Heparins and Venous Thromboembolism: Current Practice and Future Directions

Paolo Prandoni

doi:10.1055/s-0037-1616246

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2001; 86(01): 488-498
DOI: 10.1055/s-0037-1616246

Research Article

Schattauer GmbH

Heparins and Venous Thromboembolism: Current Practice and Future Directions

Paolo Prandoni

¹Clinica Medica II, University of Padua, Italy

› Institutsangaben

Abstract

Summary

Unfractionated heparin (UFH) in adjusted doses and low-molecularweight heparins (LMWH) in fixed doses are the chosen therapy for the initial treatment of venous thromboembolism. The use of UFH protocols ensures that virtually all patients will promptly achieve the therapeutic range for the activated partial thromboplastin time. However, proper use of UFH requires considerable expertise, can cause inconvenience and has limitations. Unmonitored therapy with subcutaneous LMWH is at least as effective and safe as adjusted-dose UFH, is associated with a considerable reduction of mortality in cancer patients, and permits the treatment of suitable patients in an outpatient setting.

LMWH in high prophylactic doses is more effective than UFH and oral anticoagulants for prevention of postoperative venous thrombosis in major orthopedic surgery. Whether thromboprophylaxis should be continued for a few additional weeks after hospital discharge is controversial. LMWH and UFH are equally effective for prevention of postoperative deep-vein thrombosis in cancer patients. In a recent controlled randomized trial, enoxaparin in high prophylactic doses was an effective and safe measure of thromboprophylaxis in ordinary bedridden patients.

The efficacy and safety of pentasaccharide (the smallest antithrombin binding sequence of heparin) in the treatment and prevention of venous thromboembolic disorders is currently under investigation.

Key words

Unfractionated heparin - low-molecular-weight heparin - deep-vein thrombosis - pulmonary embolism - pentasaccharide

Volltext

Referenzen

References
1 Brandjes DPM, Heijboer H, Büller HR. et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992; 327: 1485-9.
2 Hirsh J, Warkentin TE, Raschke R. et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy and safety. Chest 1998; 114 (Suppl) 489-510.
3 White RH, Zhou H, Mungall D. Effect of weight, sex, age, clinical diagnosis, and thromboplastin reagent on steady-state intravenous heparin requirements. Arch Intern Med 1997; 157: 2468-72.
4 Raschke RA, Reilly BM, Guidry JR. et al. The weight-based heparin dosing normogram compared with a “standard care” normogram. A randomized controlled trial. Ann Intern Med 1993; 119: 874-81.
5 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: 1109-14.
6 Bernardi E, Piccioli A, Oliboni G. et al. Nomograms for the administration of unfractionated heparin in the initial treatment of acute thromboembolism. An overview. Thromb Haemost 2000; 84: 22-6.
7 Cruickshank MK, Levine MN, Hirsh J. et al. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991; 151: 333-7.
8 de Groot MR, Büller HR, ten Cate JW. et al. Use of a heparin nomogram for treatment of patients with venous thromboembolism in a community hospital. Thromb Haemost 1998; 80: 70-3.
9 Hull RD, Raskob GE, Rosenbloom D. et al. Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med 1992; 152: 1589-95.
10 Elliott GC, Hiltunen SJ, Suchyta M. et al. Physician-guided treatment compared with a heparin protocol for deep vein thrombosis. Arch Intern Med 1994; 154: 999-1004.
11 Hommes DW, Bura A, Mazzolai L. et al. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. A meta-analysis. Ann Intern Med 1992; 116: 279-84.
12 Prandoni P, Bagatella P, Bernardi E. et al. Use of an algorithm for administering subcutaneous heparin in the treatment of deep venous thrombosis. Ann Intern Med 1998; 129: 299-302.
13 Anand S, Ginsberg JS, Kearon C. et al. 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: 1677-81.
14 Hull RD, Raskob GE, Brant RF. et al. The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy. Arch Intern Med 1997; 157: 2317-21.
15 Hull RD, Raskob GE, Brant RF. 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: 2562-8.
16 Anand SS, Bates S, Ginsberg JS. et al. Recurrent venous thrombosis and heparin therapy: an evaluation of the importance of early activated partial thromboplastin times. Arch Intern Med 1999; 27: 2029-32.
17 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.
18 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: 677-81.
19 The Columbus Investigators.. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997; 37: 657-62.
20 Levine MN, 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.
21 Baker BA, Adelman MD, Smith PA. et al. Inability of the activated partial thromboplastin time to predict heparin levels. Arch Intern Med 1997; 157: 2475-9.
22 Brill-Edwards P, Ginsberg JS, Johnston M. et al. Establishing a therapeutic range for heparin therapy. Ann Intern Med 1993; 119: 104-9.
23 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: 1260-4.
24 Gallus A, Jackaman J, Tiillett J. et al. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet 1986; 2: 1293-6.
25 White RH, Zhou H, Romano PS. Length of hospital stay for treatment of deep venous thrombosis and the incidence of recurrent thromboembolism. Arch Intern Med 1998; 158: 1005-10.
26 Juergens CP, Semsarian C, Keech AC. et al. Hemorrhagic complications of intravenous heparin use. Am J Cardiol 1997; 80: 150-4.
27 Campbell NRC, Hull RD, Brant R. et al. Aging and heparin-related bleeding. Arch Intern Med 1996; 156: 857-60.
28 Zidane M, Schram MT, Planken EW. et al. Frequency of major hemorrhage in patients treated with unfractionated intravenous heparin for deep venous thrombosis or pulmonary embolism. Arch Intern Med 2000; 160: 2369-73.
29 Nand S, Wong W, Yuen B. et al. Heparin-induced thrombocytopenia with thrombosis: incidence analysis of risk factors and clinical outcomes in 108 consecutive patients treated at a single institution. Am J Hematol 1997; 56: 12-6.
30 Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337: 688-98.
31 Warkentin TE, Levine MN, Hirsh J. et al. Heparin-induced thrombocytopenia in patients with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332: 1330-5.
32 Lensing AWA, Prins MH, Davidson BL. et al. Treatment of deep venous thrombosis with low-molecular-weight heparin: a meta-analysis. Arch Intern Med 1995; 155: 601-7.
33 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: 269-77.
34 Leizorovicz A, Simonneau G, Decousus H. et al. Comparison of efficacy and safety of low-molecular-weight heparins and unfractionated heparin in the initial treatment of deep venous thrombosis: a meta-analysis. Br Med J 1994; 309: 299-304.
35 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: 441-5.
36 Hull RD, Raskob GL, Pineo GF. et al. Subcutaneous low molecular-weight heparin compared with intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326: 975-82.
37 Lopaciuk S, Meissner AJ, Zawilska K. et al. Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial. Thromb Haemostas 1992; 68: 14-8.
38 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: 1541-6.
39 Lindmarker P, Holmstrom M, Granquist S. et al. Comparison of once-daily subcutaneous Fragmin with continuous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemostas 1994; 72: 186-90.
40 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 Haemostas 1996; 76: 195-9.
41 Luomanmaki K, Granqvist S, Hallert C. et al. A multicentre comparison of once-daily subcutaneous dalteparin (low-molecular-weight heparin) and continuous intravenous heparin in the treatment of deep vein thrombosis. J Int Med 1996; 240: 85-92.
42 van den Belt AGM, Bossuyt PMM, Prins MH, Büller HR. Replacing in-patient care by outpatient care in the treatment of deep venous thrombosis. An economic evaluation. Thromb Haemost 1998; 97: 259-63.
43 O’Brien B, Levine M, Willan A. et al. Economic evaluation of outpatient treatment with low-molecular-weight heparin for proximal vein thrombosis. Arch Intern Med 1999; 159: 2298-304.
44 Harrison L, McGinnis J, Crowther M. et al. Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin. Arch Intern Med 1998; 158: 2001-3.
45 Mattiasson I, Berntorp E, Bornhov S. et al. Out-patient treatment of acute deep vein thrombosis. Int Angiol 1998; 17: 146-50.
46 Grau E, Real E, Pastor E. et al. Home treatment of deep vein thrombosis: a two-year experience of a single institution. Haematologica 1998; 83: 438-41.
47 Boccalon H, Elias A, Chalé JJ. et al, for the Vascular Midi-Pyrenees Network Group.. Clinical outcome and cost of hospital vs home treatment of proximal deep vein thrombosis with a low-molecular-weight heparin. Arch Intern Med 2000; 160: 1769-73.
48 Wells PS, Kovacs MJ, Bormanis J. et al. Expanding eligibility for outpatient treatment of deep venous thrombosis and pulmonary embolism with low-molecular-weight heparin: a comparison of patient self-injection with homecare injection. Arch Intern Med 1998; 158: 1809-12.
49 Hyers TM, Agnelli G, Hull RD. et al. Antithrombotic therapy for venous thromboembolic disease. Chest 1998; 114 Suppl 561-78.
50 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; 7: 663-9.
51 Kovacs MJ, Anderson D, Morrow B. et al. Outpatient treatment of pulmonary embolism with dalteparin. Thromb Haemost 2000; 83: 209-11.
52 Hull R, Delmore T, Carter C. et al. Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med 1982; 306: 189-94.
53 Monreal M, Lafoz E, Olive A. et al. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin. Thromb Haemost 1994; 71: 7-11.
54 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: 191-7.
55 Das SK, Cohen AT, Edmondson RA. et al. Low-molecular-weight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomised trial. World J Surg 1996; 20: 521-7.
56 Lopaciuk S, Bielska-Falda H, Noszczyk W. et al. Low molecular weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis. Thromb Haemost 1999; 81: 26-31.
57 Gonzales-Fajardo JA, Arreba E, Castrodeza J. et al. Venographic comparison of subcutaneous low-molecular-weight heparin with oral anticoagulant therapy in the long-term treatment of deep venous thrombosis. J Vasc Surg 1999; 30: 283-92.
58 Veiga F, Escribà A, Maluenda P. et al. Low molecular weight heparin (enoxaparin) versus oral anticoagulant therapy (acenocoumarol) in the long-term treatment of deep venous thrombosis in the elderly: a randomized trial. Thromb Haemost 2000; 84: 559-64.
59 Monreal M. Long-term treatment of venous thromboembolism with low-molecular-weight heparin. Curr Opin Pulm Med 2000; 6: 326-9.
60 Gould MK, Dembitzer AD, Doyle RL. 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: 800-9.
61 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. Arch Intern Med 2000; 160: 181-8.
62 Samama MM, Bara L, Walenga J. Comparative mechanism of action and pharmacokinetics of pentasaccharide and LMW heparins. 16th International Congress on Thrombosis. State of the Art. Porto, May 5-8 2000 pp. 99-101.
63 Clagett GP, Anderson Jr FA, Geerts WA. et al. Prevention of venous thromboembolism. Chest 1998; 114 (Suppl. 05) 531-60.
64 Consensus Statement.. Prevention of venous thromboembolism. Intern Angiol 1997; 16: 3-38.
65 Stratton MA, Anderson FA, Bussey HI. et al. Prevention of venous thromboembolism. Adherence to the 1995 American College of Chest Physicians Consensus Guidelines for surgical patients. Arch Intern Med 2000; 160: 334-40.
66 Anderson DR, O’Brien BJ, Levine MN. et al. Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty. Ann Intern Med 1993; 19: 1105-12.
67 Hull R, Raskob G, Pineo G. et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med 1993; 329: 1370-6.
68 RD Heparin Arthroplasty Group.. RD Heparin compared with warfarin for prevention of venous thromboembolic disease following total hip or knee arthroplasty. J Bone Joint Surg 1994; 76A: 1174-85.
69 Hamulyak K, Lensing AWA, van der Meer J. et al., for the Fraxiparine Oral Anticoagulant Study Group.. Subcutaneous low-molecular-weight heparin or oral anticoagulants for the prevention of deep-vein thrombosis in elective hip and knee replacement?. Thromb Haemost 1995; 74: 1428-31.
70 Leclerc JR, Geerts WH, Desjardins L. et al. Prevention of venous thromboembolism after knee arthroplasty. A randomized, double-blind trial comparing enoxaparin with warfarin. Ann Intern Med 1996; 124: 619-26.
71 Francis CW, Pellegrini VD, Totterman S. et al. Prevention of deep-vein thrombosis after total hip arthroplasty. Comparison of warfarin and dalteparin. J Bone Joint Surg 1997; 79A: 1365-72.
72 Hull RD, Pineo GF, Francis C. et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized comparison. The North American Fragmin Trial Investigators. Arch Intern Med 2000; 160: 2199-207.
73 Colwell CW, Collis DK, Paulson R. et al. Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthroplasty. Evaluation during hospitalization and three months after discharge. J Bone Joint Surg 1999; 81-A: 932-40.
74 Hull RD, Raskob GE, Pineo GF. et al. Subcutaneous low-molecular-weight heparin vws warfarin for prophylaxis of deep vein thrombosis after hip or knee implantation. An economic perspective. Arch Intern Med 1997; 157: 298-303.
75 Bergqvist D, Benoni G, Bjorgell O. et al. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med 1996; 335: 696-700.
76 Planes A, Vochelle N, Darmon JY. et al. Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomized comparison of enoxaparin versus placebo. Lancet 1996; 348: 224-8.
77 Lassen MR, Borris LC, Anderson BS. et al. Efficacy and safety of prolonged thromboprophylaxis with a low molecular weight heparin (Dalteparin) after total hip arthroplasty. The Danish Prolonged Prophylaxis Study. Thromb Res 1998; 89: 281-7.
78 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 (Fragmin). Thromb Haemost 1997; 77: 26-31.
79 Hull RD, Pineo GF, Francis C. et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs. in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients. A double-blind, randomised comparison. Arch Intern Med 2000; 160: 2208-15.
80 Manganelli D, Pazzagli M, Mazzantini D. et al. Prolonged prophylaxis with unfractionated heparin is effective to reduce delayed deep vein thrombosis in total hip replacement. Respiration 1998; 65: 369-74.
81 Warwick D, Williams MH, Bannister GC. Death and thromboembolic disease after total hip replacement. A series of 1162 cases with no routine chemical prophylaxis. J Bone Joint Surg 1995; 77-B: 6-10.
82 Leclerc JR, Gent M, Hirsh J. et al., for the Canadian Collaborative Group.. The incidence of symptomatic venous thromboembolism during and after prophylaxis with enoxaparin. Arch Intern Med 1998; 158: 873-8.
83 Heit JA, Elliott G, Trowbridge AA. et al., for the Ardeparin Arthroplasty Study Group.. Ardeparin sodium for extended out-of-hospital prophylaxis against venous thromboembolism after total hip or knee replacement. Ann Intern Med 2000; 132: 853-61.
84 Kearon C, Hirsh J. Starting prophylaxis postoperatively. Arch Intern Med 1995; 4: 366-72.
85 Hull RD, Brant RF, Pineo GF. et al. Pre-operative vs post-operative initiation of low-molecular-weight heparin prophylaxis against venous thromboembolism in patients undergoing elective hip replacement. Arch Intern Med 1999; 159: 137-41.
86 Palareti G, Borghi B, Coccheri S. et al. Postoperative versus preoperative initiation of deep-vein thrombosis prophylaxis with a low-molecular-weight heparin (Nadroparin) in elective hip replacement. Clin Appl Thromb Hemost 1996; 2: 18-24.
87 Jorgensen PS, Strandberg C, Wille-Jorgensen P. et al. Early preoperative thromboprophylaxis with Klexane in hip fracture surgery: a placebo-controlled study. Clin Appl Thromb Hemost 1998; 4: 141-2.
88 Eriksson B, Wille-Jorgensen P, Kalebo P. et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997; 337: 1329-35.
89 Eriksson BI, Lindbratt JS, Kalebo P. et al. Methro II: Dose-response study of the novel oral, direct thrombin inhibitor, H 376/95 and its subcutaneous formulation melagatran, compared with dalteparin as thromboembolic prophylaxis after total hip or total knee replacement. Haemostasis 2000; 30 (Suppl. 01) 20-1.
90 Prandoni P. Antithrombotic strategies in patients with cancer. Thromb Haemost 1997; 78: 141-4.
91 Godwin J. Use of low molecular weight heparins in malignancy-related thromboembolic disorders: a clinical review. Clin Appl Thromb Hemost 1996; 2 (Suppl. 01) 28-34.
92 Enoxacan Study group.. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. Br J Surg 1997; 84: 1099-103.
93 Bergqvist D, Burmark US, Flordal PA. et al. Low molecular weight heparin started before surgery as prophylaxis against deep vein thrombosis: 2500 versus 5000 XaI units in 2070 patients. Br J Surg 1995; 82: 496-501.
94 Di Carlo V, Agnelli G, Prandoni P. et al. Dermatan sulphate for the prevention of postoperative venous thromboembolism in patients with cancer. Thromb Haemost 1999; 82: 30-34.
95 Thromboembolic Risk Factors Consensus Group.. Risk of and prophylaxis for venous thromboembolism in hospital patients. Br Med J 1992; 79: 1-17.
96 Dumas R, Woitinas F, Kutnowski M. et al. A multicentre, double-blind, randomized study to compare the safety and efficacy of once-daily ORG 10172 and twice-daily low-dose heparin in preventing deep-vein thrombosis in patients with acute ischaemic stroke. Age Ageing 1994; 23: 512-6.
97 McCarthy ST, Turner J. Low-dose subcutaneous heparin in the prevention of deep-vein thrombosis and pulmonary emboli following acute stroke. Age Ageing 1986; 15: 84-8.
98 Turpie AGG, Gent M, Côte R. et al. A low molecular weight heparinoid compared with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. Ann Intern Med 1992; 117: 353-7.
99 Turpie AGG, Levine MN, Hirsh J. et al. A double-blind randomized trial of ORG 10172 low molecular weight heparinoid in the prevention of deep vein thrombosis in thrombotic stroke. Lancet 1987; 1: 523-6.
100 Belch JJ, Lowe GDO, Ward AG. et al. Prevention of deep venous thrombosis in medical patients by low-dose heparin. Scott Med J 1981; 26: 115-7.
101 Gallus AS, Hirsh J, Tuttle RJ. et al. Small subcutaneous doses of heparin in prevention of venous thrombosis. N Engl J Med 1973; 288: 545-51.
102 Samama M, Cohen AT, Darmon JY. et al. for the Prohylaxis in Medical Patients with Enoxaparin Study Group. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999; 341: 793-800.
103 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: 14-9.