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UNFRACTIONATED AND LOW-MOLECULAR-WEIGHT HEPARIN
0025-7125/98 $8.00
CURRENT CONCEPTS OF THROMBOSIS
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UNFRACTIONATED AND LOWMOLECULAR-WEIGHT HEPARIN Comparisons and Current Recommendations Graham F. Pineo, MD, and Russell D. Hull, MB, BS
Unfractionated heparin has been used extensively in the treatment
of venous thromboembolism. More recently, various low-molecularweight heparins (LMWHs) have been evaluated against a number of different controls for these same clinical problems. In a number of countries, the LMWHs have replaced unfractionated heparin for both the prevention and the treatment of venous thromboembolism. This article reviews the problems related to the use of unfractionated heparin, compares the LMWHs with unfractionated heparin, and discusses the role of LMWH in the treatment of venous thromboembolism. UNFRACTIONATED HEPARIN
Unfractionated heparin from either porcine or bovine sources has been available for clinical use for several decades. Although heparin has been studied extensively, much remains uncertain about its mode of action, particularly the nonanticoagulant properties, and some of the complications have only recently been better u n d e r ~ t o o d Because .~~ of the problems and complications related to heparin therapy, there has been great interest in the use of the LMWHs in a variety of clinical settings. The anticoagulant activity of unfractionated heparin depends on a unique pentasaccharide that binds to antithrombin I11 (ATIII) and po-
From the Thrombosis Research Unit, Foothills Hospital; and the University of Calgary, Calgary, Alberta, Canada
MEDICAL CLINICS OF NORTH AMERICA ~~
VOLUME 82 NUMBER 3 * MAY 1998
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tentiates the inhibition of thrombin and activated factor X (X,) by ATIII.52, About one third of all heparin molecules contain the unique pentasaccharide sequence regardless of whether they are low or high in molecular weight fractions. The pentasaccharide sequence confers the molecular high affinity for ATIII.56,70 The remaining two thirds of heparin has minimal anticoagulant activity at the therapeutic concentrations that are used clinically. For the inhibition of thrombin, heparin must form a bridge between thrombin and ATIII, but for the inhibition of factor X,, this bridging is not necessary.57,70 It has been shown that molecules of heparin with fewer than 18 saccharide units are unable to bind thrombin and ATIII simultaneously and as a result cannot catalyze thrombin inhibition.22Heparin fragments with smaller numbers of saccharide units are capable of catalyzing the inhibition of factor X, by ATIII, provided that the high affinity pentasaccharide sequence is present. Unfractionated heparin is unable to inhibit thrombin bound to fibrin, whereas the specific antithrombin agents do Heparin does not inhibit factor X, bound to platelet^.^^ Heparin also catalyzes the inactivation of thrombin by another plasma cofactor (cofactor 11), which acts independently of ATIII.79Heparin has a number of other effects. Those related to the anticoagulant effects of heparin include the release of tissue factor pathway inhibitor42; binding to numerous plasma and platelet proteins, endothelial cells, and leukocytes9,52; suppression of platelet function7I;and increase in vascular permeability." The anticoagulant response to a standard dose of heparin varies widely among patients. Heparin is poorly absorbed from the subcutaneous site, especially at lower doses.'j The plasma clearance of heparin depends on a dose-related renal clearance and a non-dose-related saturable cellular mechanism.'O The binding of heparin to plasma proteins, endothelial cells, and platelets contributes to the unpredictable repatients develop relative heparin resistance and require s ~ o n s e 42 . ~Some , a large dose of heparin to achieve a response in the activated partial thromboplastin time (APTT).55Studies have documented a rebound thrombin generation when heparin is abruptly stopped.34,78 For these reasons, it is necessary to monitor the anticoagulant response of heparin using either the APTT or heparin levels and to titrate the dose to the individual patient. Unless a prescriptive heparin nomogram is used, many patients receive inadequate heparin in the initial 24 to 48 hours of treatment.25, 2y, 84 This inadequate therapy has been shown to increase the incidence 44, 69 Treatment is further of venous thromboembolism during f~llow-up.'~, complicated by the fact that there is a diurnal variation in the APTT response in patients on a constant infusion of intravenous heparin.4'j A peak response is seen at 3 AM, and a reduction of heparin infusion in response to the high APTT could result in subtherapeutic treatment later in the day.46There is a wide variation in the sensitivity of various thromboplastins used in performing the APTT, and even with the same thromboplastin, different coagulometers may yield different re~u1ts.l~ It 5h, 57
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is necessary for each laboratory to define a therapeutic range with respect to APTT in terms of heparin blood levels (therapeutic range 0.2 to 0.4 units/mL by the protamine titration method or 0.35 to 0.70 by the antifactor X, assay). The use of heparin is associated with a number of complications, the most serious of which is bleeding. Bleeding is primarily related to underlying clinical risk factors but is also increased in women and individuals over the age of 65 years.19The relationship to heparin dosage and APTT levels is less clear-cut. A second significant complication of 44, 69 Heparin-induced heparin is heparin-induced thromb~cytopenia.'~, thrombocytopenia is a well-recognized complication of heparin therapy, usually occurring within 5 to 10 days after heparin treatment has started.l4.48, Approximately 1%to 2% of patients receiving unfractionated heparin experience a fall in platelet count to less than the normal range or a 50% fall in the platelet count within the normal range. In the majority of cases, this mild to moderate thrombocytopenia appears to be a direct effect of heparin on platelets and is of no consequence. Approximately 0.1% to 0.2% of patients receiving heparin, however, develop an immune thrombocytopenia mediated by IgG antibody directed against a complex of PF4 and heparin5 The development of thrombocytopenia may be accompanied by arterial or venous thrombosis, which may lead to serious consequences, such as death or limb amputation. The diagnosis of heparin-induced thrombocytopenia, with or without thrombosis, must be made on clinical grounds because the assays with the highest sensitivity and specificity are not readily available and have a slow turnaround time.5,23, 36, 49* 50 When the diagnosis of heparin-induced thrombocytopenia is made, heparin in all forms must be stopped immediately.81In patients requiring ongoing anticoagulation, several alternatives exist: warfarin therapy, insertion of an inferior vena cava filter, the use of the defibrinogenating extract of snake venom (ancrod),2'jthe heparinoid danaparoid,6O and, more recently, the specific antithrombins hirudiIP6or argatrobarx61 Most of the reports in case series have included the use of ancrod or danaparoid, but clinical trials are currently underway to assess the efficacy and safety of the specific antithrombin agents. As mentioned previously, it has been found that danaparoid may cross-react in patients with heparin-induced thrombocytopenia, making its use less attractive. Osteoporosis has been reported in patients receiving unfractionated heparin in dosages of 20,000 U/day (or more) for more than 6 months.39 Demineralization can progress to the fracture of vertebral bodies or long bones, and the defect may not be entirely reversible. Other complications of heparin include elevated liver enzymes, hypoaldosteronism, hypersensitivity and allergic skin reactions, and heparin-induced skin necrosis.39The hope that the LMWHs may overcome some of the problems related to heparin therapy and decrease some of the complications has stimulated a large number of trials comparing LMWHs with unfractionated heparin.
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LOW-MOLECULAR-WEIGHT HEPARIN
Over the past 15 years, a number of LMWH fractions of unfractionated heparin have become available for commercial The LMWHs are manufactured from unfractionated heparin (usually of porcine origin) by controlled depolymerization using either chemical (nitrous oxide, alkaline hydrolysis, or peroxidative cleavage) or enzymatic (heparinase) techniques.27 The low-molecular-weight fractions have a molecular weight between 4000 and 6000 with 60% of the polysaccharide chains having a molecular weight between 2000 and 8000. The various LMWHs differ in terms of mean molecular weight, glycosaminoglycan content, and anticoagulant activity in terms of anti-X, and anti-11, activity.2,7, 8, 18, 21, 27, 28, 41 The various fractions have different pharmacologic profiles in terms of bioavailability, plasma clearance, and release of tissue factor pathway inhibitor, and in experimental models they have different antithrombotic and hemorrhagic properties.2,7, 8, 18, 21, 27, 28, 41 The LMWHs currently available for commercial use are shown in Table 1; the method of production, molecular weights, and anti X,-to-anti 11, ratio are shown as well. Because the LMWHs are different compounds with distinct pharmacologic properties8,27 and because different regimens have been used in clinical trials, it is considered inappropriate to use meta-analyses for comparing the effects of LMWH with placebo, unfractionated heparin, dextran, or warfarin. Despite the various differences among the LMWHs, the clinical outcomes in clinical trials are similar, particularly in prophylactic studies using lower doses. In the higher doses used in treatment of thrombotic disorders, it is possible that differences in outcomes may become apparent. It has been hoped that the LMWHs will have fewer serious complications, such as bleeding? 20, 21* 53 osteoporosis,’j2.@65, , 72 and heparinTable 1. SOME COMMERCIAL LOW-MOLECULAR-WEIGHT HEPARINS AND SOME OF THEIR PROPERTIES
Trade Name’
Logiparin lnnohep Fragmin Lovenox Fraxiparin Reviparin Normoflo
International Nonproprietary Name
Method of Production
Mean Molecular Weight
Anti XJII. Ratio
Tinzaparin
HD
5866
1.9:l
Dalteparin Enoxaparin Nadroparin Clivarin Ardeparin
NAP AH NAP NAP PC
5819 4371 4855 4653 6000
2.1:l 2.7:l 3.2:l 3.6- 6.16 2.0:l
*Manufacturers: Logiparin, Novo Nordisk; Innohep, Leo Laboratories; Fragmin, Pharmacia-Upjohn; Lovenox, Rhone Poulenc Rorer; Fraxiparin, Sonofi; Reviparin, Knoll AG; Normoflo, Wyeth-Ayerst. tRange provided by Knoll AG. HD = Heparinase digestion; NAP = nitrous acid depolymerization; AH = alkaline hydrolysis; PC = peroxidative cleavage.
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Table 2. COMPARISON BETWEEN LOW-MOLECULAR-WEIGHT HEPARIN AND UNFRACTIONATED HEPARIN
Mean molecular weight Saccharide units Anti-XJanti 11,-activity ratio Bioavailability at lower doses Dose-dependent clearance Inhibited by platelet factor IV Inhibits platelet bound X, Inhibits platelet function Increases vascular permeability
Low-MolecularWeight Heparin
Unfractionated Heparin
4000-6500 13-22 2:1-4:1
12,000-15,000 40-50 1:l
High
Low
-
+++ + ++ -
+
i -
++++ +
Modifiedfrorn Hirsh J, Levine MN: Low molecular weight heparin. Blood 79:l-17,1992;with permission.
induced thrombocytopenia,s2when compared with unfractionated heparin. Evidence is accumulating that these complications are less serious and less frequent with the use of LMWH. LMWH has not been approved for the prevention or treatment of venous thromboembolism in pregnancy. These drugs do not cross the placenta? 32 and in small case series they have been shown to be both effective and safe.63,67, 77, At present, however, the standard treatment for venous thromboembolism in pregnancy is twice-daily, adjusted-dose subcutaneous unfractionated hepain.^^ The LMWHs all cross-react with unfractionated heparin, and they can therefore not be used as alternative therapy in patients who develop heparin-induced thrombocytopenia. The heparinoid danaparoid possesses a 10% to 20% cross-reactivity with heparin, and it can be safely used in patients who have no cross-reactivity.60 The LMWHs differ from unfractionated heparin in numerous ways as demonstrated in Table 2. Of particular importance are the following: increased bioavailability2,28 (>90% after subcutaneous injection), prolonged half-life2,27 and predictable clearance enabling once or twice daily inje~tion,'~ and predictable antithrombotic response based on body weight permitting treatment without laboratory monitoring.62Other possible advantages are their ability to inhibit platelet bound factor X,I2 resistance to inhibition by platelet factor 49, 71 and their decreased effect on platelet function71and vascular permeability" (possibly accounting for less hemorrhagic effects at comparable antithrombotic doses).4,20, 21 TREATMENT OF VENOUS THROMBOEMBOLISM
In the treatment of established venous thromboembolism, the LMWHs given by subcutaneous injection have a number of advantages over continuous intravenous unfractionated heparin; they can be given by once-daily or twice-daily subcutaneous injection, and the antithrom-
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botic response to LMWH is highly correlated with body weight permitting administration of a fixed dose without laboratory monitoring. In a number of early clinical trials (some of which were dose finding), LMWH given by subcutaneous or intravenous injection was compared with continuous intravenous unfractionated heparin with repeat venography at day 7 to 10 being the primary end point.l, 16, 17, 37, 40, 73 These studies demonstrated that LMWH was at least as effective as unfractionated heparin in preventing extension or increasing resolution of thrombi on repeat venography.’,16, 17, 37, 40, 73 More recently, the more relevant clinical end points of recurrent venous thromboembolism or 58, 59, 68, 74 These studies are not death during follow-up have been all comparable because different regimens of LMWHs were used, not all studies ensured that adequate intravenous heparin therapy was given or properly monitored, and some studies entered patients with distal as well as proximal deep venous thrombosis. Only one study was doubleblinded, although others used blinded assessment of outcome measures for both efficacy and safety. LMWH was given for 6 to 10 days with warfarin therapy starting either on day 245or on day 7 to lo.%,5y, 74 Warfarin was continued for 3 months with the target International Normalized Ratio (INR) range being 2.0 to 3.0. The outcomes in terms of recurrent venous thromboembolism, major bleeding, and mortality for five clinical trials using clinical end points are summarized in Table 3. When the results of two clinical trials were pooled, there was a striking decrease in mortality in the patients receiving LMWH, particularly for patients with cancer.35Most of the abrupt deaths could not be attributed to thromboembolic events, suggesting that the benefits of LMWH may not be entirely related to thrombotic events. Most of the early studies comparing subcutaneous LMWH with
Table 3. RANDOMIZED TRIALS OF LOW-MOLECULAR-WEIGHT HEPARIN VERSUS UNFRACTIONATED HEPARIN FOR THE IN-HOSPITAL TREATMENT OF PROXIMAL DEEP VENOUS THROMBOSIS: RESULTS OF LONG-TERM FOLLOW-UP
Reference Hull et a149 Prandoni et a P Lopaciuk et alsst Simonneau et a174 Lindmarker et a15q
Treatment Tinzaparin Heparin Fraxiparine Heparin Fraxiparine Heparin Enoxaparin Heparin Dalteparin Heparin
Recurrent Venous Thromboembolism, No. (%) 6/213 (2.8) 15/219 (6.8) 6/18 (7.1) 12185 (14.1) 0174 (0) 3172 (4.1) 0167 0/67 5/101 (5.0) 31103 (2.9)
‘R.05 versus heparin. t19.570had calf vein deep venous thrombosis $42.6% distal deep venous thrombosis only.
?
Major Bleeding, No. (%)
Mortality, No. (%)
11213 (0.5)* 11/219 (5.0) 1/85 (1.2) 3185 (3.8) 0174 1/72 (1.4) 0/67 0167 11101 01103
101213 (4.7)* 211219 (9.6) 6185 (7.1) 12/85 (14.1) 0174 1172 (1.4) 3/67 (4.5) 2187 (3.0) 2/101 (2.0) 31103 (2.9)
involvement of the popliteal.
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continuous intravenous, unfractionated heparin for the treatment of venous thrombosis used a twice-daily, subcutaneous injection of LMWH. This was based on the hypothesis that maintaining a more constant antiX, level was important to suppress thrombus formation in the initial stages of treatment. In the study by Hull et al,45 a single injection of LMWH was given based on the hypothesis that achieving a therapeutic dose of LMWH would be as important as achieving therapeutic levels of heparin early on in the treatment of deep venous thrombosis to prevent recurrent thromboembolism.43 Studies with three different LMWHs have indicated that a once-daily subcutaneous injection is at least as effective and safe as twice-daily injections.30,31, 76 Therefore, oncedaily administration of LMWH will become the standard of care for the treatment of deep venous thrombosis. A study showed that once-daily LMWH was as effective as continuous intravenous unfractionated heparin in the initial treatment of patients presenting with pulmonary emboli~m.~~ A cost-effectiveness analysis indicated that LMWH was cost-effective when compared with continuous intravenous heparin under the study protocol conditions because monitoring was not necessary and there were fewer complications requiring rehospitalization and treatment.47These findings were verified by a sensitivity analysis. It was estimated that 37% of patients on LMWH could have been discharged on day 2, which would have further increased the cost-effectiveness of the LMWH.47 Two studies indicate that in selected patients LMWH treatment can be administered safely outside the hospital.51,54 Patients who met the entry criteria were randomized to receive twice-daily LMWH either entirely out of the hospital or with early discharge or continuous intravenous heparin in hospital. Warfarin was started on day 1 or 2 and continued for 3 months. Both studies showed equivalence with respect to the incidence of recurrent venous thromboembolism, major bleeding, and mortality rates.51,54 In these studies, 31% and 33% of patients with proximal venous thrombosis were eligible for entry. A third study comparing LMWH primarily out-of-hospital with continuous intravenous heparin in-hospital supports these findings.24 This study included approximately 30% of patients who presented with documented pulmonary embolism, and their outcomes with LMWH and intravenous heparin were comparable for the end points of recurrent venous thromboembolic death and major hemorrhage. This finding is supported by the clinical trial demonstrating that once-daily LMWH was as effective as intravenous unfractionated heparin in the treatment of patients presenting with pulmonary embolism.75The generalizability of these outpatient studies depends largely on the referral base of the institution. In large, tertiary care centers, it is likely that as many as 60% of patients will require in-hospital care, whereas in community hospitals, as many as 80% may be eligible for out-of-hospital treatment. The use of out-of-hospital LMWH, along with warfarin, has created a number of logistic problems, which so far defy easy solutions. This
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approach to treatment requires someone to take responsibility for either teaching the patients to self-inject or ensuring that the patients get their daily injections of LMWH, that they have daily measurement of their INR, and that somebody orders the appropriate dose of warfarin. Also, it is important that all the members of the health care team are kept informed regarding the patient’s progress and follow-up.
RECOMMENDATIONS FOR TREATMENT OF VENOUS THROMBOEMBOLISM
Based on level I evidence, the recommendations for treatment of venous thromboembolism are as follows.
Heparin Therapy
Heparin should be delivered by continuous intravenous infusion using one of the published heparin nomograms to ensure adequate heparinization in the initial 24 to 48 hours of therapy. Warfarin therapy should be started on day 1, with heparin treatment being continued until the INR is therapeutic (2.0 to 3.0) for 2 consecutive days. The platelet count should be measured at initiation of therapy and repeated every 2 days while the patient is on heparin treatment. The APTT should be used for monitoring heparin therapy and should be performed every 4 to 6 hours until a therapeutic APTT is achieved. The therapeutic range for APTT should reflect therapeutic heparin levels measured by the anti-X, assay (0.35 to 0.70 { +grk}m(-grk}/mL).
Low-Molecular-Weight Heparin Treatment
LMWH should be given by subcutaneous injection once or twice daily, beginning at the time of diagnosis. Most of the available LMWHs have been shown to be equally effective when given by once-daily as compared with twice-daily injections. The dosage and schedule should be based on evidence from level I clinical trials and the approval by regulatory bodies. The dosage schedules for the LMWHs approved in North America are as follows: tinzaparin 175 X, p/kg once daily, dalteparin 200 X, p/kg once daily, and enoxaparin 1 mg/kg twice daily (1.5 mg/kg once daily has been shown to be equally effective). No laboratory tests for monitoring LMWH therapy are required. Platelets should be measured before beginning therapy and every 2 days while on LMWH. Warfarin therapy should be started on day 1, and LMWH should be continued for 5 days or until the INR is therapeutic (2.0 to 3.0) for 2 consecutive days.
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Out-of-Hospital Treatment
Out-of-hospital treatment with LMWH and warfarin can be used for selected patients who are not at high risk of bleeding, who do not have other comorbid diseases requiring hospital admission, and who are considered to be candidates for out-of-hospital treatment by their attending physician. Out-of-hospital treatment with LMWH and warfarin requires the presence of a skilled team and the necessary infrastructure for arranging daily follow-up visits, including measurement of INR as well as close communication with all members of the health care team. It is recommended that each center undertaking out-of-hospital treatment of venous thromboembolism develop such a program as well as the necessary funding arrangements for physician services. CONCLUSION
Knowledge regarding the appropriate management of venous thromboembolism has been revolutionized by the results of a large number of level I clinical trials. Although questions remain, the clinician is in a much better position to manage venous thromboembolism in a safe, effective manner, and this will undoubtedly lead to improved patient care and a decreased threat of medical liability. The availability of LMWH for the treatment of venous thromboembolism has resulted in an effective, safe, and convenient alternative to intravenous heparin and has permitted the out-of-hospital management of many patients with venous thromboembolism, resulting in better use of hospital beds, increased patient satisfaction, and considerable cost savings for the health care system. References 1. Albada J, Nieuwenhuis HK, Sixma JJ, et al: Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin): Results of a double-blind randomized study. Circulation 80:935-940, 1989 2. Anderson L-0, Barrowcliffe TW, Holmer E, et al: Molecular weight dependency of the heparin potentiated inhibition of thrombin and activated factor X: Effect of heparin neutralization in plasma. Thromb Res 115:531-538, 1979 3. Andrew M, Cade J, Buchanan MR, et al: Low-molecular weight heparin does not cross the placenta [abstr]. Thromb Haemost 50:225, 1983 4. Andriuoli G, Mastacchi R, Barnti M, et al: Comparison of the antithrombotic and hemorrhagic effects of heparin and a new low molecular weight heparin in the rat. Haemostasis 153324-330, 1985 5. 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 104:648-654, 1995 6. Bara L, Billaud E, Gramond G, et al: Comparative pharmacokinetics of low molecular weight heparin (PK 10169) and unfractionated heparin after intravenous and subcutaneous administration. Thromb Res 39:631-636, 1985
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7. Bara L, Samama MM: Pharmacokinetics of low molecular weight heparins. Acta Chir Scand 543:65-72, 1988 8. Barrowcliffe TW, Curtis AD, Johnson EA, et al: An international standard for low molecular weight heparin. Thromb Haemost 6O:l-7, 1988 9. 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 Haemato1 26243-247, 1984 10. Bjornsson TO, Wolfram BS, Kitchell BB: Heparin kinetics determined by three assay methods. Clin Pharmacol Ther 31:104-113, 1982 11. Blajchman MA, Young E, Ofosu FA: Effects of unfractionated heparin, dermatan sulfate and low molecular weight heparin on vessel wall permeability in rabbits. AM N Y Acad Sci 556:245-254, 1989 12. Boneu B, Buchanan MR, Cade JF, et al: Effects of heparin, its low molecular weight fractions and other glycosaminoglycans on thrombus growth in vivo. Thromb Res 40:81-89, 1985 13. Boneu B, Caranobe C, Cadroy Y, et al: Pharmacokinetic studies of standard unfractionated heparin, and low molecular weight heparins in the rabbit. Semin Thromb Hemost 14~18-27,1988 14. Boshkov LK, Warkentin TE, Hayward CPM, et al: Heparin-induced thrombocytopenia and thrombosis: Clinical and laboratory studies. Br J Haematol 84:322-328, 1993 15. Brandjes DPM, Heijboer H, Buller HR, et al: Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 327:1485-1489, 1992 16. Bratt G, Aberg W, Johansson M, et al: Two daily subcutaneous injections of Fragmin as compared with intravenous standard heparin in the treatment of deep venous thrombosis (DVT). Thromb Haemost 64:506-510, 1990 17. Bratt G, Tornebohm E, Granqvist S, et al: A comparison between low molecular weight heparin (KABI 2165) and standard heparin in the intravenous treatment of deep venous thrombosis. Thromb Haemost 54:813-817, 1985 18. Briant L, Caranobe C, Saivin S, et al: Unfractionated heparin and CY216: Pharmacokinetics and bioavailabilities of the anti-factor Xa and IIa: Effects of intravenous and subcutaneous injection in rabbits. Thromb Haemost 61:348-353, 1989 19. Brill-Edwards P, Ginsberg S, Johnston M, et al: Establishing a therapeutic range for heparin therapy. Ann Intern Med 119:104-109, 1993 20. Cade JF, Buchanan MR, Boneu B, et al: A comparison of the antithrombotic and haemorrahagic effects of low molecular weight heparin fractions: The influence of the method of preparation. Thromb Res 35:613425, 1984 21. Carter CJ, Kelton JG, Hirsh J, et al: The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparins and heparin. Blood 59x1239-1245, 1982 22. Casu B, Oreste P, Torri G, et al: The stucture of heparin oligosaccharide fragments with high anti-(factor Xa) activity containing the minimal antithrombin 111-binding sequence. Biochem J 197599-609, 1981 23. Chong BH, Burgess J, Ismail F: The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost 69:344350, 1993 24. Columbus Investigators: Low molecular weight heparin is an effective and safe treatment of deep vein thrombosis and pulmonary embolism. Blood 88:624-626, 1996 25. Cruickshank MK, Levine MN, Hirsh J, et al: A standard nomogram for the management of heparin therapy. Arch Intern Med 151:333-337,1991 26. Demers C, Ginsberg JS, Brill-Edwards P, et al: Rapid anticoagulation using ancrod for heparin-induced thrombocytopenia. Blood 78:2194-2197, 1991 27. Fareed J, Walenga JM, Hoppensteadt D, et al: Comparative study on the in vitro and in vivo activities of seven low-molecular weight heparins. Haemostasis 18(suppl 3):3-15, 1988 28. Fareed J, Walenga JM, Racanelli A, et al: Validity of the newly established low molecular weight heparin standard in cross referencing low molecular weight heparins. Haemostasis 3(suppl):3347, 1988
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29. Fennerty A, Thomas P, Backhouse G, et al: Audit of control of heparin treatment. BMJ 290~27-28, 1985 30. Fiessinger JN, Charbonnier BA, Sigma JJ, et al: Comparison of a once daily with a twice daily subcutaneous nadroparin calcium regiment in the treatment of deep vein thrombosis: The FRAXODI study. Thromb Haemost 1582388, 1997 31. 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 76:195-199, 1996 32. Forestier F, Daffos F, Capella-Pavlovsky M: Low molecular weight heparin (PH 10169) does not cross the placenta during the second trimester of pregnancy: Study by direct foetal blood samdine under ultrasound. Thromb Res 34:557-560. 1984 33. Ginsberg JS, Hirih JyUse of antithrombotic agents during pregnancy. Chest 108:305S311% 1995 ----, -- - -
34. Granger CB, Miller JM, Bovill EG, et al: Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acture coronary syndromes. Circulation 91:1929-1935, 1995 35. Green D, Hull RD, Brant R, et al: Lower mortality in cancer patients treated with lowmolecular-weight versus standard heparin. Lancet 339:1476, 1992 36. Greinacher A, Michels I, Kietel V, et al: A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia. Thromb Haemost 66:734-736, 1991 37. Harenberg J, Huck K, Bratsch H, et al: Therapeutic application of subcutaneous LMWH in acute venous thrombosis. Haemostasis 20(suppl):205-219, 1990 38. Hirsh J, Levine MN: Low molecular weight heparin. Blood 79:l-17, 1992 39. Hirsh J, Raschke R, Warkentin TE, et al: Heparin: Mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 108:2585-275s, 1995 40. Holm HA, Ly B, Handeland GF, et a1 Subcutaneous heparin treatment of deep venous thrombosis: A comparison of unfractionated and low molecular weight heparin. Haemostasis 16:30-37, 1986 41. Holmer E, Soderberg K, Bergqvist D, et al: Heparin and its low molecular weight derivatives: Anticoagulant and antithrombotic properties. Haemostasis 16(suppl 2):1-7, 1986 42. Hoppensteadt D, Walenga JM, Fasanella A, et al: TFPI antigen levels in normal human volunteers after intravenous and subcutaneous administration of unfractionated heparin and low molecular weight heparin. Thromb Res 77175-185, 1995 43. Hull RD, Raskob GE, Brant RF, et al: The 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 1572562-2568, 1997 44. 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 315:1109-1114, 1986 45. Hull RD, Raskob GE, Pineo GF, et al: Subcutaneous LMWH compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 326:975-988, 1992 46. Hull RD, Raskob GE, Rosenbloom DR, et al: Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med 1523589-1595, 1992 47. Hull RD, Raskob G, Rosenbloom D, et al: Treatment of proximal vein thrombosis with subcutaneous low molecular weight heparin vs intravenous heparin: An economic perspective. Arch Intern Med 157289-294, 1997 48. Kelton JG, Sheridan D, Santos A, et al: Heparin-induced thrombocytopenia: Laboratory studies. Blood 721:925-930, 1988 49. Kelton JG: The laboratory diagnosis of heparin-induced thrombocytopenia: Still a journey, not yet a destination [edit]. Am J Clin Pathol 104611-613, 1995 50. Kelton TG. Sheridan D. Brian H. et al: Clinical usefulness of testine for a heuarindependent platelet aggregation factor in patients with suspected hgparin-asso'ciated thrombocytopenia. J Lab Clin Med 103:606-612, 1984 51. Koopman MMW, Prandoni P, Piovella F, et al: Treatment of venous thrombosis with ,
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intravenous unfractionated heparin administered in the hospital as compared with subcutaneous LMWH administered at home. N Engl J Med 334:682-687,1996 52. Lane DA: Heparin binding and neutralizing protein. In Lane DA, Lindahl U (eds): Heparin, Chemical and Biological Properties, Clinical Applications. London, Edward Arnold, 1989, pp 36S391 53. Lensing AW, Prins MH, Davidson BL, et al: Treatment of deep venous thrombosis with LMWHs. Arch Intern Med 155:601-607, 1995 54. Levine M, Gent M, Hirsh J, et al: A comparison of LMWH administered primarily at home with unfractionated heparin administered in the hospital for proximal deep vein thrombosis. N Engl J Med 334677-681,1996 55. 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 154:49-56, 1994 56. Lindahl U, Backstrom G, Hook M, et al: Structure of the antithrombin-binding site of heparin. Proc Natl Acad Sci U S A 76:3198-3206, 1979 57. Lindahl U, Thunberg L, Backstrom G, et al: Extension and structural variability of the antithrombin-binding sequence in heparin. J Biol Chem 259:12368-12376, 1984 58. Lindmarker P, Holmstrom M, Granqvist S, et al: Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep venous thrombosis. Thromb Haemost 72:186-190, 1994 59. 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 multicentre trial. Thromb Haemost 68:14-18, 1992 60. Magnani HN: Heparin-induced thrombocytopenia (HIT): An overview of 230 patients treated with Orgaran (Org 10172). Thromb Haemost 703554-561, 1993 61. Matsuo T, Kario K, Chikahira Y, et al: Treatment of heparin-induced thrombocytopenia by use of argatroban, a synthetic thrombin inhibitor. Br J Haematol 82627429, 1992 62. Matzsch T, Bergqvist D, Hedner U, et al: Effects of low molecular weight heparin and unfragmented heparin on induction of osteoporosis in rates. Thromb Haemost 63:505-509, 1990 63. Melissari E, Parker CJ, Wilson NV, et a1 Use of low molecular weight heparin in pregnancy. Thromb Haemost 68:652456, 1992 64. Monreal M, Lafoz E, Salvador R, et a1 Adverse effects of three different forms of heparin therapy: Thrombocytopenia, increased transaminases, and hyperkalaemia. Eur J Clin Pharmacol37415418, 1989 65. Monreal M, Vinas L, Monreal L, et al: Heparin-related osteoporosis in rats: A comparative study between unfractionated heparin and a low molecular weight heparin. Haemostasis 20:204-207, 1990 66. Nand S: Hirudin therapy for heparin-associated thrombocytopenia and deep venous thrombosis. Am J Hematol43:310-311, 1993 67. Omri A, Delaloye FJ, Andersen H, et al: Lmwh Novo (LHN-I) does not cross the placenta during the second trimester of pregnancy. Thromb Haemost 61:55-56, 1989 68. Prandoni P, Lensing AW, Buller HR, et al: Comparison of subcutaneous LMWH with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 339:441445, 1992 69. Raschke RA, Reilly BM, Guidry JR, et al: The weight-based heparin dosing nomogram compared with a ”standard care” nomogram. Ann Intern Med 119:874-881, 1993 70. Rosenberg RD, Lam L: Correlation between structure and function of heparin. Proc Natl Acad Sci U S A 76:1218-1222, 1979 71. Salzman EW, Rosenberg RD, Smith MH, et al: Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest 65:64-73, 1980 72. Shaughnessy SG, Young E, Deschamps P, et al: The effects of low molecular weight and standard heparin on calcium loss from fetal rat calvaria. Blood 86:1368-1373, 1995 73. 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 LMWHNovo. Thromb Res 55267-278, 1989 74. Simonneau G, Charbonnier B, Decousus H, et al: Subcutaneous LMWH compared I
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81.
82. 83. 84.
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with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med 153:1541-1546, 1993 Simonneau G, Sors H, Charbonnier B, et al: Once daily low molecular weight heparin tinzaparin vs. unfractionated heparin in the treatment of acute pulmonary embolism. Thromb Haemost 3080:753, 1997 Spiro TE: Clinical use of low molecular weight heparins. Thromb Haemost 1527373, 1997 Sturridge F, de Swiet M, Letsky E: The use of low molecular weight heparin for thromboprophylaxis in pregnancy. Br J Obstet Gynaecol 101:69-71, 1994 Theroux P, Waters D, Latn J, et a1 Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med 327141-145, 1992 Tollefsen DM, Majerus DW, Blank MK Heparin cofactor I 1 Purification and properties of a heparin-dependent inhibitor of thrombin in human plasma. J Biol Chem 25721622169, 1982 Wahlberg TB, Kher A Low molecular weight heparin as thromboprophylaxis in pregnancy: A retrospective analysis from 14 European clinics. Haemostasis 2455-56, 1994 Warkentin TE, Kelton JG: Heparin-induced thrombocytopenia. Prog Hemost Thromb 10~1-34,1991 Warkentin TE, Levine MN, Hirsh J, et al: Heparin-induced thrombocytopenia in patients treated with LMWH or unfractionated heparin. N Engl J Med 3321330-1335, 1995 Weitz JI, Hudoba M, Massel D, et a 1 Clot-bound thrombin is protected from inhibition by heparin-antithrombin I11 but is susceptible to inactivation by antithrombin IIIindependent inhibitors. J Clin Invest 86:385-391, 1990 Wheeler AP, Jaquiss RD, Newman J H Physician practices in the treatment of pulmonary embolism and deep-venous thrombosis. Arch Intern Med 148:1321-1325,1988
Address reprint requests to Russell D. Hull, MB, BS Thrombosis Research Unit 601 South Tower Foothills Hospital 1403-29 Street NW Calgary, AB T2N 2T9 Canada
CURRENT CONCEPTS OF THROMBOSIS
+ .OO
UNFRACTIONATED AND LOWMOLECULAR-WEIGHT HEPARIN Comparisons and Current Recommendations Graham F. Pineo, MD, and Russell D. Hull, MB, BS
Unfractionated heparin has been used extensively in the treatment
of venous thromboembolism. More recently, various low-molecularweight heparins (LMWHs) have been evaluated against a number of different controls for these same clinical problems. In a number of countries, the LMWHs have replaced unfractionated heparin for both the prevention and the treatment of venous thromboembolism. This article reviews the problems related to the use of unfractionated heparin, compares the LMWHs with unfractionated heparin, and discusses the role of LMWH in the treatment of venous thromboembolism. UNFRACTIONATED HEPARIN
Unfractionated heparin from either porcine or bovine sources has been available for clinical use for several decades. Although heparin has been studied extensively, much remains uncertain about its mode of action, particularly the nonanticoagulant properties, and some of the complications have only recently been better u n d e r ~ t o o d Because .~~ of the problems and complications related to heparin therapy, there has been great interest in the use of the LMWHs in a variety of clinical settings. The anticoagulant activity of unfractionated heparin depends on a unique pentasaccharide that binds to antithrombin I11 (ATIII) and po-
From the Thrombosis Research Unit, Foothills Hospital; and the University of Calgary, Calgary, Alberta, Canada
MEDICAL CLINICS OF NORTH AMERICA ~~
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tentiates the inhibition of thrombin and activated factor X (X,) by ATIII.52, About one third of all heparin molecules contain the unique pentasaccharide sequence regardless of whether they are low or high in molecular weight fractions. The pentasaccharide sequence confers the molecular high affinity for ATIII.56,70 The remaining two thirds of heparin has minimal anticoagulant activity at the therapeutic concentrations that are used clinically. For the inhibition of thrombin, heparin must form a bridge between thrombin and ATIII, but for the inhibition of factor X,, this bridging is not necessary.57,70 It has been shown that molecules of heparin with fewer than 18 saccharide units are unable to bind thrombin and ATIII simultaneously and as a result cannot catalyze thrombin inhibition.22Heparin fragments with smaller numbers of saccharide units are capable of catalyzing the inhibition of factor X, by ATIII, provided that the high affinity pentasaccharide sequence is present. Unfractionated heparin is unable to inhibit thrombin bound to fibrin, whereas the specific antithrombin agents do Heparin does not inhibit factor X, bound to platelet^.^^ Heparin also catalyzes the inactivation of thrombin by another plasma cofactor (cofactor 11), which acts independently of ATIII.79Heparin has a number of other effects. Those related to the anticoagulant effects of heparin include the release of tissue factor pathway inhibitor42; binding to numerous plasma and platelet proteins, endothelial cells, and leukocytes9,52; suppression of platelet function7I;and increase in vascular permeability." The anticoagulant response to a standard dose of heparin varies widely among patients. Heparin is poorly absorbed from the subcutaneous site, especially at lower doses.'j The plasma clearance of heparin depends on a dose-related renal clearance and a non-dose-related saturable cellular mechanism.'O The binding of heparin to plasma proteins, endothelial cells, and platelets contributes to the unpredictable repatients develop relative heparin resistance and require s ~ o n s e 42 . ~Some , a large dose of heparin to achieve a response in the activated partial thromboplastin time (APTT).55Studies have documented a rebound thrombin generation when heparin is abruptly stopped.34,78 For these reasons, it is necessary to monitor the anticoagulant response of heparin using either the APTT or heparin levels and to titrate the dose to the individual patient. Unless a prescriptive heparin nomogram is used, many patients receive inadequate heparin in the initial 24 to 48 hours of treatment.25, 2y, 84 This inadequate therapy has been shown to increase the incidence 44, 69 Treatment is further of venous thromboembolism during f~llow-up.'~, complicated by the fact that there is a diurnal variation in the APTT response in patients on a constant infusion of intravenous heparin.4'j A peak response is seen at 3 AM, and a reduction of heparin infusion in response to the high APTT could result in subtherapeutic treatment later in the day.46There is a wide variation in the sensitivity of various thromboplastins used in performing the APTT, and even with the same thromboplastin, different coagulometers may yield different re~u1ts.l~ It 5h, 57
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is necessary for each laboratory to define a therapeutic range with respect to APTT in terms of heparin blood levels (therapeutic range 0.2 to 0.4 units/mL by the protamine titration method or 0.35 to 0.70 by the antifactor X, assay). The use of heparin is associated with a number of complications, the most serious of which is bleeding. Bleeding is primarily related to underlying clinical risk factors but is also increased in women and individuals over the age of 65 years.19The relationship to heparin dosage and APTT levels is less clear-cut. A second significant complication of 44, 69 Heparin-induced heparin is heparin-induced thromb~cytopenia.'~, thrombocytopenia is a well-recognized complication of heparin therapy, usually occurring within 5 to 10 days after heparin treatment has started.l4.48, Approximately 1%to 2% of patients receiving unfractionated heparin experience a fall in platelet count to less than the normal range or a 50% fall in the platelet count within the normal range. In the majority of cases, this mild to moderate thrombocytopenia appears to be a direct effect of heparin on platelets and is of no consequence. Approximately 0.1% to 0.2% of patients receiving heparin, however, develop an immune thrombocytopenia mediated by IgG antibody directed against a complex of PF4 and heparin5 The development of thrombocytopenia may be accompanied by arterial or venous thrombosis, which may lead to serious consequences, such as death or limb amputation. The diagnosis of heparin-induced thrombocytopenia, with or without thrombosis, must be made on clinical grounds because the assays with the highest sensitivity and specificity are not readily available and have a slow turnaround time.5,23, 36, 49* 50 When the diagnosis of heparin-induced thrombocytopenia is made, heparin in all forms must be stopped immediately.81In patients requiring ongoing anticoagulation, several alternatives exist: warfarin therapy, insertion of an inferior vena cava filter, the use of the defibrinogenating extract of snake venom (ancrod),2'jthe heparinoid danaparoid,6O and, more recently, the specific antithrombins hirudiIP6or argatrobarx61 Most of the reports in case series have included the use of ancrod or danaparoid, but clinical trials are currently underway to assess the efficacy and safety of the specific antithrombin agents. As mentioned previously, it has been found that danaparoid may cross-react in patients with heparin-induced thrombocytopenia, making its use less attractive. Osteoporosis has been reported in patients receiving unfractionated heparin in dosages of 20,000 U/day (or more) for more than 6 months.39 Demineralization can progress to the fracture of vertebral bodies or long bones, and the defect may not be entirely reversible. Other complications of heparin include elevated liver enzymes, hypoaldosteronism, hypersensitivity and allergic skin reactions, and heparin-induced skin necrosis.39The hope that the LMWHs may overcome some of the problems related to heparin therapy and decrease some of the complications has stimulated a large number of trials comparing LMWHs with unfractionated heparin.
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LOW-MOLECULAR-WEIGHT HEPARIN
Over the past 15 years, a number of LMWH fractions of unfractionated heparin have become available for commercial The LMWHs are manufactured from unfractionated heparin (usually of porcine origin) by controlled depolymerization using either chemical (nitrous oxide, alkaline hydrolysis, or peroxidative cleavage) or enzymatic (heparinase) techniques.27 The low-molecular-weight fractions have a molecular weight between 4000 and 6000 with 60% of the polysaccharide chains having a molecular weight between 2000 and 8000. The various LMWHs differ in terms of mean molecular weight, glycosaminoglycan content, and anticoagulant activity in terms of anti-X, and anti-11, activity.2,7, 8, 18, 21, 27, 28, 41 The various fractions have different pharmacologic profiles in terms of bioavailability, plasma clearance, and release of tissue factor pathway inhibitor, and in experimental models they have different antithrombotic and hemorrhagic properties.2,7, 8, 18, 21, 27, 28, 41 The LMWHs currently available for commercial use are shown in Table 1; the method of production, molecular weights, and anti X,-to-anti 11, ratio are shown as well. Because the LMWHs are different compounds with distinct pharmacologic properties8,27 and because different regimens have been used in clinical trials, it is considered inappropriate to use meta-analyses for comparing the effects of LMWH with placebo, unfractionated heparin, dextran, or warfarin. Despite the various differences among the LMWHs, the clinical outcomes in clinical trials are similar, particularly in prophylactic studies using lower doses. In the higher doses used in treatment of thrombotic disorders, it is possible that differences in outcomes may become apparent. It has been hoped that the LMWHs will have fewer serious complications, such as bleeding? 20, 21* 53 osteoporosis,’j2.@65, , 72 and heparinTable 1. SOME COMMERCIAL LOW-MOLECULAR-WEIGHT HEPARINS AND SOME OF THEIR PROPERTIES
Trade Name’
Logiparin lnnohep Fragmin Lovenox Fraxiparin Reviparin Normoflo
International Nonproprietary Name
Method of Production
Mean Molecular Weight
Anti XJII. Ratio
Tinzaparin
HD
5866
1.9:l
Dalteparin Enoxaparin Nadroparin Clivarin Ardeparin
NAP AH NAP NAP PC
5819 4371 4855 4653 6000
2.1:l 2.7:l 3.2:l 3.6- 6.16 2.0:l
*Manufacturers: Logiparin, Novo Nordisk; Innohep, Leo Laboratories; Fragmin, Pharmacia-Upjohn; Lovenox, Rhone Poulenc Rorer; Fraxiparin, Sonofi; Reviparin, Knoll AG; Normoflo, Wyeth-Ayerst. tRange provided by Knoll AG. HD = Heparinase digestion; NAP = nitrous acid depolymerization; AH = alkaline hydrolysis; PC = peroxidative cleavage.
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Table 2. COMPARISON BETWEEN LOW-MOLECULAR-WEIGHT HEPARIN AND UNFRACTIONATED HEPARIN
Mean molecular weight Saccharide units Anti-XJanti 11,-activity ratio Bioavailability at lower doses Dose-dependent clearance Inhibited by platelet factor IV Inhibits platelet bound X, Inhibits platelet function Increases vascular permeability
Low-MolecularWeight Heparin
Unfractionated Heparin
4000-6500 13-22 2:1-4:1
12,000-15,000 40-50 1:l
High
Low
-
+++ + ++ -
+
i -
++++ +
Modifiedfrorn Hirsh J, Levine MN: Low molecular weight heparin. Blood 79:l-17,1992;with permission.
induced thrombocytopenia,s2when compared with unfractionated heparin. Evidence is accumulating that these complications are less serious and less frequent with the use of LMWH. LMWH has not been approved for the prevention or treatment of venous thromboembolism in pregnancy. These drugs do not cross the placenta? 32 and in small case series they have been shown to be both effective and safe.63,67, 77, At present, however, the standard treatment for venous thromboembolism in pregnancy is twice-daily, adjusted-dose subcutaneous unfractionated hepain.^^ The LMWHs all cross-react with unfractionated heparin, and they can therefore not be used as alternative therapy in patients who develop heparin-induced thrombocytopenia. The heparinoid danaparoid possesses a 10% to 20% cross-reactivity with heparin, and it can be safely used in patients who have no cross-reactivity.60 The LMWHs differ from unfractionated heparin in numerous ways as demonstrated in Table 2. Of particular importance are the following: increased bioavailability2,28 (>90% after subcutaneous injection), prolonged half-life2,27 and predictable clearance enabling once or twice daily inje~tion,'~ and predictable antithrombotic response based on body weight permitting treatment without laboratory monitoring.62Other possible advantages are their ability to inhibit platelet bound factor X,I2 resistance to inhibition by platelet factor 49, 71 and their decreased effect on platelet function71and vascular permeability" (possibly accounting for less hemorrhagic effects at comparable antithrombotic doses).4,20, 21 TREATMENT OF VENOUS THROMBOEMBOLISM
In the treatment of established venous thromboembolism, the LMWHs given by subcutaneous injection have a number of advantages over continuous intravenous unfractionated heparin; they can be given by once-daily or twice-daily subcutaneous injection, and the antithrom-
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botic response to LMWH is highly correlated with body weight permitting administration of a fixed dose without laboratory monitoring. In a number of early clinical trials (some of which were dose finding), LMWH given by subcutaneous or intravenous injection was compared with continuous intravenous unfractionated heparin with repeat venography at day 7 to 10 being the primary end point.l, 16, 17, 37, 40, 73 These studies demonstrated that LMWH was at least as effective as unfractionated heparin in preventing extension or increasing resolution of thrombi on repeat venography.’,16, 17, 37, 40, 73 More recently, the more relevant clinical end points of recurrent venous thromboembolism or 58, 59, 68, 74 These studies are not death during follow-up have been all comparable because different regimens of LMWHs were used, not all studies ensured that adequate intravenous heparin therapy was given or properly monitored, and some studies entered patients with distal as well as proximal deep venous thrombosis. Only one study was doubleblinded, although others used blinded assessment of outcome measures for both efficacy and safety. LMWH was given for 6 to 10 days with warfarin therapy starting either on day 245or on day 7 to lo.%,5y, 74 Warfarin was continued for 3 months with the target International Normalized Ratio (INR) range being 2.0 to 3.0. The outcomes in terms of recurrent venous thromboembolism, major bleeding, and mortality for five clinical trials using clinical end points are summarized in Table 3. When the results of two clinical trials were pooled, there was a striking decrease in mortality in the patients receiving LMWH, particularly for patients with cancer.35Most of the abrupt deaths could not be attributed to thromboembolic events, suggesting that the benefits of LMWH may not be entirely related to thrombotic events. Most of the early studies comparing subcutaneous LMWH with
Table 3. RANDOMIZED TRIALS OF LOW-MOLECULAR-WEIGHT HEPARIN VERSUS UNFRACTIONATED HEPARIN FOR THE IN-HOSPITAL TREATMENT OF PROXIMAL DEEP VENOUS THROMBOSIS: RESULTS OF LONG-TERM FOLLOW-UP
Reference Hull et a149 Prandoni et a P Lopaciuk et alsst Simonneau et a174 Lindmarker et a15q
Treatment Tinzaparin Heparin Fraxiparine Heparin Fraxiparine Heparin Enoxaparin Heparin Dalteparin Heparin
Recurrent Venous Thromboembolism, No. (%) 6/213 (2.8) 15/219 (6.8) 6/18 (7.1) 12185 (14.1) 0174 (0) 3172 (4.1) 0167 0/67 5/101 (5.0) 31103 (2.9)
‘R.05 versus heparin. t19.570had calf vein deep venous thrombosis $42.6% distal deep venous thrombosis only.
?
Major Bleeding, No. (%)
Mortality, No. (%)
11213 (0.5)* 11/219 (5.0) 1/85 (1.2) 3185 (3.8) 0174 1/72 (1.4) 0/67 0167 11101 01103
101213 (4.7)* 211219 (9.6) 6185 (7.1) 12/85 (14.1) 0174 1172 (1.4) 3/67 (4.5) 2187 (3.0) 2/101 (2.0) 31103 (2.9)
involvement of the popliteal.
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continuous intravenous, unfractionated heparin for the treatment of venous thrombosis used a twice-daily, subcutaneous injection of LMWH. This was based on the hypothesis that maintaining a more constant antiX, level was important to suppress thrombus formation in the initial stages of treatment. In the study by Hull et al,45 a single injection of LMWH was given based on the hypothesis that achieving a therapeutic dose of LMWH would be as important as achieving therapeutic levels of heparin early on in the treatment of deep venous thrombosis to prevent recurrent thromboembolism.43 Studies with three different LMWHs have indicated that a once-daily subcutaneous injection is at least as effective and safe as twice-daily injections.30,31, 76 Therefore, oncedaily administration of LMWH will become the standard of care for the treatment of deep venous thrombosis. A study showed that once-daily LMWH was as effective as continuous intravenous unfractionated heparin in the initial treatment of patients presenting with pulmonary emboli~m.~~ A cost-effectiveness analysis indicated that LMWH was cost-effective when compared with continuous intravenous heparin under the study protocol conditions because monitoring was not necessary and there were fewer complications requiring rehospitalization and treatment.47These findings were verified by a sensitivity analysis. It was estimated that 37% of patients on LMWH could have been discharged on day 2, which would have further increased the cost-effectiveness of the LMWH.47 Two studies indicate that in selected patients LMWH treatment can be administered safely outside the hospital.51,54 Patients who met the entry criteria were randomized to receive twice-daily LMWH either entirely out of the hospital or with early discharge or continuous intravenous heparin in hospital. Warfarin was started on day 1 or 2 and continued for 3 months. Both studies showed equivalence with respect to the incidence of recurrent venous thromboembolism, major bleeding, and mortality rates.51,54 In these studies, 31% and 33% of patients with proximal venous thrombosis were eligible for entry. A third study comparing LMWH primarily out-of-hospital with continuous intravenous heparin in-hospital supports these findings.24 This study included approximately 30% of patients who presented with documented pulmonary embolism, and their outcomes with LMWH and intravenous heparin were comparable for the end points of recurrent venous thromboembolic death and major hemorrhage. This finding is supported by the clinical trial demonstrating that once-daily LMWH was as effective as intravenous unfractionated heparin in the treatment of patients presenting with pulmonary embolism.75The generalizability of these outpatient studies depends largely on the referral base of the institution. In large, tertiary care centers, it is likely that as many as 60% of patients will require in-hospital care, whereas in community hospitals, as many as 80% may be eligible for out-of-hospital treatment. The use of out-of-hospital LMWH, along with warfarin, has created a number of logistic problems, which so far defy easy solutions. This
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approach to treatment requires someone to take responsibility for either teaching the patients to self-inject or ensuring that the patients get their daily injections of LMWH, that they have daily measurement of their INR, and that somebody orders the appropriate dose of warfarin. Also, it is important that all the members of the health care team are kept informed regarding the patient’s progress and follow-up.
RECOMMENDATIONS FOR TREATMENT OF VENOUS THROMBOEMBOLISM
Based on level I evidence, the recommendations for treatment of venous thromboembolism are as follows.
Heparin Therapy
Heparin should be delivered by continuous intravenous infusion using one of the published heparin nomograms to ensure adequate heparinization in the initial 24 to 48 hours of therapy. Warfarin therapy should be started on day 1, with heparin treatment being continued until the INR is therapeutic (2.0 to 3.0) for 2 consecutive days. The platelet count should be measured at initiation of therapy and repeated every 2 days while the patient is on heparin treatment. The APTT should be used for monitoring heparin therapy and should be performed every 4 to 6 hours until a therapeutic APTT is achieved. The therapeutic range for APTT should reflect therapeutic heparin levels measured by the anti-X, assay (0.35 to 0.70 { +grk}m(-grk}/mL).
Low-Molecular-Weight Heparin Treatment
LMWH should be given by subcutaneous injection once or twice daily, beginning at the time of diagnosis. Most of the available LMWHs have been shown to be equally effective when given by once-daily as compared with twice-daily injections. The dosage and schedule should be based on evidence from level I clinical trials and the approval by regulatory bodies. The dosage schedules for the LMWHs approved in North America are as follows: tinzaparin 175 X, p/kg once daily, dalteparin 200 X, p/kg once daily, and enoxaparin 1 mg/kg twice daily (1.5 mg/kg once daily has been shown to be equally effective). No laboratory tests for monitoring LMWH therapy are required. Platelets should be measured before beginning therapy and every 2 days while on LMWH. Warfarin therapy should be started on day 1, and LMWH should be continued for 5 days or until the INR is therapeutic (2.0 to 3.0) for 2 consecutive days.
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Out-of-Hospital Treatment
Out-of-hospital treatment with LMWH and warfarin can be used for selected patients who are not at high risk of bleeding, who do not have other comorbid diseases requiring hospital admission, and who are considered to be candidates for out-of-hospital treatment by their attending physician. Out-of-hospital treatment with LMWH and warfarin requires the presence of a skilled team and the necessary infrastructure for arranging daily follow-up visits, including measurement of INR as well as close communication with all members of the health care team. It is recommended that each center undertaking out-of-hospital treatment of venous thromboembolism develop such a program as well as the necessary funding arrangements for physician services. CONCLUSION
Knowledge regarding the appropriate management of venous thromboembolism has been revolutionized by the results of a large number of level I clinical trials. Although questions remain, the clinician is in a much better position to manage venous thromboembolism in a safe, effective manner, and this will undoubtedly lead to improved patient care and a decreased threat of medical liability. The availability of LMWH for the treatment of venous thromboembolism has resulted in an effective, safe, and convenient alternative to intravenous heparin and has permitted the out-of-hospital management of many patients with venous thromboembolism, resulting in better use of hospital beds, increased patient satisfaction, and considerable cost savings for the health care system. References 1. Albada J, Nieuwenhuis HK, Sixma JJ, et al: Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin): Results of a double-blind randomized study. Circulation 80:935-940, 1989 2. Anderson L-0, Barrowcliffe TW, Holmer E, et al: Molecular weight dependency of the heparin potentiated inhibition of thrombin and activated factor X: Effect of heparin neutralization in plasma. Thromb Res 115:531-538, 1979 3. Andrew M, Cade J, Buchanan MR, et al: Low-molecular weight heparin does not cross the placenta [abstr]. Thromb Haemost 50:225, 1983 4. Andriuoli G, Mastacchi R, Barnti M, et al: Comparison of the antithrombotic and hemorrhagic effects of heparin and a new low molecular weight heparin in the rat. Haemostasis 153324-330, 1985 5. 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 104:648-654, 1995 6. Bara L, Billaud E, Gramond G, et al: Comparative pharmacokinetics of low molecular weight heparin (PK 10169) and unfractionated heparin after intravenous and subcutaneous administration. Thromb Res 39:631-636, 1985
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Address reprint requests to Russell D. Hull, MB, BS Thrombosis Research Unit 601 South Tower Foothills Hospital 1403-29 Street NW Calgary, AB T2N 2T9 Canada