Levien, Lewis

Louridas, George

Veller, Martin

English

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declines until a steady state is reached where HBVtransmission is maintained at low endemic levels. On thebasis of this model of HBV transmission, vaccination of agecohorts with an increasing prevalence of HBV markers couldcontribute substantially to interrupting HBV transmission bydecreasing the number of susceptibles (members of thepopula ion with no HBV markers). Hence, vaccinationwastage may not be an important factor mitigating againstvaccination of children in the first decade of life.Which is the best vaccinationoption for South Africa?Given the high levels of HBV transmission in childhood,particularly during the preschool and primary school years, itis important to have the cohort of children from birth to 10years protected as soon as possible. Option 3 is myproposed option. It is unfortunate that this decision was notmade in 1994/95 so that the dual vaccination age couldhave been implemented right at the start of the HBVvaccination programme. Even though HBV vaccination is inits 3rd year, the introduction in 1998 of routine HBVvaccination at both birth and 5 years would substantiallyspeed up HBV protection in childhood. This approach wouldmean that by the year 2000, the cohort of birth to 7 yearswill be vaccinated. This catch-up vaccination at 5 yearswould need to be implemented for 3 years only, from 1998to 2000. Thereafter, only the routine newborn vaccinationneed continue.Why select 5 years for the catch-up vaccination?HBV transmission is still well below its peak at 5 years.There are high levels of susceptibles at 5 years. The routineEPI of the South African health service includes avaccination visit at 5 years for 01. Including the first dose ofHBV vaccine at this visit will minimise the effort involved ininforming mothers to bring their children for HBV vaccinationat 5 years. During vaccination with the first dose,appointments for the follow-up doses can be providedtogether with counselling on the importance of not missingthem. A further point is that HBV vaccination coverage in 5-year-old children can be monitored at 6 years when thechildren enter school.In conclusion, data on the age-specific prevalence of HBVinfection suggest that a dual-age HBV vaccination strategyis a better option than the current strategy of infantvaccination. HBV control is within our grasp in South Africa;using a dual-age strategy will mean that we can realise thisgoal sooner rather than later.Salim S. Abdool KarimCentre for Epidemiological Research in South AfricaMedical Research CouncIlDurbanWest DJ. Calandra GB. Hesley TM. loll V. Miller WJ. Control of hepatitis 8through routme ImmunizatIOn of Infants' the need for flexible schedules and newcombination vaccine formulations Vaccme 1993: 11: suppl 1. 521-S27.2 Edmunds WJ, Medley GF. Nokes DJ. The transmiSSIon dynamics and control ofhepatitis B VirUS In the Gambia Stat Med 1996: 15: 2215-2233__ \'olume t SO. 6 June /9911 AM]3. Stevens CE, Toy PT. Taylor PE, Lee T. Ylp HY. Prospects for control of hepatitis Bvirus infection: Implications of childhood vaCCination and long-term protection.Paediatrics 1992: 90: 170-173.4. Epidemiological Comments 1995; 22: 192.5. Zanetti AR, Tanzi E, Romano L. Grappasonni I. Vaccmation against hepatitis B:the italian strategy. Vaccme 1993; 11: 521-524.6. Abdool Karlm SS, Coovadla HM, Windsor IM, Thejpal R, Van den Ende J, FoucheA. The prevalence and transmission of hepatitiS B VirUS infection in urban, ruraland institutionalized black children of Natal/KwaZulu. South Africa. Int JEpidemlol 1988: 17: 168·173Clinical LessonLow-molecular-weightheparins allow selectedoutpatient treatment forvenous thrombosisThe conventional treatment for patients with an acute deep-vein thrombosis (DVT) at present consists of an initialcontinuous intravenous infusion of unfractionated heparin,administered for a minimum of 5 - 7 days.' Oralanticoagulation is started at the same time, while the patientis still in hospital, and is continued for at least 3 months. Theinitial treatment with heparin, which aims to preventpulmonary embolism and recurrent thrombosis, has beenfound to be effective! but the anticoagulant response tounfractionated heparin varies markedly. As a consequencethe dosage of unfractionated heparin must be monitoredcarefUlly by frequent measurement of activated partialthromboplastin times (aPTIs), necessitating hospitalisationof the patient for the period that the unfractionated heparinis being administered.Low-molecular-weight heparins (LMWHs), prepared fromdigestion of heparin by chemical or enzymaticdepolymerisation (to produce molecules that are usually lessthan 18 saccharide units in length), have several advantagesover the parent compound.1. The anticoagulant activity of the heparins resides in aunique pentasaccharide sequence which is randomlydistributed along the heparin chains and binds with highaffinity to antithrombin. Any heparin (no matter how long themolecule), containing this pentasaccharide sequence,inactivates factor Xa simply by binding to antithrombin andthereby accelerating the interaction between factor Xa andantithrombin. In contrast, the inactivation of thrombin byunfractionated heparin requires heparin to bind to bothantithrombin and thrombin. This complex can only beformed if the heparin chains are at least 18 saccharide unitslong and also include the pentasaccharide sequence (mostmolecules of unfractionated heparin are at least 18saccharide units in length). As a result, unfractionatedheparin has equivalent inhibitory activity against both factorXa and thrombin, while LMWHs preferentially inactivatefactor Xa.2. Unlike unfractionated heparin, LMWHs can inactivateplatelet-bound factor Xa and can resist inhibition by plateletfactor 4, which is released during clotting.SAMJE d tor a I3. LMWHs may also cause fewer haemorrhagiccomplications as a result of their less pronounced effect onplatelet and vascular endothelial function.These characteristics result in a longer half-life, better bio-availability, and more predictable anticoagulant activity.3.'The LMWHs can therefore be administered subcutaneously,without laboratory monitoring, in a dosage determined bythe patient's weight alone.Initially, LMWHs were used in small doses in theprevention of venous thrombosis in high-risk patients' Inthis setting they are as effective at preventing thedevelopment of DVTs as low-dose subcutaneousunfractionated heparin (Kakkar's regimen), if not more so. Inaddition, bleeding complications appear to be reduced andthe drug can generally be administered as a single dailydose when used for this indication.Subsequently, a number of excellent randomised studieshave demonstrated that weight-adjusted fixed-dose LMWHgiven subcutaneously is as effective as intravenousunfractionated heparin (dose-adjusted to prolong the aPTT)in the initial treatment of hospitalised patients with DVT.~14These studies have recently been summarised in a meta-analysis.'s1. The venographically determined thrombus size (5th to10th day after treatment was started) was reduced in 64%of patients receiving LMWH compared with 50% in thosereceiving unfractionated heparin (P < 0.001.) Similarly, therewas an increase in thrombus size in 6% of patients receivingLMWH compared with 12% in those receivingunfractionated heparin (P < 0.001).2. The incidence of major bleeding was 3.2% in thepatients receiving unfractionated heparin compared with0.9% in those receiving LMWH (risk reduction 68%;P < 0.005).3. The recurrence rate of clinically apparent DVT waslower in those patients receiving LMWH (unfractionatedheparin 7% v. LMWH = 2.7%; risk reduction 61 %;P < 0.005), as was mortality (unfractionated heparin 8.1 % v.LMWH 4.3%; risk reduction 48%; P < 0.03).As a result of these studies, many centres (particularly inEurope) have used LMWH in an outpatient setting as theinitial form of therapy in selected patients presenting withDVT. That this is effective and safe has been shown in tworecently published studies.'·17 In both these studiesunfractionated heparin given intravenously to hospitalisedpatients was compared with LMWH given subcutaneously topatients at home. The use of LMWH in an outpatient settingfor the treatment of DVT not only increases patientconvenience but also reduces hospital costs dramatically.The major concern regarding the use of LMWHs in anoutpatient setting is the possible complications. The twostudies mentioned above revealed that life-threateningpulmonary embolism was exceedingly rare with bothmodalities of treatment, and when death did occur it wasnot clear that the outcome would have been improved if thepatients had been treated in hospital. On the other hand,bleeding complications are potentially more treatable inhospital. It is therefore prudent to treat patients with acoexisting risk of bleeding in a hospital environment,irrespective of the type of heparin used.In conclusion, LMWHs given in a fixed dose withoutlaboratory monitoring are at least as effective as carefullymonitored standard unfractionated heparin administered bycontinuous intravenous infusion. As they produce lessbleeding for eqUivalent antithrombotic effects, their use inoutpatient treatment of DVT has been studied and beenfound to be safe in selected patients. The resultant increasein patient convenience and reduction in hospitalisation makethis a very attractive alternative to the standard form of initialanticoagulation for DVT in selected patients suitable for thistreatment.Martin VellerGeorge LouridasLewis LevienDepartment of SurgeryUniverSIty of the WitwatersrandJohannesburg1. Hirsh J. Heparin. N Engl J Med 1991; 324: 1565-1574.2. Brandjes DPM, Heijboer H, Buller HR, de Rljk M, Jag! H, ten Cate JW.Acenocoumarol and heparm compared With acenocoumarol alone in the initialtreatment of proximal-vem thrombosis. N Eng/ J Med 1992; 327: 1485-1489.3. Fareed J. Hoppensteadt OA. Pharmacology of the low·molecular·welght heparins.Semin Thromb Hemosl 1996; 22: suppl2, 13-18.4. Hirsh J. LevlOe MN. Low mole-cular weight heparin. Blood 1992; 79: 1-17.5. Haas 5, Haas P. The efficacy of low molecular weight heparm. In: Bergvist 0,Comerota AJ, Nicolatdes AN, Scurr JH, eds. Prevention of VenousThromboembolism. London: Med-Onon, 1994; 149-161.6. Holm HA, Ly 8, Handeland GF, et al. Subcutaneous heparin treatment of deepvein thrombosis: A comparison of unfractionated and low molecular weightheparin. Haemostasis 1986; 16: suppl 2, 30-37.7. Faivre R, Neuhart E, Kleffer Y, et al. Subcutaneous administration of a lowmol~ular weight heparin CY222 compared with subcutaneous administration ofstandard heparin in patients with acute deep vein thrombosis. Thromb Haemost1987; 58: suppl, 430.8. Bratt G, Tornebohm E. Granqvist S, Aberg W, Lockner D. A comparison betweenlow molecular weight heparin (Kabi 2165) and standard heparin in the intravenoustreatment of deep venous thrombosis (DVl). Thromb Haemost 1985; 54: 813-817.9. Bratt G, Aberg W, Johansson E, Tornebohm E, Granqvist S, Lockner D. Two dailysubcutaneous injections of Fragmm as compared with intravenous standardheparin in the intravenous treatment of deep venous thrombosis (DVT). ThrombHaemost 1990; 64: 506-510.10. Duroux P, Beclere A. A randomized trial of subcutaneous low molecular weightheparin (CY216) compared With intravenous unfractionated heparin in thetreatment of deep vein thrombosis. Thromb Haemost 1991; 65: 251-256.". Slmonneau G. Subcutaneous fixed dose enoxaparin versus Intravenous adjusteddoses of unfractianated heparin in the treatment 0 deep venous thrombosis.Thromb Haemost 1991; 65: suppl, 754.12. Prandani P, Lensing AWA, Buller HR, et aJ. Comparison of subcutaneous low-molecular weight heparin with intravenous standard heparin in proximal deep·vein thrombosis. Lancet 1992; 339: 441-445.13. Lopaciuk S, Meissner AJ, Filipecki S, et al. Subcutaneous low molecular weightheparin versus subcutaneous Intravenous unfractionated heparin in the treatmentof deep vein thrombosis: A Polish multicenter triat Thromb Haemost 1992; 68:14-18.14. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low molecular weight heparincompared with continuous intravenous heparin in the treatment of proximal veinthrombosis. N £ngl J Med 1992; 326: 975-982.15. Lensing AWA, Prins MH, Davidson BL, Hirsh J. Treatment of deep venousthrombosis With low-molecular-weight hepanns: A meta·analysls. Arch InternMed 1995; 155: 601-607.16. Levine M, Gent M, Hlrsch J. et al. A comparison of low-molecular-weight heparinadministered primarily at home With unfractionated heparin administered in thehospital for proximal deep-vein thrombOSIs. N Eng/ J Med 1996; 334: 677-681.17. Koopman MMW, Pradoni P, Piovella F, et al. Treatment of venous thrombosIs withintravenous unfractionated hepann administe~ed in the hospital compared Withsubcutaneous law·malecular-wetght heparin administered at home N Engl J Med1996; 334: 682-687SAMJ Volume 88 No. 6 June /998

Low-molecular-weight heparins allow selected outpatient treatment for venous thrombosis

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Low-molecular-weight heparins allow selected outpatient treatment for venous thrombosis

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