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Relative efficacy and safety of low molecular weight heparin preparations for non-hospital prophylaxis… British Columbia Office of Health Technology Assessment Jan 31, 1998

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Centre for Health Servicesand Policy ResearchRELATIVE EFFICACY ANDSAFETY OF LOW MOLECULARWEIGHT HEPARIN PREPARATIONSFOR NON-HOSPITAL PROPHYLAXISAND TREATMENT OF VENOUSTHROMBO-EMBOLIC DISEASEBCOHTA 98:3J          JANUARY 1998British Columbia Office of Health Technology AssessmentJoint Health Technology Assessment SeriesU N I V E R S I T Y  O F  B R I T I S H  C O L U M B I ALow molecular weight heparin preparations 1BC OFFICE OF HEALTH TECHNOLOGY ASSESSMENTTable of ContentsINTRODUCTION TO THE SERIES 21.0   REQUEST 32.0   BACKGROUND 33.0   ASSESSMENT OF CLINICAL RESEARCH 66.0   CONCLUSIONS 9REFERENCES 10Low molecular weight heparin preparations 2BC OFFICE OF HEALTH TECHNOLOGY ASSESSMENTIntroduction to the SeriesThe Joint Heath Technology Assessment Series reports on projects initiated bythe British Columbia Office of Health Technology Assessment (BCOHTA) andevidence-based medicine programs in BC. These programs are dedicated toproducing unbiased, systematic reviews of clinical efficacy and effectivenessevidence for health care providers, administrators, policy makers, and thegeneral public, and currently include:· Therapeutics Initiative (TI), Department of Pharmacology and Therapeutics,Faculty of Medicine, University of BC, Vancouver· Technology Assessment Committee, Capital Health Region, Victoria· Drug Benefit Committee, Pharmacare, and ad hoc Health TechnologyAssessment Committees, the Ministry of Health and Ministry Responsible forSeniors, Victoria· Technology Assessment Committee, Workers' Compensation Board of BC,Richmond· Population Testing Programs, Boundary Health Unit, South Fraser HealthUnit, Surrey· BC Research Institute for Child and Family Health, BC Women’s andChildren’s Hospital, Vancouver· Public Health Nursing, Boundary Health Unit, South Fraser Health Region,Surrey·    Centre for Clinical Epidemiology and Evaluation, Vancouver Hospital andHealth Sciences Centre, VancouverTopics reflect initiative and institutional needs. Priority is given to topics withsignificant impact on patient health and health care costs, and with issues inmore than one context. The goal is to teach systematic review and criticalappraisal skills and coordinate efforts among geographically separate andinstitutionally diverse contexts.Two different types of evidence-based medicine problems are addressed:1. uncertainty regarding new technology2. discrepancy between evidence and practice for established technology.The Joint HTA Series will produce scientifically valid systematic reviews that keyindividuals in each receptor site support. The key individuals are needed topresent and defend the systematic review conclusions during ongoing committeedebates. This step is essential to connect health policy, including fundingdecisions, to the available efficacy and effectiveness evidence.Low molecular weight heparin preparations 3BC OFFICE OF HEALTH TECHNOLOGY ASSESSMENTRelative efficacy and safety of low molecular weightheparin preparations for non-hospital prophylaxis andtreatment of venous thrombo-embolic disease1.0  RequestPharmacare currently faces the difficult task of coordinating its non-hospital low molecularweight heparin (LMWH) reimbursement policy with the diverse reimbursement policiesfound among hospitals in the British Columbia.1  As part of this coordination effort,Pharmacare asked the Therapeutics Initiative (TI) for an evidence-based opinion on therelative efficacy and safety of LMWH preparations. Whereas BC hospitals conduct theirown literature reviews and set independent formulary policy, Pharmacare tends to turn tothe TI for systematic reviews and critical appraisal expertise.Pharmacare asked about the relative efficacy and safety of LMWHs because its currentreimbursement policy is under review. At issue is the question of substitution. The currentpolicy is:1) to restrict funding of all LMWHs to known indications, as part of its Special AuthorityProcess2) to recommend use of the least expensive LMWH, tinzaparin3) to accept requests for funding of other, more expensive preparations: enoxaparin anddalteparin. In relation to this policy, Pharmacare asked TI: Is there any scientific evidence thatsubstituting one LMWH for another results in decreased efficacy or safety?  Important tonote, Pharmacare acknowledges the differences in molecular structure, pharma okinetics,and biological activity among LMWH preparations. Nevertheless, Pharmacare askedwhether, despite these known differences, is there evidence that substitution diminishespatient outcome?2.0  BackgroundLMWH and unfractionated heparin (UH) are glycosaminoglycans consisting of chains ofalternating reisidues of glucuronic acid or iduronic acid.2 LMWHs available in Canada areall derived, albeit differently, by de-polymerization of porcine (and perhaps in part bovine)mucosal heparin. Most LMWHs have a molecular weight of about one-third that ofheparin.The rationale for using LMWH, as opposed to UH, in humans is from animal studies thatfound it possible to dissociate the antithrombotic from the hemorrhagic effect of theseagents.3  In particular, LMWHs provide the opportunity to maintain the sameantithrombotic effect while decreasing the hemorrhagic effect.Low molecular weight heparin preparations 4BC OFFICE OF HEALTH TECHNOLOGY ASSESSMENTAnimal studies comparing the antithrombotic and hemorrhagic effect of various LMWHspreparations found no significant differences among the preparations.4,5  The studieconcluded that method of preparation of LMWH did not influence in vivo antithromboticactivity or hemorrhagic effect.2.1 ManufacturingThe following quotation from a recent review of LMWH pharmacology6 summarizes themain drug manufacturing features:Enoxaparin (Levenox) is obtained by enzlation followed by alkalinedepolymerization (beta elimination). Large amounts of sodium bisulfite are addedto prevent oxidation of the terminal groups, since this product contains a doublebond at the reducing end. However, a recent formulation does not contain anysodium bisulfate and the new formulation is claimed to exhibit pharmacologicaleffects similar to those of the original product.Dalteparin (Fragmin) is obtained by nitrous acid depolymerization followed byion exchange chromatography. This drug markedly differs from the other LMWHsin physiochemical characteristics and pharmacological profile.Tinzaparin (Innohep) is prepared by enzymatic digestion using FlavobacteriumHeparinicum heparinase. This drug also contains large amounts of sodiumbisulfate as an antioxidant.Fareed et al. 1996:p.78Each depolymerization process results in structural changes to UH. Benzlation(enoxaparin) and heparinase digestion (tinzaparin) result in introduction of a double bondat the end grouping. Nitrous acid depolymerization (dalteparin) results in formation ofanhydromannose (5 member ring).Chemical modifications of the end groups and internal structures, charge density,and degree of desulfination during manufacturing all add to the individualitydisplayed by the resulting products.5p.79Molecular weightenoxaparin                       4200 Daltonsdalteparin                         6000 Daltonstinzaparin                         4500 DaltonsLow molecular weight heparin preparations 5BC OFFICE OF HEALTH TECHNOLOGY ASSESSMENT2.2  Mechanism of actionA recent review of LMWHs originating at McMaster University in Hamilton7 summarizeswhat is seen as the main difference in mechanism of action between LMWH and UH:a) anti-thrombotic activity:Both UH and LMWHs exert their anticoagulant activity by activating ntithrombin(previously known as antithrombin III). Their interaction with antithrombin ismediated by a unique pentasaccharide sequence that is randomly distributed alongthe heparin chains....Binding of the pentasaccharide to antithrombin causes a conformational change inantithrombin that accelerate its interaction with thrombin and activated factor X(factor Xa) and thrombin....In contrast, to inactivate thrombin, heparin must bind to both antithrombin andthrombin, forming a ternary complex. This complex can only be formed bypentasaccharide-containing heparin chains of at least 18 s cch ride units. Whereasmost of the chains of unfractionated heparin are at least 18 saccharide units long,fewer than half of those of LMWHs are of sufficient length to bind to bothantithrombin and thrombin. Consequently, unlike unfractionated heparin, which hasequivalent activity against factor X  and thrombin,  LMWHs have greater activityagainst factor Xa.Weitz JI 1997:p.688The authors of the review also note other mechanisms of action. For example, they explainthat both UH and LMWHs release tissue-factor-pathway inhibitor which inhibits factor Xaactivity and ultimately thrombin formation.2.3  Hemorrhagic effectLMWHs causes less bleeding than UH. LMWHs bind less to platelets, do not increasemicro vascular permeability, and cause less interference in the interaction between plateletsand vessel walls.6p.6902.4  PharmacokineticsThe half life of LMWHs is two to four times that of UH: intravenous = 2 - 4 hrs;and subcutaneous = 3 - 6 hrs. LMWHs, in contrast to UH, bind less to plasma proteins,endothelial cells, and macrophages.6p.690  A  a result, LMWHs have more predictableanticoagulation effect and better bioavailability.2.5  StandarizationLow molecular weight heparin preparations 6BC OFFICE OF HEALTH TECHNOLOGY ASSESSMENTEfforts to establish assays to determine bioequivalence have failed.5p.87  In particular, anti-Xa  methods have not allowed adjustment of LMWH potency. Anti-Xa is only one ofmany different biological properties of these agents. Tissue factor pathway inhibitor, forexample, is recognized as an important contributor to the anti-thr mbotic action of theseagents.3.0  Assessment of clinical research3.1 Principles1) Conclusive scientific evidence of problems related to substituting LMWHs could onlybe produced in one way:  a well designed and properly conducted clinical trialcomparing two or more LMWHs, for the same clinical indication. If one LMWH wasshown to be superior to another in either efficacy or safety, then  substitution shouldnot occur. 2) Evidence of problems related to substitution, albeit indirect and inconclusive, couldalso derive from a collection of high quality clinical trials for the same clinicalindication, each using a single LMWH. The LMWH could be compared to placebo,alternate anti-thrombotic drugs such as UH and warfarin, or mechanical devices (in thecase of surgical prophylaxis). All trials would need full critical appraisal. Ifmethodologically sound trials found one LMWH safer or more effective for a clinicalindication than another, then the less effective LMWH would need, at minimum,additional clinical trial evidence v sus placebo to show that it is equivalent beforsubstitution could be made. Ideally, the LMWHs in question should be compared in asingle clinical trial. 3) Evidence of problems related to substitution cannot arise if only one LMWH has beenstudied for a clinical indication. Substitution, in this instance, would be based strictlyon pharmaco-economics or policy principles. 4) Clinical trials of various agents, including LMWHs, for DVT prophylaxis andtreatment have been too small to link specific therapies to final health outcomes suchas clinically significant pulmonary embolism or death.Low molecular weight heparin preparations 7BC OFFICE OF HEALTH TECHNOLOGY ASSESSMENT3.2  Methodology3.2.1 Search strategyThe search was conducted from 1966 to 1997 using MEDLINE database and CurrentContents. Key words used were DVT, LMWH, Dalteparin, enoxaparin, adroparin,tinzaparin, thromboembolic disease and orthopedic procedures: knee and hip replacementsurgery. To identify all systematic reviews on LMWH, the Cochrane Library was searchedfrom 1993 to 1997. Subject headings used were “heparin, low molecular weight”.Textwords were used to complement the search such as “heparin NEAR low NEARmolecular”. Other clinical subjects headings were combined with the above search termsto ensure relevance: “thrombophlebitis” (MeSH), “thromboembolism” (tw), “dvt or deepNEAR venous NEAR thrombosis” (tw). Wherever possible the MeSH subject headingswere “exploded” to maximize the scope of the search.3.2.2 Inclusion/exclusion criteriaThe principle search objective was for double-blind, randomized controlled clinical trials(RCTs) comparing two or more LMWHs for prophylaxis or treatment of thrombo-embolic disease.Also included were RCTs comparing single LMWH with placebo, UH, and warf rin forprophylaxis and treatment of venous thrombo-embolic disease. Clinical trials involvingsingle LMWHs for venous, as opposed to arterial, clinical indications were includedbecause of their potential relevance to Pharmacare, that is, non-hospital patient care.Excluded were trials with weaker study design or for clinical conditions treated exclusivelywithin the hospital setting.3.2.3 Search findings and critical appraisal results1) Clinical trials comparing LMWHsClinical studies have not examined the relative efficacy and safety of LMWHs available inCanada, for any clinical indication, inside or outside hospitals.The only published study directly comparing two LMWHs examined enoxaparin(benzylation, followed by alkaline hydrolysis, mw 4200)  and reviparin (nitrous aciddigestion, mw4653, not available in Canada) for the in-hospital prevention of DVT in416 patients undergoing total hip replacement.8  Both groups had similar efficacy, (venousthrombosis 9 and 10%, respectively) and rate of major bleeding (1% in each group).Low molecular weight heparin preparations 8BC OFFICE OF HEALTH TECHNOLOGY ASSESSMENT2) Clinical trials using different LMWHs, but for the same clinical indication, potentiallytreated in the non-hospital settingSeveral high quality trials were found involving single LMWHs for treatment of clinicalindications of potential relevance to Pharmacare: non-hospital treatment of DVT andprophylaxis of hip and knee surgery.Non-hospital treatment of venous thrombo-embolic diseaseNon-hospital treatment of DVT is the first clinical indication for which LMWHreimbursement by Pharmacare is possible. Prior to non-hospital treatment of DVT,virtually all LMWH in BC was provided in and paid for by acute care hospitals.In 1996, the TI conducted a systematic review and subjected the relevant trials to fullcritical appraisal. Two very similar, well designed and conducted, albeit open RCTs9,10compared LMWH administered primarily at home versus UH administered primarily inhospital for treatment of deep vein thrombosis (DVT). Each used a different LMWH,enoxaparin 1mg/kg bid (benzylation, followed by alkaline hydrolysis, mw 4200)  andfraxiparin /kg dose (Nadroparin, nitrous acid depolymerization, mw4500). Results werevery similar for efficacy (5.3% and 6.9% had symptomatic recurrent venous thrombosis,respectively) and safety (2% and 1% had major bleeds, respectively). These trials wererated as excellent, by the TI.It seems reasonable to conclude, based on these similar, high quality clinical trials thatenoxaparin and fraxiparin can be safely interchanged for the non-hospital treatment ofDVT.Prophylaxis of venous thrombo-embolic disease in patients undergoing total kneeand hip replacement surgeryVenous-thrombo-embolic-disease prophylaxis in patients undergoing total kneereplacement surgery could potentially become part of Pharmacare’s jurisdiction in thefuture. Patients receiving total knee replacement (and perhaps hip replacement) may needLMWH prophylaxis subsequent to early hospital discharge.In the instance of total knee replacement, two separate RCTs compare LMWHs(tinzaparin and enoxaparin, respectively) with a common comparator (warfarin) forprophylaxis of venous thrombo-embolism in patients undergoing total kneereplacement.11,12  Both studies found the LMWH more effective than warfarin and equallysafe.T = 45% and E = 37% versus W = 55% and 52% DVT, respectivelyT = 3% and E = 2% major bleed versus W = 1% and 2%, respectivelySubsequent studies have compared enoxaparin, but not tinzaparin, to UH during totalknee replacement. Conclusions regarding the validity of these trials and theinterchangability of LMWHs for this clinical indication, will have to await full criticalLow molecular weight heparin preparations 9BC OFFICE OF HEALTH TECHNOLOGY ASSESSMENTappraisal. Full critical appraisal by the TI, in turn, will depend on local demand for non-hospital LMWH prophylaxis.6.0 Conclusions1) Despite the known pharmacological differences in LMWH , o clinical outcomeevidence has established a clinical significant advantage for one LMWH preparationover another for non-hospital clinical indications. 2) Clinical evidence in general, albeit scant, suggests that LMWHs are interchangeable.The one study7 directly comparing LMWHs had similar results for both preparationsfor patients undergoing hip replacement. In the outpatient treatment of DVT (the oneclinical indication in which trials were critically appraised) both preparations had thesame efficacy and safety. 3) Indication by indication, systematic reviews and critical appraisals will be needed todetermine the relative efficacy and safety of LMWHs. This level of critical analysis willbe needed both for ideal studies that compare LMWHs directly to one another or themore common studies that continue to examine single LMWHs versus alternate drugtherapyLow molecular weight heparin preparations 10BC OFFICE OF HEALTH TECHNOLOGY ASSESSMENTReferences                                         1  Pharmacare Briefing Note: Low Molecular Weight Heparing.  December 1997.2 Rosenberg RD, Bauer KA.  The heparin-antithrombin system: a natural anticoagulant mechanism. In:Coleman RW,  Hirsch J, Marder VJ, Salzman EW, eds.  Hemostasis and thrombosis: basic principles andclinical practice. 3rd ed.  Philadephia: J.B. Lippincott, 1994:837-60.3 Carter, CJ,  Kelton JG, Hirsh J, Cerskus A, Santos AV,  Gent M.  The relationship between thehemorrhagic and antithrombotic properties of the low molecular weight heparin in rablits.  Blood1982;59(6):1239-1245.4 Cade JF, Buchanan MR, Boneu B, Ockelford P, Carter CJ, erskus AL, Hirsh J.  A comparison of theantithrombotic and hemorrhagic effects of low molecular weight heparin fractions: the influence of themethod of preparation.   Thrombosis Research 1984;35:613-625.5 Boneu B, Buchanan MR, Cade JF, Van Ryan J, Fernandez FF, Ofosu FA, Hirsh J.  Effects of heparin, itslow molecular weight fractions and other glycosaminoglycans on thrombus growth in vivo. ThrombosisResearch 1985;40:81-89.6 Fareed J,  Jeske W,  Hoppensteadt D, Clarizio R, and Walenga, JM.  Are the Available Low-Molecular-Weight Heparin Preparations the Same?  Seminars in Thrombosis and Hem stasis, 1996;22(1):77-91.7 Weitz JI.  Low-Molecular Weight Heparins.  NEJM, 1997;337(10):688-698.8 Boneu B.  An international multicentre study: Clivarin in the prevention of venous thr mboembolism inpatients undergoing general surgery:  report of the International Clivarin Assessment Group.  BloodCoagul Fibrinolysis 1993;4 Suppl 1:S21-S22.9 Levine M et al.  A comparison of LMWH administered primarily at home with unfractionated heparinadministered in the hospital for proximal deep-vein thrombosis.  NEJM 1996;334:671-81.10 Koopman MM et al.  Treatment of venous thrombosis with intravenous u fractionated heparinadministered in the hospital as compared with subcutaneous heparin adminst red at home. NEJM1996;334:682-87.11 Hull R et al.  A comparison of subcutaneous low-molecular weight heparin with warfarin sodium forprophylaxis against deep vein thrombosis after hip or knee implantation.  NEJM, 1993;329:1370-.12 Leclerc JR et al.  Prevention of venous thr mbo-embolism (VTE) after knee arthroplasty - Arandomized double-blind trial comparing enoxaparin with warfarin.  Annals of IntMed 1996;124:619-626.


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