral deep vein thrombosis and are treated with once- or twice-daily low-molecular-weight heparin. J Vasc Surg 1996;24:774-782. [CrossRef][ISI][Medline]
16. The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997;337:657-662. [Free Full Text]
17. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996;334:677-681. [Free Full Text]
18. 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. N Engl J Med 1996;334:682-7. [Erratum, N Engl J Med 1997;337:1251.]
19. Charbonnier BA, Fiessinger JN, Banga JD, Wenzel E, d'Azemar P, Sagnard L. Comparison of a once daily with a twice daily subcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis. Thromb Haemost 1998;79:897-901. [ISI][Medline]
20. Spiro TE. A multicenter clinical trial comparing once and twice-daily subcutaneous enoxaparin and intravenous heparin in the treatment of acute deep vein thrombosis. Thromb Haemost 1997;77:Suppl:373-374.abstract 
21. Simonneau G, Sors H, Charbonnier B, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997;337:663-669. [Free Full Text]
22. Leizorovicz A, Simonneau G, Decousus H, Boissel JP. 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;309:299-304. [Free Full Text]
23. Lensing AWA, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins: a meta-analysis. Arch Intern Med 1995;155:601-607. [Abstract]
24. van den Belt AGM, Prins MH, Lensing AWA, et al. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism (Cochrane review). In: Cochrane database system review. No. 1. London: Update Software, 2000.
25. Marder VJ, Soulen RL, Atichartakarn V, et al. Quantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy. J Lab Clin Med 1977;89:1018-1029. [ISI][Medline]
26. Kirchmaier CM, Wolf H, Schäfer H, Ehlers B, Breddin HK. Efficacy of low molecular weight heparin administered intravenously or subcutaneously in comparison with intravenous unfractionated heparin in the treatment of deep venous thrombosis. Int Angiol 1998;17:135-145. [ISI][Medline]
27. Farrington CP, Manning G. Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat Med 1990;9:1447-1454. [ISI][Medline]
28. Yanagawa T, Tango T, Hiejima Y. Mantel-Haenszel-type tests for testing equivalence or more than equivalence in comparative clinical trials. Biometrics 1994;50:859-64. [Erratum, Biometrics 1995;51:392.]
29. Blackwelder WC. "Proving the null hypothesis" in clinical trials. Control Clin Trials 1982;3:345-353. [CrossRef][ISI][Medline]
30. The European Fraxiparin Study (EFS) Group. Comparison of a low molecular weight heparin and unfractionated heparin for the prevention of deep vein thrombosis in patients undergoing abdominal surgery. Br J Surg 1988;75:1058-1063. [ISI][Medline]
31. Kakkar VV, Cohen AT, Edmonson RA, et al. Low molecular weight heparin versus standard heparin for prevention of venous thromboembolism after major abdominal surgery. Lancet 1993;341:259-265. [CrossRef][ISI][Medline]
32. Dahl OE, Andreassen G, Aspelin T, et al. Prolonged thromboprophylaxis following hip replacement surgery -- results of a double-blind, prospective, randomised, placebo-controlled study with dalteparin. Thromb Haemost 1997;77:26-31. [ISI][Medline]
33. Huisman MV, Büller HR, ten Cate JW, et al. Unexpected high prevalence of silent pulmonary embolism in patients with deep venous thrombosis. Chest 1989;95:498-502. [Free Full Text]
34. Harenberg J, Schmidt JA, Koppenhagen K, Tolle A, Huisman MV, Buller HR. Fixed-dose, body weight-independent subcutaneous LMW heparin versus adjusted dose unfractionated intravenous heparin in the initial treatment of proximal venous thrombosis. Thromb Haemost 2000;83:652-656. [ISI][Medline]

The following institutions and investigators participated in the study. Executive Committee: H.K. Breddin, V.V. Kakkar, V. Hach-Wunderle, and R. Nakov; Writing Committee: H.K. Breddin, P. Bacher, F. Misselwitz, R. Nakov, S. Schäffer, P. Volkers, and V.V. Kakkar; Adjudication Committee: W. Hach, J. Müller, G. Hör, and V. Hach-Wunderle; Safety Committee: H. Schäfer, H. Boccalon, and V. Puchmayer; Coordination and Data Management: R. Zeitouni-Savarino; and participating centers: Argentina — M. Lucas, H. Caldevilla, D. Sfarcich, S. Giancinti, J.M. Ceresetto, and D. Onorati, Buenos Aires; A. Bossio, Mar del Plata; J. Pozzi and H. Mazzurco, Rosario; E. Pataro, Avellaneda; and V. Diego and M. Serrao, Santa Fé; Austria — E. Pilger, Graz; Czech Republic — V. Cepelák and O. Mayer, Plzen; J. Bruthans, D. Karetová, Prague; V. Procházka, Ostrava; B. Semrád, Brno-Bohunice; M. Soucek, Brno; M Scudlová, Olomouc; P. Stverák, Ostrava-Poruba; and J. Trefanec, Praha-Motol; Denmark — S. Kiilerich, Hillerød; and M.S. Jensen, Viborg; Germany — G. Pöhlmann, Jena; E. Altmann, O. Altmann, and S.M. Schellong, Dresden; J. Baitsch, Bad Säckingen; G. Bechara, Westerstede; A. Beck, Konstanz; H.J. Bröker, Kassel; J.J. Bronisch, Erfurt; C. Diehm, Karlsbad-Langensteinbach; R. Bauersachs, E. Lindhoff-Last, W. Mondorf, and R. Hopf, Frankfurt/Main; I. Flessenkämper, C. Heinrichs, H. Landgraf, and J. Marsch, Berlin; W. Habscheid, Ostfildern; W. Häßler, Saalfeld/Saale; D. Hey, Bietigheim-Bissingen; H. Keller, Rastatt; F. Meier, Rudolstadt; M. Meisel, Halle; G. Naumann, Rostock; C. Ranke, Herne; J. Ranft, Bottrop; W.J. Rexroth and U. Stein, Heidelberg; C. Rühlmann, Leipzig; J.A. Schmidt, Magdeburg; T. Störk, Stuttgart; F. Tató, Munich; C. Thalhammer, Berlin-Buch; J.A. Timmermann, Essen; G. Tippel, Speyer; P. Waldhausen, Krefeld; M. Wiersbitzky, Greifswald; and T. Wuppermann, Darmstadt-Eberstadt; Hungary — G. Acsády and A. Káli, Budapest; S. Timár, Kecskemét; É. Meskó, Kerepestarcsa; S. Kornél, Székesfehérvár; I. Sárosi, H. Losonczy, and L. Kollár, Pécs; T. Gunther, Györ; F. Halmos, Kaposvár; F. Tárnok, Zalaegerszeg; and L. Mátyás, Miskolc; Israel — G. Lugassy, Ashkelon; A. Berrebi, Rehovot; A. Eldor, Tel Aviv; D. Varon, Tel Hashomer; B. Brenner and D. Attias, Haifa; and M. Lahav and M. Lishner, Kfar Saba; Poland — S. Lopaciuk, W. Noszczyk, and S. Filipecki, Warsaw; M. Bielawiec, Bialystok; Z. Mackiewicz, Bydgoszcz; L. Ciesielski, Lodz; J. Michalak, Lublin; W. Witkiewicz, Wroclaw; E. Czestochowska, Gdynia; and K. Zawilska, Poznan; Norway — P.M. Sandset, Oslo; United Kingdom — A.T. Cohen, D. Quinlan, R.A. Edmondson, and A. Nicolaides, London; G. Dolan, Nottingham; S. Dzumhur, Goodmayes; C. Fox, Northampton; H.H. Kadr, Romford; G. Lip, Birmingham; D.J. Newberry, Ashford; J.E. Pohl, Leicester; A. Sutton, Guildford; and A. Wood, Cardiff.

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