Heparin and Low-Molecular-Weight Heparin Therapy for Venous Thromboembolism: Will Unfractionated Heparin Survive?

Recent improvements in clinical trials methodology and the use of accurate objective tests to detect venous thromboembolism (VTE) have made it possible to carry out a series of randomized trials to evaluate various treatments for VTE. The results of these trials have resolved many of the uncertainties a clinician confronts in selecting the appropriate course of anticoagulant therapy. These trials have shown that the intensity of both initial heparin treatment and long-term anticoagulant therapy must be sufficient to prevent unacceptable rates of recurrence of VTE. Patients with proximal deep vein thrombosis who receive inadequate anticoagulant therapy have a risk of clinically evident, objectively documented recurrent VTE that approaches 20% to 25%. The need for adequate therapy with heparin and the importance of monitoring blood levels of the effect of heparin have been established. The importance of achieving adequate heparinization was suggested by a nonrandomized trial in 1972 and randomized trials in the 1980s have confirmed this finding. Furthermore, randomized trials have demonstrated the importance of achieving adequate heparinization early in the course of therapy.

Unfractionated heparin by continuous intravenous infusion has provided an effective therapy for more than half a century, but the need to monitor therapy and establish therapeutic levels is a fundamental problem. It is evident that validated heparin protocols are more successful in establishing adequate heparinization than intuitive ordering by the clinician. However, even with the best of care using a heparin protocol, some patients treated with intravenous heparin will receive subtherapeutic treatment. In this context, subtherapeutic treatment reflects a practical limitation of the use of unfractionated heparin, rather than a poor standard of care. Furthermore, it is recognized that the practical difficulties associated with heparin administration are compounded by the substantive practical difficulties of standardizing activated partial thromboplastin time (aPTT) testing and the therapeutic range.

Our findings have emphasized the confounding effect that initial heparin treatment has on long-term outcome. In all trials of long-term treatment, it is imperative that the initial therapy is of adequate intensity and duration; failure to administer adequate initial treatment may lead to a poor outcome that is falsely attributed to the long-term therapy under evaluation.

Treatment with low-molecular-weight heparin (LMWH), which does not require monitoring or dose finding, has largely replaced unfractionated heparin for the initial management of VTE. Efficacy in terms of recurrent VTE or extension of thrombus has been at least as good with LMWH as unfractionated heparin and there is evidence that the incidence of major bleeding, heparin-induced thrombocytopenia, and osteoporosis are less with LMWH as compared with unfractionated heparin. Although unfractionated heparin may survive as a treatment option for acute VTE, its use has been largely supplanted by LMWH.

Venous thromboembolism - heparin - low-molecular-weight heparin

REFERENCES

• 1 Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg.  Arch Surg. 1972;  104 134-144
• 2 Wheeler H B, O'Donnell J A, Anderson Jr F A et al.. Occlusive impedance phlebography: a diagnostic procedure for venous thrombosis and pulmonary embolism.  Prog Cardiovasc Dis. 1974;  17 199-205
• 3 Hull R D, Hirsh J, Sackett D L et al.. Combined use of leg scanning and impedance plethysmography in suspected venous thrombosis: an alternative to venography.  N Engl J Med. 1977;  296 1497-1500
• 4 Hull R D, Carter C J, Jay R M et al.. The diagnosis of acute, recurrent, deep-vein thrombosis; a diagnostic challenge.  Circulation. 1983;  67 901-906
• 5 Dalen J E, Brooks H L, Johnson L W et al.. Pulmonary angiography in acute pulmonary embolism: indications, techniques, and results in 367 patients.  Am Heart J. 1971;  81 175-185
• 6 Brookstein J J, Silver T M. The angiographic differential diagnosis of acute pulmonary embolism.  Radiology. 1974;  110 25-33
• 7 Hull R D, Hirsh J, Carter C et al.. Diagnostic value of ventilation-perfusion lung scanning in patients with suspected pulmonary embolism.  Chest. 1985;  88 819-828
• 8 The PIOPED Investigators .Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA. 1990 263: 2753-2759
• 9 Salzman E W, Deykin D, Shapiro R M et al.. Management of heparin therapy: Controlled prospective trial.  N Engl J Med. 1975;  292 1046-1050
• 10 Glazier R L, Crowell E B. Randomized prospective trial of continuous vs intermittent heparin therapy.  JAMA. 1976;  236 1365-1367
• 11 Mant M J, O'Brien B D, Thong K L et al.. Haemorrhagic complications of heparin therapy.  Lancet. 1977;  1 1133-1135
• 12 Hull R D, Raskob G E, 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
• 13 Brandjes D P, Heijboer H, Büller H R et al.. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis.  N Engl J Med. 1992;  327 1485-1489
• 14 Raschke R A, Reilly B M, Guidry J R et al.. The weight-based heparin dosing nomogram compared with a ‘standard care’ nomogram.  Ann Intern Med. 1993;  119 874-881
• 15 Hull R D, Delmore T, Genton E et al.. Warfarin sodium versus low-dose heparin treatment of venous thrombosis.  N Engl J Med. 1979;  301 855-858
• 16 Basu D, Gallus A, Hirsh J et al.. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time.  N Engl J Med. 1972;  287 324-327
• 17 Bara L, Billaud E, Gramond G et al.. Comparative pharmacokinetics of a low molecular weight heparin (PK 10 169) and unfractionated heparin after intravenous and subcutaneous administration.  Thromb Res. 1985;  39 631-636
• 18 Barzu T, Molho P, Tobelem G et al.. Binding of heparin and low molecular weight heparin fragments to human vascular endothelial cells in culture.  Nouv Rev Fr Haematol. 1984;  26 243-247
• 19 Bjornsson T, Wolfram B S, Kitchell B B. Heparin kinetics determined by three assay methods.  Clin Pharmacol Ther. 1982;  31 104-113
• 20 Theroux P, Waters D, Lam J et al.. Reactivation of unstable angina after the discontinuation of heparin.  N Engl J Med. 1992;  327 141-145
• 21 Granger C B, Miller J M, Bovill E G et al.. Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes.  Circulation. 1995;  91 1929-1935
• 22 Hoppensteadt D, Walenga J M, Fasanella A et al.. TFPI antigen levels in normal human volunteers after intravenous and subcutaneous administration of unfractionated heparin and a low molecular weight heparin.  Thromb Res. 1995;  77 175-185
• 23 Levine M, Hirsh J, Gent M et al.. A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin.  Arch Intern Med. 1994;  154 49-56
• 24 Fennerty A, Thomas P, Backhouse G et al.. Audit of control of heparin treatment.  BMJ. 1985;  290 27-28
• 25 Wheeler A P, Jaquiss R D, Newman J H. Physician practices in the treatment of pulmonary embolism and deep-venous thrombosis.  Arch Intern Med. 1988;  148 1321-1325
• 26 Cruickshank M K, Levine M N, Hirsh J et al.. A standard heparin nomogram for the management of heparin therapy.  Arch Intern Med. 1991;  151 333-337
• 27 Hull R D, Raskob G E, Brant R F et al.. Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis.  Arch Intern Med. 1997;  157 2562-2568
• 28 Hull R D, Raskob G E, Rosenbloom D et al.. Optimal therapeutic level of heparin therapy in patients with venous thrombosis.  Arch Intern Med. 1992;  152 1589-1595
• 29 Brill-Edwards P, Ginsberg J, Johnston M et al.. Establishing a therapeutic range for heparin therapy.  Ann Intern Med. 1993;  119 104-109
• 30 Hull R D, Raskob G E, 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
• 31 Campbell N R, Hull R D, Brant R F et al.. Aging & heparin related bleeding.  Arch Intern Med. 1996;  156 857-859
• 32 Warkentin T E, Kelton J G. Heparin-induced thrombocytopenia.  Prog Hemost Thromb. 1991;  10 1-34
• 33 Warkentin T E, Kelton J G. Temporal aspects of heparin-induced thrombocytopenia.  N Engl J Med. 2001;  344 1286-1292
• 34 Kelton J G, Sheridan D, Brain H et al.. Clinical usefulness of testing for a heparin-dependent platelet aggregation factor in patients with suspected heparin-associated thrombocytopenia.  J Lab Clin Med. 1984;  103 606-612
• 35 Greinacher A, Michels I, Krefel V et al.. A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia.  Thromb Haemost. 1991;  66 734-736
• 36 Chong B H, Burgess J, Ismail F. The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia.  Thromb Haemost. 1993;  69 344-350
• 37 Arepally G, Reynolds C, Tomaski A et al.. Comparison of PF4/heparin ELISA assay with the [[14]C] serotonin release assay in the diagnosis of heparin-induced thrombocytopenia.  Am J Clin Pathol. 1995;  104 648-654
• 38 Warkentin T E. Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia: recommendations of the College of American Pathologists.  Arch Pathol Lab Med. 2002;  126 1415-1423
• 39 Warkentin T E. Current agents for the treatment of patients with heparin-induced thrombocytopenia.  Curr Opin Pulm Med. 2002;  8 405-412
• 40 Hirsh J, Warkentin T E, Shaughnessy S G et al.. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety.  Chest. 2001;  119(suppl) 64-94
• 41 Anand S, Ginsberg J, Kearon C, Gent M, Hirsh J. The relation between the activated partial thromboplastin time response and recurrence in patients with venous thrombosis treated with continuous intravenous heparin.  Arch Intern Med. 1996;  156 1677-1681
• 42 Hull R D, Raskob G E, Pineo G F 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
• 43 Sacks H, Berrier J, Reitman D, Ancora-Beck V, Chalmers T. Meta-analyses of randomized controlled trials.  N Engl J Med. 1987;  316 450-455
• 44 Greenland S. A critical look at some popular meta-analytic methods.  Am J Epidemiol. 1994;  140 290-296
• 45 Olkin I. A critical look at some popular meta-analytic methods.  Am J Epidemiol. 1994;  140 297-299
• 46 Hull R D, Raskob G E, Brant R F et al.. The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy.  Arch Intern Med. 1997;  157 2317-2321
• 47 Topol E J, Galliff R M, Welsman H F et al.. Randomized trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months.  Lancet. 1994;  343 881-886
• 48 The GUSTO Angiographic Investigators .The effects of tissue plasminogen activator, streptokinase or both on coronary artery patency, ventricular function and survival after acute myocardial infarction. N Engl J Med. 1993 329: 71615-71622
• 49 Late Assessment of Thrombolytic Efficacy (LATE) .Study with alteplase 6-24 hours after onset of acute myocardial infarction. Lancet. 1993 342: 759-766
• 50 Prandoni P, Lensing A WA, Büller H R et al.. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis.  Lancet. 1992;  339 441-445
• 51 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
• 52 Elliott C G, Hiltunen S, Suchyta M et al.. Physician-guided treatment compared with a heparin protocol for deep-vein thrombosis.  Arch Intern Med. 1994;  154 999-1004
• 53 Raschke R A, Gollihare B, Peirce J C. The effectiveness of implementing the weight-based nomogram as a practice guideline.  Arch Intern Med. 1996;  156 1645-1649
• 54 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
• 55 Koopman M MW, 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;  334 682-687
• 56 Hirsh J, Levine M N. Low molecular weight heparin.  Blood. 1992;  79 1-17
• 57 Fareed J, Walenga J M, Hoppensteadt D, Huan S, Racanelli A. Comparative study on the in vitro and in vivo activities of seven low-molecular-weight heparins.  Haemostasis. 1988;  18(suppl 3) 3-15
• 58 Bara L, Samama M M. Pharmacokinetics of low molecular weight heparins.  Acta Chir Scand. 1988;  543(suppl) 65-72
• 59 Briant L, Caranobe C, Saivin S et al.. Unfractionated heparin and CY 216 pharmacokinetics and bioavailabilities of the anti-factor X_a and II_a effects after intravenous and subcutaneous injection in the rabbit.  Thromb Haemost. 1989;  61 348-353
• 60 Andersson L-O, Barrowcliffe T W, Holmer E, Johnson E A, Soderstrøm G. Molecular weight dependency of the heparin potentiated inhibition of thrombin and activated factor X. Effect of heparin neutralization in plasma.  Thromb Res. 1979;  15 531-541
• 61 Fareed J, Walenga J M, Racanelli A, Hoppensteadt D, Huan X, Messmore H L. Validity of the newly established low-molecular-weight heparin standard in cross-referencing low-molecular-weight heparins.  Haemostasis. 1988;  3(suppl) 33-47
• 62 Barrowcliffe T W, Curtis A D, Johnson E A, Thomas D P. An international standard for low molecular weight heparin.  Thromb Haemost. 1988;  60 1-7
• 63 Holmer E, Soderberg K, Bergqvist D, Lindahl U. Heparin and its low molecular weight derivatives: anticoagulant and antithrombotic properties.  Haemostasis. 1986;  16(suppl 2) 1-7
• 64 Carter C J, Kelton J G, Hirsh J, Cerskus A, Santos A V, Gent M. The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits.  Blood. 1982;  59 1239-1245
• 65 Cade J F, Buchanan M R, Boneu B et al.. A comparison of the antithrombotic and haemorrhagic effects of low molecular weight heparin fractions: the influence of the method of preparation.  Thromb Res. 1984;  35 613-625
• 66 Andriuoli G, Mastacchi R, Barbanti M, Sarret M. Comparison of the antithrombotic and haemorrhagic effects of heparin and a new low molecular weight heparin in rats.  Haemostasis. 1985;  15 324-330
• 67 Mismetti P, Laporte-Simitsidis S, Tardy B et al.. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials.  Thromb Haemost. 2000;  83 14-19
• 68 Gould M K, Dembitzer A D, Doyle R L et al.. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials.  Ann Intern Med. 1999;  130 800-809
• 69 Dolovich L R, Ginsberg J S, Douketis D ID 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;  160 181-188
• 70 van den Belt A G, Prins M H, Lensing A W et al.. Fixed dose subcutaneous low-molecular weight heparin versus adjusted dose unfractionated heparin for venous thromboembolism.  Cochrane Database Syst Rev. 2000;  CD001100 , Available at www.cochrane.org
• 71 Dalman T C, Lindvall N, Hellgren M. Osteopenia in pregnancy during long-term heparin treatment: a radiological study post-partum.  Br J Obstet Gynaecol. 1990;  97 221-228
• 72 Douketis D ID, Ginsberg J S, Burrows R F et al.. The effects of long-term heparin therapy during pregnancy on bone density: a prospective matched cohort study.  Thromb Haemost. 1996;  75 254-257
• 73 Monreal M, Vinas L, Monreal L, Lavin S, Lafoz E, Angles A M. Heparin-related osteoporosis in rats. A comparative study between unfractionated heparin and a low-molecular-weight heparin.  Haemostasis. 1990;  20 204-207
• 74 Matzsch T, Bergqvist D, Hedner U, Nilsson B, Østergaard P. Effects of low molecular weight heparin and unfragmented heparin on induction of osteoporosis in rats.  Thromb Haemost. 1990;  63 505-509
• 75 Shaughnessy S G, Young E, Deschamps P, Hirsh J. The effects of low molecular weight and standard heparin on calcium loss from fetal rat calvaria.  Blood. 1995;  86 1368-1373
• 76 Pettila V, Kaaja R, Leinonen P, Ekblad U, Kataja M, Ikkala E. Thromboprophylaxis with low-molecular weight heparin (Dalteparin) in pregnancy.  Thromb Res. 1999;  96 275-282
• 77 Pettila V, Leinonen P, Markkola A, Hiilesmaa V, Kaaja R. Postpartum bone mineral density in women treated for thromboprophylaxis with unfractionated heparin or LMW heparin.  Thromb Haemost. 2002;  87 180-181
• 78 Muir J M, Hirsh J, Weitz J L et al.. A histomorphometric comparison of the effects of heparin and low-molecular-weight heparin on cancellous bone in rats.  Blood. 1997;  89 3236-3242
• 79 Warkentin T E, Levine M N, Hirsh J et al.. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.  N Engl J Med. 1995;  332 1374-1376
• 80 Lindhoff-Last E, Nakov R, Misselwitz F et al.. Incidence and clinical relevance of heparin-induced antibodies in patients with deep vein thrombosis treated with unfractionated or low-molecular-weight heparin.  Br J Haematol. 2002;  118 1137-1142
• 81 Wilson S J, Wilbur K, Burton E et al.. Effect of patient weight on the anticoagulant response to adjusted therapeutic dosage of low-molecular-weight heparin for the treatment of venous thromboembolism.  Haemostasis. 2001;  31 42-48
• 82 Hainer J W, Barrett J S, Assaid C A et al.. Dosing in heavy-weight/obese patients with the LMWH, tinzaparin: a pharmacodynamic study.  Thromb Haemost. 2002;  87 817-823
• 83 Harenberg J. Fixed dose versus adjusted-dose low molecular weight heparin for the initial treatment of patients with deep venous thrombosis.  Curr Opin Pulm Med. 2002;  8 383-388
• 84 Forestier F, Daffos F, Capeila-Pavlovsky M. Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy: study by direct fetal blood sampling under ultrasound.  Thromb Res. 1984;  34 557-560
• 85 Andrew M, Cade J, Buchanan M R et al.. Low-molecular-weight heparin does not cross the placenta.  Thromb Haemost. 1983;  50(suppl) 225(abst)
• 86 Omri A, Delaloye F J, Anderson H, Bachmann F. Low molecular weight heparin Novo (LHN-1) does not cross the placenta during the second trimester of pregnancy.  Thromb Haemost. 1989;  61 55-56
• 87 Nelson-Piercy C, Letsky E A, deSwiet M. Low-molecular-weight heparin for obstetric thromboprophylaxis: experience of sixty-nine pregnancies in sixty-one women at high risk.  Am J Obstet Gynecol. 1997;  176 1062-1068
• 88 Wahlberg T B, Kher A. Low molecular weight heparin as thromboprophylaxis in pregnancy. A retrospective analysis from 14 European clinics.  Haemostasis. 1994;  24 55-56
• 89 Ginsberg J S, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy.  Chest. 2001;  119 122S-131S
• 90 Hyers T N, Agnelli G, Hull R D, Weg J G. Antithrombotic therapy for venous thromboembolic disease.  Chest. 2001;  119 176S-193S
• 91 Bratt G, Tornebohm E, Granqvist S, Aberg W, Lockner D. A comparison between low molecular weight heparin (KABI 2165) and standard heparin in the intravenous treatment of deep venous thrombosis.  Thromb Haemost. 1985;  54 813-817
• 92 Holm H A, Ly B, Handeland G F et al.. Subcutaneous heparin treatment of deep venous thrombosis: a comparison of unfractionated and low molecular weight heparin.  Haemostasis. 1986;  16 30-37
• 93 Albada J, Nieuwenhuis H K, Sixma J J. Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin): results of a double-blind randomized study.  Circulation. 1989;  80 935-940
• 94 Bratt G, Aberg W, Johansson M, Tornebohm E, Granqvist S, Lockner D. Two daily subcutaneous injections of Fragmin as compared with intravenous standard heparin in the treatment of deep venous thrombosis (DVT).  Thromb Haemost. 1990;  64 506-510
• 95 Harenberg J, Huck K, Bratsch H et al.. Therapeutic application of subcutaneous low-molecular-weight heparin in acute venous thrombosis.  Haemostasis. 1990;  20(suppl 1) 205-219
• 96 Siegbahan A, Y-Hassan S, Boberg J et al.. Subcutaneous treatment of deep venous thrombosis with low molecular weight heparin. A dose finding study with LMWH-Novo.  Thromb Res. 1989;  55 767-778
• 97 Lopaciuk S, Meissner A J, Filipecki S et al.. Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicentre trial.  Thromb Haemost. 1992;  68 14-18
• 98 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;  72 186-190
• 99 The Columbus Investigators .Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997 337: 657-662
• 100 Decousus H, Leizorovicz F, Parent F et al.. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis.  N Engl J Med. 1998;  338 409-415
• 101 Merli G, Spiro T E, Olsson C G et al.. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease.  Ann Intern Med. 2001;  134 191-202
• 102 Green D, Hull R D, Brant R, Pineo G F. Lower mortality in cancer patients treated with low-molecular-weight versus standard heparin (letter).  Lancet. 1992;  339 1476
• 103 Hull R D, Raskob G E, Rosenbloom D et al.. Treatment of proximal vein thrombosis with subcutaneous low-molecular-weight heparin vs. intravenous heparin. An economic perspective.  Arch Intern Med. 1997;  157 289-294
• 104 van den Belt A GM, Bossuyt P MM, Prins M H, Gallus A S, Büller H R. for the TASMAN Group . Replacing inpatient care by outpatient care in the treatment of deep vein thrombosis: an economic evaluation.  Thromb Haemost. 1998;  79 259-263
• 105 Simonneau G, Sors H, Charbonnier B et al.. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group.  N Engl J Med. 1997;  337 663-669
• 106 Hull R D, Raskob G E, Brant R F et al.. Low-molecular-weight heparin vs. heparin in the treatment of patients with pulmonary embolism.  Arch Intern Med. 2000;  160 229-236
• 107 Kovacs M J, Anderson D, Morrow B, Gray L, Touchie D, Wells P S. Outpatient treatment of pulmonary embolism with dalteparin.  Thromb Haemost. 2000;  83 209-211