To review the recent literature on the approved uses of enoxaparin, dalteparin, ardeparin, and tinzaparin and the evidence for therapeutic equivalence.
DATA SOURCES:
A MEDLINE search (1993–January 2001) was conducted to identify English-language literature available on enoxaparin, dalteparin, ardeparin, and tinzaparin.
STUDY SELECTION:
All controlled trials evaluating low-molecular-weight heparins (LMWHs) versus standard therapy powered to detect a significant difference were reviewed.
DATA EXTRACTION:
Agents were reviewed with regard to safety and efficacy.
DATA SYNTHESIS:
As a class, LMWHs have chemical, physical, and clinical similarities. LMWHs have greater bioavailability, longer half-lives, a more predictable pharmacologic response, possible improved safety, and similar or greater efficacy compared with unfractionated heparin (UFH). Because of this, enoxaparin, dalteparin, ardeparin, and tinzaparin are being considered as alternatives to UFH or warfarin, and there is potential for therapeutic interchange. Evaluation of clinical trials is limited because of differing diagnostic methods, drug administration times, dose equivalencies, and outcome measurements.
CONCLUSIONS:
Only 1 trial has evaluated 2 LMWHs in a direct comparison in the same study. There is insufficient evidence for determining the therapeutic equivalence of LMWHs.
HirshJWarkentinTEShaugnessySGAnandSSHalperinJLRaschkeRHeparin and low-molecular weight heparin. Chest2001;119 (Suppl):64S–94S.
2.
WeitzJI. Low-molecular-weight heparins. N Engl J Med1997;337: 688–98.
3.
GuyattGSchunemannHCookDJaeschkeRPaukerSBucherH. Grades of recommendation for antithrombotic agents. Chest2001;119(Suppl):3S–7S.
4.
FareedJJeskeWHoppensteadtDClarizioRWalengaJM. Are the available low molecular weight heparin preparations the same?Semin Thromb Hemost1996;22: 77–91.
5.
BickRLFareedJ. Low molecular weight heparin: Differences and similarities in approved preparations in the United States. Clin Appl Thromb Hemost1999;5(suppl 1):S63–7.
6.
OfosuFASmithLMAnvariNBlajchmanMA. An approach to assigning in vitro potency to unfractionated and low molecular weight heparins based on the inhibition of prothrombin activation and catalysis of thrombin inhibition. Thromb Haemost1988;60: 193–8.
LevineMNPlanesAHirshJGoodyearMVochelleNGentM. The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparin: Low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost1989;62: 940–4.
10.
BaraLPlanesASamamaMM. Occurrence of thrombosis and haemorrhage, relationship with anti-Xa, anti-IIa activities, and D-dimer plasma levels in patients receiving a low molecular weight heparin, enoxaparin or tinzaparin, to prevent deep vein thrombosis after hip surgery. Br J Haematol1999;104: 230–40.
11.
NieuwenhuisHKAlbadaJBangaJDSixmaJJ. Identification of risk factors for bleeding during treatment of acute venous thromboembolism with heparin or low molecular weight heparin. Blood1991;78: 2337–43.
12.
LaposataMGreenDVan CottEMBarrowcliffeTWGoodnightSHSosolikRC. College of American Pathologists Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy. Arch Pathol Lab Med1998;122: 799–807.
13.
DuplagaBARiversCWNutescuE. Dosing and monitoring of low-molecular weight heparin in special populations. Pharmacotherapy2001;21: 218–34.
14.
ZmudaKNeofotistosDTs'aoCH. Effects of unfractionated heparin, low molecular-weight-heparin and heparinoid on thromboelastographic assay of blood coagulation. Am J Clin Pathol2000;113: 725–31.
15.
GeertsWHHeitJAClagettGPPineoGFColwellCWAndersonFAPrevention of venous thromboembolism. Chest2001;119(1 suppl):132S–75S.
16.
CollinsRScrimgeourAYusufSPetoR. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. N Engl J Med1988;318: 1162–73.
17.
ColditzGATudenRLOsterG. Rates of venous thrombosis after general surgery: Combined results of randomized clinical trials. Lancet1986;2: 143–6.
18.
ClagettGPReischJS. Prevention of venous thromboembolism in general surgical patients. Results of meta-analysis. Ann Surg1988;208: 227–40.
19.
BreddinHK. Low molecular weight heparin in the prevention of deep vein thrombosis in general surgery. Semin Thromb Hemost1999;25(suppl 3):83–91.
20.
KakkarVVDeLorenzoF. Prevention of venous thromboembolism in general surgery. Baillieres Clin Haematol1998;11: 605–19.
21.
DouketisJFCrowtherMAFosterGAGinsbergJS. Does the location of thrombosis determine the risk of disease recurrence in patients with proximal deep vein thrombosis?Am J Med2001;110: 515–9.
22.
NurmohamedMTVerhaegheRHaasSIriateJAVogelGVan RijAMA comparative trial of a low molecular weight heparin (enoxaparin) versus standard heparin for the prophylaxis of postoperative deep vein thrombosis in general surgery. Am J Surg1995;169: 567–71.
23.
Efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of deep vein thrombosis in elective cancer surgery: A double-blind randomized multicentre trial with venographic assessment. Enoxacan Study Group. Br J Surg1997;84: 1099–103.
24.
KakkarVVCohenATEdmonsonRAPhillipsMJCooperDJDasSKLow molecular weight versus standard heparin for prevention of venous thromboembolism after major abdominal surgery. Lancet1993;341: 259–65.
25.
Package insert. Fragmin (dalteparin). Kalamazoo, MI: The Pharmacia Corp., revised May 1999.
26.
LeclercJRGeertsWJDesjardinsLLaflammeGHl'EsperanceBDemersCPrevention of venous thromboembolism after knee arthroplasty. Ann Intern Med1996;124: 619–26.
27.
HeitJABerkowitzSDBonaRCabanasVCorsonJDElliottCGEfficacy and safety of low molecular weight heparin (ardeparin sodium) compared to warfarin for the prevention of venous thromboembolism after total knee replacement surgery: A double-blind, dose-ranging study. Thromb Haemost1997;77: 32–8.
28.
Package insert. Normiflo (ardeparin). Philadelphia, PA: Wyeth-Ayerst, revised January 1998.
29.
RaderCPKramerCKonigAHendrichCEulertJ. Low-molecular-weight heparin and partial thromboplastin time adjusted unfractionated heparin in thromboprophylaxis after total knee and total hip arthroplasty. J Arthroplasty1998;13: 180–5.
30.
ColwellCWCollisDKPausonRMcCutchenJWBiglerGTLutzSComparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthroplasty. J Bone Joint Surg Am1999;81: 932–40.
31.
PlanesASamamaMMLensingAWABullerHRBarreJVochelleNPrevention of deep vein thrombosis after hip replacement. Thromb Haemost1999;81: 22–5.
32.
FrancisCWPellegriniVDJr.TottermanSBoydADMarderVJLiebertKMPrevention of deep-vein thrombosis after total hip arthroplasty. J Bone Joint Surg Am1997;79: 1365–72.
33.
HullRDPineoGFFrancisCBergqvistDFelleniusCSoderbergKLow-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs. warfarin in hip arthroplasty patients. Arch Intern Med2000;160: 2199–207.
34.
HirschJHoakJ. Management of deep vein thrombosis and pulmonary embolism. Circulation1996;93: 2212–45.
35.
CarterCJ. The natural history and epidemiology of venous thrombosis. Prog Cardiovasc Dis1994;36: 423–38.
36.
WeinmannEESalzmanEW. Deep-vein thrombosis. N Engl J Med1994;331: 1630–41.
37.
AndersonFAWheelerHBGoldbergRJHosmerDWPatwardhanSAJovanovicBA population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. Arch Intern Med1991;151: 933–8.
38.
HyersTMAgnelliGHullRDMorrisTASamamaMTapsonVAntithrombotic therapy for venous thromboembolic disease. Chest2001;119(Suppl):176S–93S.
39.
SimonneauGCharbonnierBDecoususHPlanchonBNinetJSiePSubcutaneous low-molecular weight heparin compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med1993;153: 1541–6.
40.
MarderVJSoulenRLAtichartakarnVBudzynskiAZParulekarSKimJRQuantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy. J Lab Clin Med1977;89: 1018–29.
41.
HullRDRaskobGEBrantRFPineoGFValentineKA. The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy. Arch Intern Med1997;157: 2317–21.
42.
LevineMGentMHirshJLeclercJAndersonDWeitzJA 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 Med1996;334: 677–81.
43.
MerliGSpiroTEOlssonCGAbildgaardUDavidsonBLEldorASubcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med2001;134: 191–202.
44.
FiessingerJNLopez-FernandezMGattererEGranqvistSKherAOlssonCGOnce-daily subcutaneous dalteparin, a low molecular weight heparin, for the initial treatment of acute deep vein thrombosis. Thromb Haemost1996;76: 195–9.
45.
LuomanmakiKGranqvistSHallertCJauroIKetolaKKimHCA multicentre comparison of once-daily subcutaneous dalteparin (low molecular weight heparin) and continuous intravenous heparin in the treatment of deep vein thrombosis. J Intern Med1996;240: 85–92.
46.
SimonneauGSorsHCharbonnierBPageYLaabanJPAzarianRA comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. N Engl J Med1997;337: 663–9.
47.
HullRDRaskobGEBrantRFPineoGFElliottGSteinPDLow-molecular-weight heparin vs. heparin in the treatment of patients with pulmonary embolism. Arch Intern Med2000;160: 229–36.
48.
Package insert. Innohep (tinzaparin). Wilmington, DE: Dupont Pharmaceutical Co., July 2000.
49.
OlerAWhooleyMAOlerJGradyD. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. JAMA1996;276: 811–5.
50.
TherouxPOuimetHMcCansJLatourJGJolyDLevyGAspirin, heparin or both to treat unstable angina. N Engl J Med1988;19: 1105–50.
51.
Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet1990;336: 827–30.
52.
HoldrightDPatelDCunninghamDThomasRHubbardWHendryGComparison of the effect of heparin versus aspirin alone on transient myocardial ischemia and in-hospital prognosis in patients with unstable angina. J Am Coll Cardiol1994;24: 39–45.
53.
CairnsJATherouxPLewisHDEzekowitzMMeadeTW. Antithrombotic agents in coronary artery disease. Chest2001;119(Suppl):228S–52S.
54.
CohenMDemersCGurfinkelEPTurpieAGGFromellGJGoodmanSA comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med1997;337: 447–52.
55.
GoodmanSGCohenMBigonziFGurfinkelEPRadleyDRLe IourerVRandomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: One-year results of the ESSENCE study: Eficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events. J Am Coll Cardiol2000;36: 693–8.
56.
FergusonJJ. Meeting highlights: 47th Annual Scientific Sessions of the American College of Cardiology. Circulation1998;97: 2377–82.
57.
AntmanEMMcCabeCHGurfinkelEPTurpieAGGBernikPJLMSaleinDEnoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation1999;100: 1593–601.
58.
AntmanEMCohenMRadleyDMcCabeCRushJPremmereruJAssessment of the treatment effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction: TIMI 11B-ESSENCE meta-analysis. Circulation1999;100: 1602–8.
59.
Low-molecular-weight heparin during instability in coronary artery disease. Fragmin during Instability in Coronary artery disease (FRISC) study group. Lancet1996;347: 561–8.
60.
Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease FRISC II) investigators. Lancet1999;354: 701–7.
61.
KleinWBuchwaldAHillisSEMonradSSanzGTurpieAGGComparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in Unstable Coronary Artery Disease Study (FRIC). Circulation1997;96: 61–8.
62.
SpinlerSA. Unfractionated heparin dosing in the FRIC study (letter). Circulation1998;97:1424.
63.
KaulSShahPK. Low molecular-weight heparin in acute coronary syndrome: Evidence for superior or equivalent efficacy compared to unfractionated heparin?J Am Coll Cardiol2000;35: 1699–712.
64.
RacineE. Differentiation of the low-molecular-weight heparins. Pharmacotherapy2001;21(6 Pt. 2):62s–70s.
65.
LopezLM. Low-molecular weight heparins are essentially the same for treatment and prevention of venous thomboembolism. Pharmacotherapy2001;21(6 Pt. 2):56s–61s.
66.
PlanesAVochelleNFagolaMBellaudM. Comparison of two low molecular weight heparins for the prevention of post operative venous thromboembolism after elective hip surgery. Reviparin Study Group. Blood Coag Fibrinolysis1998;9: 499–505.
