Thromboprophylaxis in medical patients: the role of low-molecular-weight heparin

Summary

Many hospitalised medical patients are at increased risk of venous thromboembolism (VTE). Consensus statements recommend that such patients be assessed for risk of VTE on admission to hospital and receive thromboprophylaxis where appropriate. However, VTE prophylaxis is not widely used in medical patients. One explanation is that assessing medical patients’ risk of VTE is complicated. The risk depends not only on the current illness but also on multiple intrinsic factors, and a variety of strategies for identifying patients who should receive thromboprophylaxis have been suggested. Thromboprophylaxis with unfractionated heparin (UFH) has proved to be effective in reducing the incidence of deep-vein thrombosis and overall mortality in medical patients. Clinical trial evidence, including a meta-analysis, suggests that thromboprophylaxis with low-molecular-weight heparin (LMWH) is at least as effective as with UFH, and also has the advantage of fewer bleeding complications. In particular, two large, randomised clinical trials – Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) and Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT) – showed that thromboprophylaxis with the LMWHs enoxaparin (40 mg s.c. once daily) or dalteparin (5,000 IU once daily) is more effective than placebo and well tolerated in medical patients. In addition, the Thromboembolism-Prevention in Cardiopulmonary Diseases with Enoxaparin (THE-PRINCE) trial showed that enoxaparin treatment was as effective as UFH. These studies provide solid evidence for the widespread use of thromboprophylaxis in medical patients.

Keywords

Venous thromboembolism - deep-vein thrombosis - pulmonary embolism - thromboprophylaxis - low-molecular-weight heparin - medical patients

• References

• 1 Geerts WH, Heit JA, Clagett GP. et al. Prevention of venous thromboembolism. Chest 2001; 119 (01) Suppl: 132S-75S.
• 2 Sandler DA, Martin JF. Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis?. J R Soc Med 1989; 82: 203-5.
• 3 Baglin TP, White K, Charles A. Fatal pulmonary embolism in hospitalised medical patients. J Clin Pathol 1997; 50: 609-10.
• 4 Hull RD, Raskob GE, LeClerc JR. et al. The diagnosis of clinically suspected venous thrombosis. Clin Chest Med 1984; 05: 439-56.
• 5 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.
• 6 Agnelli G, Sonaglia F. Prevention of venous thromboembolism. Thromb Res 2000; 97: V49-62.
• 7 Thromboembolic Risk Factors (THRIFT) Consensus Group. Risk of and prophylaxis for venous thromboembolism in hospital patients. Br Med J 1992; 305: 567-74.
• 8 Bouthier J. The venous thrombotic risk in nonsurgical patients. Drugs 1996; 52 Suppl: (Suppl. 07) 16-29.
• 9 Gensini GF, Prisco D, Falciani M. et al. Identification of candidates for prevention of venous thromboembolism. Semin Thromb Hemost 1997; 23: 55-67.
• 10 Verstraete M, Prentice CRM, Samama M. et al. A European view on the North American fifth consensus on antithrombotic therapy. Chest 2000; 117: 1755-70.
• 11 Nicolaides AN, Breddin HK, Fareed J. et al. Prevention of venous thromboembolism. International Consensus Statement. Guidelines compiled in accordance with the scientific evidence. Int Angiol 2001; 20: 1-37.
• 12 Anderson FA, Wheeler HB, Goldberg RJ. et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. Arch Intern Med 1991; 151: 933-8.
• 13 Anderson FA, Wheeler HB. Physician practices in the management of venous thromboembolism: a community-wide survey. J Vasc Surg 1992; 16: 707-14.
• 14 Collins R, Scrimgeour A, Yusuf S. et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomised trials in general, orthopedic, and urologic surgery. N Engl J Med 1988; 318: 1162-73.
• 15 The SCATI (Studio sulla Calciparina nell’Angina e nella Trombosi Ventricolare nell’Infarto) Group. Randomised controlled trial of subcutaneous calcium-heparin in acute myocardial infarction. Lancet 1989; 02: 182-6.
• 16 Sandercock PAG, van den Belt AGM, Lindley RI. et al. Antithrombotic therapy in acute ischaemic stroke: an overview of the completed randomised trials. J Neurol Neurosurg Psychiatry 1993; 56: 17-25.
• 17 Warlow C, Ogston D, Douglas AS. Deep venous thrombosis of the legs after strokes. Br Med J 1976; 01: 1178-83.
• 18 Cairns JA, Theroux P, Lewis Jr HD . et al. Antithrombotic agents in coronary artery disease. Chest 2001; 119 (01) Suppl: 228S-52S.
• 19 Belch JJ, Lowe GDO, Ward AG. et al. Prevention of deep vein thrombosis in medical patients by low-dose heparin. Scott Med J 1981; 26: 115-17.
• 20 Prandoni P. Prevention of thrombosis in patients with malignancy. Cardiovascular Risk Factors 1995; 05: 299-304.
• 21 Gladman DD, Urowitz MB. Venous syndromes and pulmonary embolism in systemic lupus erythematosus. Ann Rheum Dis 1980; 39: 340-3.
• 22 Prandoni P, Polistena P, Bernardi E. et al. Upper-extremity deep vein thrombosis. Risk factors, diagnosis and complications. Arch Intern Med 1997; 157: 57-62.
• 23 De Cicco M, Matovic M, Balestreri L. et al. Central venous thrombosis: an early and frequent complication in cancer patients bearing long-term silastic catheter. A prospective study. Thromb Res 1997; 86: 101-13.
• 24 Joynt GM, Kew J, Gomersall CD. et al. Deep venous thrombosis caused by femoral venous catheters in critically ill adult patients. Chest 2000; 117: 178-83.
• 25 Mian NZ, Bayly R, Schreck DM. et al. Incidence of deep venous thrombosis associated with femoral venous catheterization. Acad Emerg Med 1997; 04: 1118-21.
• 26 Goodnough LT, Saito H, Manni A. et al. Increased incidence of thromboembolism in stage IV breast cancer patients treated with a five-drug chemotherapy regimen. A study of 159 patients. Cancer 1984; 54: 1264-8.
• 27 Levine MN, Gent M, Hirsh J. et al. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med 1988; 318: 404-7.
• 28 Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 1991; 09: 286-94.
• 29 Pritchard KI, Paterson AHG, Paul NA. et al., for the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomised trial of adjuvant therapy for women with breast cancer. J Clin Oncol 1996; 14: 2731-7.
• 30 von Tempelhoff GF, Niemann F, Schneider DM. et al. Blood rheology during chemotherapy in patients with ovarian cancer. Thromb Res 1998; 90: 73-82.
• 31 Laffan M, Tuddenham E. Science, medicine and the future: assessing thrombotic risk. Br Med J 1998; 317: 520-3.
• 32 Meijers JCM, Tekelenburg WLH, Bouma BN. et al. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000; 342: 696-701.
• 33 von dem Borne PAK, Meijers JCM, Bouma BN. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995; 86: 3035-42.
• 34 National Institutes of Health: Prevention of venous thromboembolism and pulmonary embolism. NIH Consensus Development. JAMA 1986; 256: 744-9.
• 35 Samama MM, Cohen AT, Darmon JY. et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341: 793-800.
• 36 Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000; 160: 3415-20.
• 37 Clagett GP, Reisch JS. Prevention of venous thromboembolism in general surgical patients. Results of meta-analysis. Ann Surg 1988; 208: 227-40.
• 38 Hirsh J. Is the dose of warfarin prescribed by American physicians unnecessarily high?. Arch Intern Med 1987; 147: 769-71.
• 39 Bern MM, Lokich JJ, Wallach SR. et al. Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomized prospective trial. Ann Intern Med 1990; 112: 423-8.
• 40 Bern MM, Bothe Jr A, Bistrian B. et al. Prophylaxis against central vein thrombosis with low-dose warfarin. Surgery 1986; 99: 216-21.
• 41 Bona RD, Sivjee KY, Hickey AD. et al. The efficacy and safety of oral anticoagulation in patients with cancer. Thromb Haemost 1995; 74: 1055-8.
• 42 Bern MM, Bothe Jr A, Bistrian BR. et al. Effects of low-dose warfarin on antithrombin III levels in morbidly obese patients. Surgery 1983; 94: 78-83.
• 43 Cade JF. High risk of the critically ill for venous thromboembolism. Crit Care Med 1982; 10: 448-50.
• 44 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.
• 45 Gårdlund B. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. The Heparin Prophylaxis Study Group. Lancet 1996; 347: 1357-61.
• 46 Halkin H, Goldberg J, Modan M. et al. Reduction of mortality in general medical inpatients by low-dose heparin prophylaxis. Ann Intern Med 1982; 96: 561-5.
• 47 Ibarra-Pérez C, Lau-Cortés E, Colmenero-Zubiate S. et al. Prevalence and prevention of deep vein thrombosis of the lower extremities in high-risk pulmonary patients. Angiology 1988; 39: 505-13.
• 48 International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569-81.
• 49 Bergmann JF, Caulin C. Heparin prophylaxis in bedridden patients. Lancet 1996; 348: 205-6.
• 50 Schuurman B, den Heijer M, Nijs AM. Thrombosis prophylaxis in hospitalised medical patients: does prophylaxis in all patients make sense?. Neth J Med 2000; 56: 171-6.
• 51 Dahan R, Houlbert D, Caulin CE. et al. Prevention of deep vein thrombosis in elderly medical in-patients by a low molecular weight heparin: a randomized double-blind trial. Haemostasis 1986; 16: 159-64.
• 52 Fraisse F, Holzapfel L, Couland JM. et al. Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. The Association of Non-University Affiliated Intensive Care Specialist Physicians of France. Am J Respir Crit Care Med 2000; 161: 1109-14.
• 53 Leizorovicz A, Cohen AT, Turpie AGG. et al. A randomized placebo controlled trial of dalteparin for the prevention of venous thromboembolism in 3706 acutely Ill medical patients: the PREVENT medical thromboprophylaxis study. Journal of Thrombosis and Haemostasis. 2003 01. Suppl 1: Abstract number OC 396.
• 54 Bath PMW, Lindenstrom E, Boysen G. et al. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial. Lancet 2001; 358: 702-10.
• 55 Bergmann JF, Neuhart E. A multicenter randomized double-blind study of enoxaparin compared with unfractionated heparin in the prevention of venous thromboembolic disease in elderly in-patients bedridden for an acute medical illness. The Enoxaparin in Medicine Study Group. Thromb Haemost 1996; 76: 529-34.
• 56 Lechler E, Schramm W, Flosbach CW. The venous thrombotic risk in non-surgical patients: epidemiological data and efficacy/safety profile of a low-molecular-weight heparin (enoxaparin). The Prime Study Group. Haemostasis 1996; 26 Suppl: (Suppl. 02) 49-56.
• 57 Kleber FX, Witt C, Vogel G. et al. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003; 145: 614-21.
• 58 Green D, Lee MY, Lim AC. et al. Prevention of thromboembolism after spinal cord injury using low-molecular-weight heparin. Ann Intern Med 1990; 113: 571-4.
• 59 Harenberg J, Roebruck P, Heene DL. Subcutaneous low-molecular-weight heparin versus standard heparin and the prevention of thromboembolism in medical inpatients. The Heparin Study in Internal Medicine Group. Haemostasis 1996; 26: 127-39.
• 60 Alikhan R, Cohen AT. A safety analysis of thromboprophylaxis in acute medical illness. Thromb Haemost 2003; 89: 590-1.
• 61 Cohen AT, Davidson BL, Gallus AS. et al. Fondaparinux for the prevention of VTE in acutely ill medical patients. Blood. 2003 102. Abstract number 42.
• 62 Mismetti P, Laporte-Simitsidis S, Tardy B. et al. Prevention of venous thromboembolism in internal medicine with unfractionated or lowmolecular-weight heparins: a meta-analysis of randomised clinical trials. Thromb Haemost 2000; 83: 14-19.
• 63 Bergmann JF, Mouly S. Thromboprophylaxis in medical patients: focus on France. Semin Thromb Hemost 2002; 28 Suppl: (Suppl. 03) 51-5.
• 64 Tapson VF, Decousus H, Piovella F. et al., for the IMPROVE investigators. A multinational observational cohort study in acutely ill medical patients of practices in prevention of venous thromboembolism: findings of the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE). Blood. 2003 102. Abstract number 1154..
• 65 Pechevis M, Detournay B, Pribil C. et al. Economic evaluation of enoxaparin vs. placebo for the prevention of venous thromboembolism in acutely ill medical patients. Value Health 2000; 03: 389-96.
• 66 Lloyd AC, Anderson PM, Quinlan DJ. et al. Economic evaluation of the use of enoxaparin for thromboprophylaxis in acutely ill medical patients. J Med Econ 2001; 04: 99-113.
• 67 Lamy A, Wang X, Kent R. et al. Economic evaluation of the MEDENOX trial: A Canadian perspective. Can Respir J 2002; 09: 169-77.