Key words: anticoagulant therapy; bed rest; deep vein thrombosis; pulmonary embolism; recurrences; vena cava filters

Transcription

1 Bed Rest or Ambulation in the Initial Treatment of Patients With Acute Deep Vein Thrombosis or Pulmonary Embolism* Findings From the RIETE Registry Javier Trujillo-Santos, MD, PhD; Emilio Perea-Milla, MD, PhD; Alberto Jiménez-Puente, MD, PhD; Emilio Sánchez-Cantalejo, MD, PhD; Jorge del Toro, MD; Enric Grau, MD, PhD; and Manuel Monreal, MD, PhD; for the RIETE Investigators Background: Traditionally, many patients with acute deep vein thrombosis (DVT) are treated not only by anticoagulation therapy but additionally by strict bed rest, which is aimed at reducing the risk of pulmonary embolism (PE) events. However, this risk has not been subjected to empirical verification. Patients and methods: The Registro Informatizado de la Enfermedad TromboEmbólica is a Spanish registry of consecutively enrolled patients with objectively confirmed, symptomatic acute DVT or PE. In this analysis, the clinical characteristics, details of anticoagulant therapy, and clinical outcomes of enrolled patients with and without strict bed rest prescribed during the first 15 days were compared. Patients in whom ambulation was not possible were not included in this analysis. Results: A total of 2,650 patients entered the study (DVT, 2,038 patients; PE, 612 patients). Of these patients, 1,050 DVT patients (52%) and 385 PE patients (63%) were prescribed strict bed rest. New events of symptomatic, objectively confirmed PE developed during the 15-day study period in 11 patients with DVT (0.5%) and 4 patients with PE (0.7%). Five of these 15 patients (33%) died as a result of their PE. Age < 65 years (odds ratio [OR], 3.1; 95% confidence interval [CI], 0.98 to 11) and cancer (OR, 3.0; 95% CI, 0.98 to 9.1) were associated with an increased rate of new PEs. There were not significant differences between bedridden and ambulant patients in terms of new PE events, fatal PE, or bleeding complications. Conclusions: Our findings confirm those from previous reports suggesting that bed rest has no influence on the risk of developing PE among patients with acute DVT of the lower limbs. In addition, our findings show for the first time the lack of influence of bed rest even in patients presenting with acute submassive PE. (CHEST 2005; 127: ) Key words: anticoagulant therapy; bed rest; deep vein thrombosis; pulmonary embolism; recurrences; vena cava filters Abbreviations: CI confidence interval; DVT deep vein thrombosis; LMWH low-molecular-weight heparin; OR odds ratio; PE pulmonary embolism; RIETE Registro Informatizado de la Enfermedad TromboEmbólica; VTE venous thromboembolism In addition to anticoagulant therapy, many physicians have been taught to prescribe strict bed rest for the first 2 to 4 days in patients with acute venous thromboembolism (VTE), because of the fear of *From the Unidades de Medicina Interna (Dr. Trujillo-Santos), de Investigación (Dr. Perea-Milla), and de Evaluación y Control (Dr. Jiménez-Puente), Hospital Costa del Sol, Marbella, Málaga, Spain; Escuela Andaluza de Salud Pública (Dr. Sánchez-Cantalejo), Granada, Spain; Servicio de Medicina Interna (Dr. del Toro), Hospital Gregorio Marañón, Madrid, Spain; Servicio de Hematología (Dr. Grau), Hospital Lluis Alcanyis, Xátiva, Valencia, Spain; and Servicio de Medicina Interna (Dr. Monreal), Hospital Universitari Germans Trias i Pujol, Badalona. Spain. A list of RIETE investigators is given in the Appendix. dislodging clots that may result in fatal pulmonary embolism (PE). However, this theoretical assumption has never been subjected to empirical verifica- This study was supported by Aventis Pharma with an unrestricted educational grant and by a grant (RedRespira-ISCiii-RTIC-03/ 11) from Red Respira of the Instituto Carlos III. Manuscript received July 29, 2004; revision accepted November 9, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Manuel Monreal, MD, PhD, Servicio de Medicina Interna, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; mmonreal@ns.hugtip.scs.es CHEST / 127 / 5/ MAY,

2 tion. The current guidelines from the American College of Chest Physicians, 1,2 based on evidence from clinical trials, recommend that all patients with VTE be treated acutely with either unfractionated heparin or body weight-adjusted low-molecularweight heparin (LMWH) for at least 5 days with bridging to long-term therapy for at least 3 months using an oral anticoagulant agent. There is no mention of bed rest. Three small-sized trials 3 5 did not find significant differences between bed rest vs compression and walking in patients with proximal deep vein thrombosis (DVT) of the lower limbs. However, until now no studies have been published in patients presenting with acute PE. The Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) was initiated in March 2001 to record the current clinical management of VTE within Spanish hospitals. It is an ongoing, multicenter, observational registry of consecutively enrolled patients, which is designed to gather and analyze data on the treatment patterns and outcomes in patients with symptomatic, objectively confirmed, acute VTE. 6 9 The aim of the present observational study was to evaluate the differences in clinical outcomes during the first 15 days of VTE therapy among patients treated with strict bed rest vs those who were allowed to ambulate. Patient Entry Criteria Materials and Methods Participating hospitals in the RIETE registry prospectively enroll consecutive patients with symptomatic, acute DVT or PE that has been confirmed by objective tests (ie, for suspected DVT: contrast venography, ultrasonography, impedance plethysmography, or CT scan; for suspected PE: pulmonary angiography, lung scintigraphy, or helical CT scan). Patients are excluded if they are currently participating in a therapeutic clinical trial or if they will not be available for follow-up. For this specific analysis, patients with immobility prior to VTE development, initial therapy with unfractionated heparin or thrombolytic therapy, massive PE, or recent bleeding were not included, since they could not have been allocated to walking. Clinical Definitions Immobilization was defined as total bed rest or being sedentary for up to 3 days, with or without bathroom privileges. Fatal PE, in the absence of autopsy, was defined as death within 48 h of PE diagnosis, in the absence of any alternative cause of death. Bleeding complications were classified as major if they were overt, and were associated with a decrease in the hemoglobin level of 2.0 g/dl ( 20 g/l), required a transfusion of 2U blood, or the bleeding was retroperitoneal or intracranial. Any other clinically relevant bleeding events was considered to be minor. Study End Points The parameters recorded by the registry comprise details of each patient s baseline characteristics, clinical status including any coexisting or underlying conditions such as chronic heart or lung disease, the use of antiplatelet drugs, thromboprophylaxis received prior to study enrollment, treatment received on VTE diagnosis, and the outcome during the first 3 months of therapy. Details of VTE treatment recorded by the registry included information on the dose, duration, and type of treatment (eg, anticoagulant drugs, antiplatelet drugs, and physical methods) received by the patients. The major outcome for this study was the development of symptomatic, objectively confirmed PE events during the first 15 days of therapy. Secondary outcomes were the development of bleeding complications and death. Follow-up All patients were followed up for the first 3 months. Any signs or symptoms suggesting VTE recurrences or bleeding complications were noted during each visit. Each episode of clinically suspected recurrent DVT or PE was documented by repeat compression ultrasonography, venography, lung scanning, helical CT scan, or pulmonary angiography. Data Collection All patients provide oral consent to their participation in the registry, according to the requirements of the ethics committee within each hospital. The data are recorded on to a computerbased case report form by a RIETE registry coordinator at each participating hospital and are submitted to a centralized coordinating center through a secure web site. The coordinators also ensure that eligible patients are consecutively enrolled. Patient identities remain confidential because they are identified by a unique number assigned by the study coordinator center, which is responsible for all data management. The study end points are adjudicated by the RIETE registry coordinators. At regular intervals, data quality is monitored and documented electronically to detect inconsistencies or errors, which are resolved by the coordinators. Data quality is also monitored by periodic visits to participating hospitals by contract research organizations who compare the medical records with data on the secure website, as is the case for most clinical trials. In the event of substantial or unjustifiable inconsistencies from a particular center, patients enrolled from that center are not included in the database. A full data audit is performed at periodic intervals. Statistical Analysis A commercial software package (SPSS, version 11.5; SPSS; Chicago, IL) was used to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs), and a p value of 0.05 was considered to be statistically significant. The significance of a number of clinical variables on the risk of developing new PE events was tested by fitting bivariate proportional hazards models. Candidate variables based on the published literature and on expert opinion were selected from the clinical variables. Results As of November 2003, 5,720 patients with acute VTE have been enrolled at 88 participating hospitals in Spain. Of those patients, 3,070 patients were not included in the present analysis due to the following reasons: immobility prior to VTE development, 1,552 patients; initial therapy with unfractionated 1632 Clinical Investigations

3 heparin, 670 patients; upper-extremity venous DVT, 205 patients; massive PE with hemodynamic instability, 173 patients; recent bleeding, 151 patients; thrombolytic therapy, 41 patients; other causes, 338 patients. Thus, the study included 2,650 patients, 1,118 men and 1,532 women, aged 14 to 98 years (mean age, 66 years). Of these, 2,038 patients (77%) had acute symptomatic DVT and 612 had PE. DVT Patients Of the 2,038 patients with acute DVT, 1,050 (52%) were prescribed bed rest. Patients immobilized in bed were more often women than those who ambulated (Table 1). Underlying conditions such as cancer or recent surgery, and the use of antiplatelets or corticosteroids occurred significantly more often in patients remaining in bed. They experienced proximal DVT more often and received lower doses of LMWH as initial therapy. Eleven of these 2,038 patients (0.5%) developed symptomatic, objectively confirmed PE events during the 15-day study period. Four of these 11 patients (36%) died as a consequence of the PE. There were no differences in the PE rate between patients immobilized in bed (7 of 1,050 patients; 0.7%) and those allowed to ambulate (4 of 988; 0.4%), as shown in Table 2. There were no differences either in the bleeding rate or the mortality rate. PE Patients Of the 612 patients with PE, 385 (63%) were immobilized in bed. These patients had arterial Po 2 levels of 60 mm Hg significantly more often than those who were allowed to ambulate, and they received lower LMWH doses as initial therapy (Table 3). Five immobilized patients (1.3%) and no patients ambulating died from their initial PE episode. Four patients (two in each group) developed new PE episodes, and one died (Table 2). There were no differences in the rate of either fatal PE or major bleeding complications, but both minor bleeding and overall mortality were significantly more common in patients immobilized in bed (Table 2). Univariate Analysis A univariate analysis including all patients with DVT and PE revealed that age 65 years and cancer were associated with a significantly increased risk of developing new PE events (Table 4). When considered overall, 9 of 1,435 patients (0.6%) who were immobilized in bed, and 6 of 1,215 patients (0.5%) allowed to ambulate developed new PEs. Unexpectedly, there were no significant differences in the doses of LMWH between patients whose PE recurred and those whose PE did not (Table 4). Discussion Our findings, extracted from a large series of consecutive patients with VTE demonstrate that there are no differences in the rate of new PE episodes between patients who have been immobi- Table 1 Clinical Characteristics of the 2,038 Patients With DVT* Characteristics Bed Rest (n 1,050) Ambulation (n 988) OR (95% CI) p Value Clinical Male gender 543 (52) 575 (58) 0.8 ( ) Age 65 yr 620 (59) 586 (59) 1.0 ( ) NS Body weight 70 kg 591 (56) 597 (60) 0.8 ( ) NS Risk factors for VTE Previous VTE 222 (21) 211 (21) 1.0 ( ) NS Cancer 250 (24) 198 (20) 1.2 ( ) 0.05 Surgery 189 (18) 143 (14) 1.3 ( ) 0.05 Underlying diseases Chronic lung disease 116 (11) 91 (9.2) 1.2 ( ) NS Heart failure 31 (3.0) 33 (3.3) 0.9 ( ) NS Antiplatelet therapy 152 (15) 103 (10) 1.4 ( ) 0.01 Corticosteroid therapy 85 (8.1) 49 (5.0) 1.7 ( ) VTE Proximal DVT 861 (82) 762 (77) 1.3 ( ) 0.01 Painful leg 957 (91) 915 (93) 0.8 ( ) NS Swollen leg 1021 (98) 949 (96) 1.4 ( ) NS Initial therapy Inferior vena cava filter 9 (0.9) 6 (0.6) 1.4 ( ) NS LMWH Mean ( SD) dose, IU/kg/d Dose 175 IU/kg/d 520 (50) 350 (36) 1.8 ( ) *Values given as No. (%), unless otherwise indicated. NS not significant. CHEST / 127 / 5/ MAY,

4 Table 2 Clinical Outcomes Within 15 Days After VTE Diagnosis* Outcomes Bed Rest Ambulation OR (95% CI) p Value DVT patients (n 1050) (n 988) New PE 7 (0.7) 4 (0.4) 1.6 ( ) NS Fatal new PE 3 (0.3) 1 (0.1) 2.8 (0.3 71) NS Recurrent DVT 8 (0.8) 2 (0.2) 3.8 (0.7 26) NS Recurrent VTE 15 (1.4) 6 (0.6) 2.4 ( ) NS Minor bleeding 7 (0.7) 13 (1.3) 0.5 ( ) NS Major bleeding 11 (1.0) 7 (0.7) 1.5 ( ) NS Fatal bleeding 1 (0.1) 0 NS Overall death 14 (1.3) 6 (0.6) 2.2 ( ) NS PE patients (n 385) (n 227) New PE 2 (0.5) 2 (0.9) 0.6 ( ) NS Fatal new PE 0 1 (0.4) NS Fatal initial PE 5 (1.3) 0 NS Recurrent DVT 1 (0.3) 0 NS Recurrent VTE 3 (0.8) 2 (0.9) 0.9 ( ) NS Minor bleeding 10 (2.6) Major bleeding 5 (1.3) 2 (0.9) 1.5 ( ) NS Fatal bleeding 0 0 NS Overall death 14 (3.6) 1 (0.5) 8.5 ( ) 0.01 *Values given as No. (%), unless otherwise indicated. See Table 1 for abbreviation not used in the text. lized in bed and those who are allowed to walk, among either DVT or PE patients. Three small-sized studies 3 5 have suggested that early ambulation does not increase the risk for PE in patients with acute DVT, but ours is the first study revealing similar results in patients presenting with acute PE. This finding may have clinical consequences, since it may make it possible to increase the ambulatory treatment of patients with PE. Traditionally, many physicians have been taught to prescribe strict bed rest in patients with acute VTE, because of the fear that thrombotic masses will break Table 3 Clinical Characteristics of the 612 Patients With PE* Characteristics Bed Rest (n 385) Ambulation (n 227) OR (95% CI) p Value Clinical Male gender 205 (53) 106 (47) 1.3 ( ) NS Age 65 yr 257 (67) 149 (66) 1.0 ( ) NS Body weight 70 kg 205 (53) 126 (55) 0.9 ( ) NS Risk factors for VTE Previous VTE 99 (26) 45 (20) 1.4 ( ) NS Cancer 105 (27) 50 (22) 1.3 ( ) NS Surgery 53 (14) 29 (13) 1.1 ( ) NS Underlying diseases Chronic lung disease 58 (15) 27 (12) 1.3 ( ) NS Heart failure 21 (5.5) 17 (7.5) 0.7 ( ) NS Antiplatelet therapy 50 (13) 32 (14) 0.9 ( ) NS Corticosteroid therapy 23 (6.0) 20 (8.8) 0.7 ( ) NS PE Heart rate 100 beats/min 82 (21) 45 (20) 1.1 ( ) NS Po 2 60 mm Hg 159 (41) 64 (28) 1.8 ( ) Oxygen saturation 90% 127 (33) 64 (22) 1.3 ( ) NS Dyspnea 323 (84) 185 (81) 1.2 ( ) NS Chest pain 206 (54) 109 (48) 1.2 ( ) NS Initial therapy Inferior vena cava filter 13 (3.4) 7 (3.1) 1.1 ( ) NS LMWH Mean ( SD) dose, IU/kg/d Dose 175 IU/kg/d 121 (31) 43 (19) 2.0 ( ) *Values given as No. (%), unless otherwise indicated. See Table 1 for abbreviation not used in the text Clinical Investigations

5 Table 4 Univariate Analysis on the Risk of Developing New PE Among the 2,650 Patients Presenting With VTE* Characteristics New PE (n 15) No New PE (n 2,635) OR (95% CI) p Value Clinical Male gender 11 (73) 1408 (53) 2.4 ( ) NS Age 65 yr 5 (33) 1607 (61) 0.3 ( ) 0.04 Body weight 70 kg 10 (67) 1510 (57) 1.5 ( ) NS Risk factors for VTE Previous VTE 3 (20) 574 (22) 0.9 ( ) NS Cancer 7 (47) 596 (23) 3.0 ( ) 0.03 Surgery 3 (20) 411 (16) 1.4 ( ) NS Underlying diseases Chronic lung disease 7 (47) 1302 (49) 0.9 ( ) NS Heart failure 1 (6.7) 101 (3.8) 1.8 (1.2 14) NS Antiplatelet therapy 3 (20) 334 (13) 1.7 ( ) NS Corticosteroid therapy 1 (6.7) 176 (6.7) 1.0 ( ) NS VTE DVT 11 (73) 2027 (77) 0.8 ( ) NS Initial therapy LMWH Mean ( SD) dose, IU/kg/d NS Dose 175 IU/kg/d 5 (33) 1030 (39) 0.8 ( ) NS Early mobilization 6 (40) 1209 (46) 0.8 ( ) NS *Values given as No. (%), unless otherwise indicated. See Table 1 for abbreviation not used in the text. loose from the deep veins by movement of the leg or the whole body, thereby causing PE. However, this theoretical assumption has not been confirmed. Three randomized trials 3 5 compared strict bed rest with ambulation in patients with acute proximal DVT. A total of 296 patients receiving initial therapy with LMWH were screened for PE at baseline and at days 4 to 9 by lung scanning. Overall, 19 of 149 immobilized patients (13%) and 25 of 147 ambulating patients (17%) developed new perfusion defects, but none of them developed respiratory symptoms. In fact, these studies revealed an exceedingly low incidence of symptomatic PE in patients with proximal DVT. In a series 10 of 1,289 patients with DVT who were treated with LMWH and immediate ambulation, lung scans performed at hospital admission and repeated at day 10 showed new perfusion defects in 77 patients, but only 6 of them (0.5%) had mild pulmonary symptoms. Our study confirms that symptomatic PE events occurring during the first 2 weeks of therapy in patients with either acute DVT or PE are infrequent. However, when they occur they are extremely serious, with one third of such patients dying of their new PE. Five of 35 patients who died during the study period in our series died as a result of their initial PE, and 5 died as a result of recurrent PE. According to our findings, the risk for developing new PE events was significantly increased in patients 65 years of age and in patients with cancer. These results are in agreement with a number of studies that have reported that cancer patients are at higher risk for recurrences, but we have no explanation for the higher rate in patients 65 years of age. The main limitation of the present study is its design, which contains several sources of potential bias. First, we are uncertain whether the patient s underlying condition may have influenced the decision to prescribe ambulation, since 54% of potentially eligible patients were excluded for reasons that are largely consistent with more severe illness. Thus, the failure of ambulation to lead a greater incidence of symptomatic PE than bed rest may reflect the fact that ambulation was prescribed to healthier patients. Nonetheless, in this large number of patients, ambulation appears to have been safe. Second, RIETE is a registry, and the data reported are not from a prospective randomized, controlled trial. As in most registries, patients were not randomly allocated but received the prescription of their doctor s choice. Each physician had a different mode of approach regarding bed rest, and some of them probably were not properly trained to follow the appropriate guidelines for treating VTE. Third, a more robust study would require the evaluation of all patients for both symptomatic and asymptomatic recurrences. Certainly, this would have a large impact on the conclusions. However, the strength of this report is the prospective collection of data from actual practice, from a very large number of consecutive patients with objectively confirmed VTE, in whom a diagnosis of recurrent PE had been obtained by strictly applying objective criteria. Although RIETE ( started as a CHEST / 127 / 5/ MAY,

6 Spanish initiative, the goal of RIETE is to improve the treatment of VTE patients through a better understanding of demographics, management, and in-hospital and post-hospital discharge outcomes. Starting as a Spanish initiative in March 2001, currently the registry has been opened to other countries, thus becoming an international registry. In contrast to a randomized controlled trial, there is no imposed experimental intervention. Management is determined solely by physicians. The data that have been captured and reported in the registry will therefore reflect real-world approaches and outcomes in the treatment of VTE. In summary, we conclude that bed rest has no influence on the risk of developing symptomatic PE, in patients presenting with either acute DVT or submassive PE. These PE events are infrequent, but when they occur they may be extremely severe. Members of the RIETE Group Appendix M. Barrón (La Rioja); J. Bugés, C. Falgá, M. Monreal, E. Raguer, A. Raventós, and C. Tolosa (Barcelona); J.I. Arcelus and I. Casado (Granada); R. Barba, C. Fernández-Capitán, J. Gutiérrez, D. Jiménez, P. Rondón, and C. Suárez (Madrid); J.L. Beato (Albacete); A. Blanco, L. López, and R. Tirado (Córdoba); J. Bosco, P. Gallego, and M.J. Soto (Cádiz); J.M. Calvo (Badajoz); F. Conget (Zaragoza); M.C. del Río (Zamora); F. Gabriel, E. Grau, P. Román, and J.A. Todolí (Valencia); F. García Bragado, A. Grau, and S. Soler (Girona); M.R. Gutiérrez and R. Otero (Sevilla); J.A. González-Fajardo (Valladolid); R. Guijarro, J.J. Martín, and J. Trujillo (Málaga); L. Hernández (Alicante); R. Lecumberri, A.L. Sampériz, and G. Tiberio (Navarra); J.L. Lobo (Vitoria); I. López (Asturias); J. Montes (Vigo); J.A. Nieto (Cuenca); M.A. Page (Murcia); J.L. Pérez-Burkhardt (Tenerife); J. Portillo (Ciudad Real); J.F. Sánchez (Cáceres); A. Sánchez (Salamanca); J.A. Torre (La Coruña); F. Uresandi (Bilbao); R. Valle (Cantabria); and F. Pajuelo (Medical Department, Aventis Pharma, Madrid). ACKNOWLEDGMENT: The authors thank S & H Medical Science Service for their logistic and administrative support. References 1 Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2001; 119(suppl): 176S 193S 2 Ansell J, Hirsh J, Dalen J, et al. Managing oral anticoagulant therapy. Chest 2001; 119(suppl):22S 38S 3 Partsch H, Blättler W. Compression and walking versus bed rest in the treatment of proximal deep venous thrombosis with low molecular weight heparin. J Vasc Surg 2000; 32: Aschwanden M, Labs KH, Engel H, et al. Acute deep vein thrombosis: early mobilization does not increase the frequency of pulmonary embolism. Thromb Haemost 2001; 85: Schellong SM, Schwarz T, Kropp J, et al. Bed rest in deep vein thrombosis and the incidence of scintigraphic pulmonary embolism. Thromb Haemost 1999; 82(suppl): Arcelus JI, Monreal M, Caprini JA, et al. The management and outcome of acute venous thrombo-embolism: a prospective registry including 4,011 patients. J Vasc Surg 2003; 38: Monreal M, Suárez C, González-Fajardo JA, et al. Management of patients with acute venous thromboembolism: findings from the RIETE Registry. Pathophysiol Haemost Thromb 2004; 33: Monreal M, López L, Montero M, et al. Venous thromboembolism treatment in the elderly: findings from the RIETE Registry [abstract]. Blood 2003; 102:166a 9 Monreal M, Kakkar AK, Caprini JA, et al. Is the natural history of venous thromboembolism different in surgical and non-surgical patients? Findings from the RIETE Registry [abstract]. Blood 2003; 102:112b 10 Partsch H. Therapy of deep vein thrombosis with low molecular weight heparin, leg compression and immediate ambulation. Vasa 2001; 30: Heit JA, Mohr DN, Silverstein MD, et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 2000; 160: Douketis JD, Foster GA, Crowther MA, et al. Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med 2000; 160: Sorensen HT, Mellemkjaer L, Olsen JH, et al. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343: Prandoni P, Lensing AWA, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: Clinical Investigations