Unfractionated versus low-molecular-weight heparin in the treatment of venous thromboembolism

Unfractionated versus low-molecular-weight heparin in the treatment of venous thromboembolism Henri Bounameaux Abstract: Low-molecular-weight heparin (LMWH) fractions are prepared from standard unfractionated heparin (UFH) and are thus similar to UFH in many aspects. The main advantages of this new class of antithrombotic agents as compared with UFH are: (1) an improved bioavailability and a prolonged half-life, which alleviate cumbersome laboratory monitoring and may permit one single daily subcutaneous injection; and (2) an improved efficacy-to-safety ratio, with less bleeding despite similar or improved efficacy. For these reasons, LMWH is progressively replacing UFH for preventing postoperative thromboembolism and for treating established deep vein thrombosis and pulmonary embolism. However, the effects of the new compounds need to be evaluated carefully in some other indications (arterial thrombosis, unstable angina, or myocardial infarction the latter also in conjunction with thrombolytic treatment) before they can generally replace UFH in pharmacotherapy. Key words: anticoagulation; low-molecular-weight heparin; unfractionated heparin Introduction Unfractionated heparin (UFH) is a heterogeneous mixture of linear polysaccharide chains with variable molecular weight and biological activity, a well-defined pentasaccharide being its minimal active fragment. 1 Low-molecularweight heparin fractions (LMWH) were developed in the late 1970s and early 1980s by fractionation of the crude UFH, a large proportion of the heparin chains being ineffective as cofactors for antithrombin III, the main inhibitor of thrombin-induced conversion of fibrinogen to fibrin. This cofactor activity is thought to be the predominant action of heparin in blood. 2 The LMWH fragments have been replacing progressively, since the mid-1980s, UFH for prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients at risk, especially during the perioperative period. During the last few years, the new compounds have also been approved for treatment of established venous thromboembolism in several European countries. In the USA, however, the only compounds approved so far are enoxaparin for prevention of venous thrombosis following elective total hip or knee arthroplasty (with two daily subcutaneous injections) or general surgery prophylaxis (40 mg subcutaneously once daily), dalteparin (once daily) for general surgery prophylaxis, and ardeparin given in a weight-adjusted dose twice daily for prophylaxis after total knee arthroplasty. It is anticipated that enoxaparin will receive approval in 1998 for treatment of unstable angina pectoris. More than a decade after the publication of the first largescale trial on the thromboprophylactic effects of LMWH, 3 Division of Angiology and Hemostasis, Department of Internal Medicine, University of Geneva School of Medicine, Geneva, Switzerland Address for correspondence: H Bounameaux, Division of Angiology and Hemostasis, University Hospital of Geneva, CH-1211 Geneva 14, Switzerland. the present review compares LMWH and UFH in the settings of prophylaxis and therapy of venous thromboembolism and discusses briefly some issues that remain to be addressed before the new agents can completely replace the old UFH. Comparison of characteristics of LMWH and UFH The mean molecular weight of LMWH fractions is about 3500 8000 daltons, compared with 15 000 daltons in the unfractionated material. Heparin molecules with a lower molecular weight inhibit activated coagulation factor X (factor Xa) via conformational change of the antithrombin III molecule more efficiently than they inhibit thrombin (also called factor IIa), with an anti-factor Xa to anti-factor IIa activity ratio range from 1.7 to 4.0, depending upon the brand considered. Because factor Xa acts earlier in the coagulation cascade than thrombin, it was hypothesized that LMWH would produce fewer bleeding complications for a given antithrombotic efficacy. This was subsequently confirmed in clinical trials even though the antithrombotic effect of LMWH, like that of UFH, occurs mainly via inhibition of thrombin and/or thrombin generation. 4 Because low-molecular-weight fractions of heparin react less with platelets than high-molecular-weight fractions, it was also anticipated that LMWH would less often induce immuno-allergic thrombocytopenia, a severe side-effect of UFH that is often complicated by arterial thrombosis. Nevertheless, several cases of heparin-induced thrombocytopenia (HIT) have been reported with the low-molecularweight compounds. 5 Due to extensive in vitro crossreactivity of the two forms of heparin, periodical monitoring of the platelet count is mandatory even with LMWH because an absolute platelet count of less than 50 000/ml or a relative drop of 50% in 24 h in patients given heparin strongly suggests immune-induced thrombocytopenia. 6 Arnold 1998 1358-863X(98)VM213MP

42 H Bounameaux However, there is no doubt that HIT is less frequently observed while patients are on LMWH than when they are given UFH. 7 Similarly, heparin-induced osteoporosis that occurs after months of administration of the compound seems less frequent after LMWH. 8 In practice, the most relevant advantages of LMWH (Table 1) are an improved bioavailability and a prolonged half-life. The improved bioavailability (more than 90%, ie twice that of UFH) is mainly due to a reduced reactivity with platelet factor 4 (PF 4 ), a release product of activated platelets acting as an anti-heparin and as such inhibiting a certain, variable amount of circulating heparin. Since the plasma concentration of PF 4 may vary considerably from one individual to another, especially during an active thrombotic process, the amount of UFH that is required in a particular patient is basically unpredictable. Consequently, the anticoagulant effect of UFH must be monitored with the activated partial thromboplastin time (APTT) or the thrombin clotting time. The plasma half-life of the antifactor Xa activity is approximately doubled both after intravenous (2 h compared with 1 h for UFH) and subcutaneous (4 h compared with 2 h for UFH) administration of LMWH. Improved bioavailability and prolonged half-life may permit administration of LMWH in one (prophylaxis) or one to two (therapy) subcutaneous injections instead of two to three injections for UFH. The improved bioavailability of LMWH also results in plasma anti-factor Xa activity that is more predictable than after administration of UFH. 9 The development of weight-adjusted dose regimens for the therapeutic indications of LMWH avoids cumbersome and costly laboratory monitoring 9,10 and is predicated upon the improved bioavailability of LMWH. In contrast to UFH, which is mainly cleared by the liver, the elimination of LMWH occurs mostly via the kidneys. However, prolonged anti-xa activity following LMWH administration is observed only in patients with end-stage renal insufficiency. In such patients, if LMWH is to be used at therapeutic doses (for treatment of established venous thromboembolism), measurement of plasma anti-xa activity might be useful after 24 48 h of treatment in order to avoid drug accumulation with possibly increased bleeding risk. 11 The target anti-xa activity for therapeutic indications is 0.5 1.0 anti-xa IU/ml. Prevention of venous thromboembolism Individual studies have demonstrated the effects of LMWH for prevention of venous thromboembolism following general surgery, orthopedic surgery and neurosurgery as well as in immobilized medical patients. Subsequently, metaanalyses permitted a systematic, quantitative overview of data from individual studies, thereby increasing statistical power. Two meta-analyses have compared subcutaneous low doses of LMWH and UFH for prevention of postoperative venous thromboembolism. 12,13 The main results of these meta-analyses are depicted in Figure 1. Briefly, in patients undergoing general surgery, there was a statistically nonsignificant 12 compared with a marginally significant 13 greater efficacy of LMWH with respect to incidence of postoperative DVT and PE compared with UFH. In patients who underwent total hip arthroplasty, both meta-analyses agreed upon the superiority of LMWH with regard to the incidence of postoperative DVT (risk reduction 17 32%) and PE (risk reduction about 50%). Following both general and orthopedic surgery, the incidence of major bleeding was almost identical with LMWH and UFH (Figure 1). Similar safety results were recently obtained in one largescale multicenter trial in the UK. 14 Thus, the efficacy to safety ratio was found to be improved for LMWH in the prophylactic setting. Following hip arthroplasty, Bachmann and Leyvraz pointed to the intriguing selective thromboprophylactic effect of LMWH on proximal DVT, which was observed in several trials. The proportion of the proximal thromboses among all postoperative DVT was indeed only Table 1 Comparison of the main characteristics of low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH). LMWH UFH Mean molecular weight (range) 4500 (2000 10 000) 15 000 (4000 30 000) Anti-Xa to anti-iia activity ratio 2 5 1 Half-life of anti-xa activity following IV application 2 h 1 h following SQ application 4 h 2 h Bioavailability 90% 40% Elimination Kidney Liver Binding to PF 4 and EC (+) ++ Application prophylaxis SQ (1 inj/day a ) SQ (2 3 inj/day) therapy SQ (1 2 inj/day) Continuous IV infusion or SQ (2 3 inj/day) Monitoring in prophylaxis No No Monitoring in therapy No Yes (APTT) Heparin-induced thrombocytopenia + ++ Heparin-induced osteoporosis? + a In the USA, enoxaparin is approved for prevention of DVT following total hip or knee arthroplasty at a dosage of 2 daily SQ injections of 30 mg (3000 IU). IV, intravenous; SQ, subcutaneous; PF 4, platelet factor 4; EC, endothelial cell; inj, injection; APTT, activated partial thromboplastin time. (+), very low importance or absent; +, low importance; ++, major importance.

Heparin in the treatment of venous thromboembolism 43 Figure 1 Prevention of postoperative deep vein thrombosis (DVT) and pulmonary embolism (PE) with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) in randomized, controlled studies. Summary of the meta-analyses of Leizorovicz et al 12 and Nurmohamed et al. 13 The odds ratios are given along with the corresponding 95% confidence interval. 32% with LMWH, compared with 54% with UFH and 57% in untreated controls, 15 an interesting and potentially clinically relevant finding because proximal DVT is the source of the larger, potentially lethal pulmonary emboli. The economical aspects of perioperative antithrombotic prophylaxis following total hip arthroplasty were studied by Menzin et al. They calculated that the LMWH enoxaparin, though more costly than low-intensity warfarin, had a costeffectiveness that compared favorably with other generally accepted medical interventions: US$ 12 000 per death averted. 16 Duration of postoperative prophylaxis is also of great clinical and economical relevance, since it was recently shown that a substantial proportion (about onefourth) of all postoperative PE following general surgery occurs during the month following discharge from hospital. 17 While the cost-effectiveness of prolonged prophylaxis was questioned by Kakkar et al, 14 Sarasin and Bounameaux 18 calculated that the marginal costs to prevent one clinical thromboembolic event in a cohort of 10 000 patients would be approximately US$ 40 000 the cost per life saved being US$ 400 000. This cost is obviously too excessive when compared with other health care interventions to recommend. Following major orthopedic surgery, Planes et al 19 and Bergqvist et al 20 demonstrated that prolongation of postoperative prophylaxis with LMWH by 3 4 weeks was associated with a substantial (about 50%) diminution of postoperative thromboembolic events following total hip replacement. On the other hand, a cost-effectiveness analy- sis could demonstrate that systematic prolongation of perioperative LMWH prophylaxis with a 6-week course of oral anticoagulants represents a safe and effective alternative management option in most patients who underwent this type of surgery. 21 Therapy of established venous thromboembolism In pooled analyses of the controlled, randomized therapeutic trials with clinically relevant endpoints, Leizorovicz et al 22 and Lensing et al 23 showed that LMWH was associated with a reduction of the risk of thromboembolic recurrence and major bleeding along with a statistically significant phlebographic reduction of the thrombus size (Figure 2) when compared with continuous intravenous infusion of UFH. Treatment of established DVT initially was found to be more expensive with LMWH than with UFH, unless medical care and nursing were reduced significantly, 24 a finding that was recently challenged by Hull et al who reported cost-savings both in the US and Canadian healthcare systems when LMWH was used instead of UFH. 25 On the other hand, the absence of monitoring and once daily subcutaneous administration open the way to outpatient treatment of DVT, which should drastically reduce treatment costs. The efficacy and safety of this approach have been assessed in two trials (in which LMWH was administered in two daily subcutaneous injections),

44 H Bounameaux Figure 2 Treatment of established proximal deep vein thrombosis with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) in randomized, controlled studies. Summary of the meta-analyses of Leizorovicz et al 22 and Lensing et al. 23 The odds ratios are given along with the corresponding 95% confidence interval. (VTE, venous thromboembolism.) with encouraging results 26,27 (Table 2). Nonetheless, treatment of proximal DVT in an outpatient setting requires appropriate infrastructures that ensure both an objective diagnosis and a controlled home therapy, which are not available in all countries or regions. Moreover, results of the published large-scale trials are not necessarily generalizable to the whole population of patients with proximal DVT because only 69% 26 or 22% 27 of eligible patients, respectively, could be included in the two trials. Widespread outpatient treatment of DVT will certainly depend on the possibility of a once-daily subcutaneous (SQ) injection of LMWH in the therapeutic setting. One single daily SQ administration of tinzaparin (175 IU/kg every 24 h) 28 or dalteparin (200 IU/kg every 24 h) 29 has already been shown to be superior 28 or equivalent 29 to continuous intravenous UFH for treatment of proximal vein thrombosis. The FRAXODI study demonstrated recently that outcomes were almost identical if patients with proximal DVT received the daily dose of nadroparin in one or two injections. 30 Preliminary data regarding the use of LMWH in patients with established non-massive PE 31 are already available from a dose-ranging study, which showed that at day 8, the improvement of the pulmonary vascular obstruction and the frequency of major bleedings were similar in the group of patients given 150 IU/kg per day (n = 35) (in two subcutaneous applications) of nadroparin and in the group of patients treated with continuous intravenous UFH (n = 33). These data were recently confirmed in the multicenter THÈSEE trial of tinzaparin (once-daily subcutaneous injection) versus UFH (continuous intravenous infusion) in more than 600 patients with symptomatic PE. 32 Table 2 Outpatient treatment of proximal deep-vein thrombosis: summary of two large-scale multicenter trials. Tasman trial 26 Canadian trial 27 UFH Nadroparin UFH Enoxaparin n 198 202 253 247 Dose IV infusion 2 100 IU/kg per day SQ IV infusion 2 1 mg/kg per day SQ Recurrent DVT 12 10 15 11 Recurrent PE 2 2 5 4 Recurrent VTE a 17 (8.6%) 14 (6.9%) 17 (6.7%) 13 (5.3%) Death 16 (8.1%) 14 (6.9%) 17 (6.7%) 11 (4.5%) Major bleeding 4 (2.0%) 1 (0.5%) 3 (1.2%) 5 (2.0%) Hospital stay b (days) 8.1 2.7 6.5 3.4 1.1 2.9 a In the Tasman trial, recurrent events at 6 months, in the Canadian Multicenter trial at 3 months. b Mean SD (when available). SQ, subcutaneous; IV, intravenous administration.

Heparin in the treatment of venous thromboembolism 45 Comparison of LMWH and UFH in hemodialysis, coronary syndromes and cerebrovascular accidents LMWHs have also been used successfully to prevent thrombosis in hemodialysis and extracorporeal circuits. However, there are no obvious advantages over UFH for this indication. 33 TIMI-11 is testing enoxaparin versus UFH in unstable angina (unpublished data), and FRISC showed that dalteparin was able to reduce by about 50% the rate of death and new myocardial infarction in more than 1500 patients with unstable coronary artery disease. 34 However, the control group was not receiving UFH but placebo. In a placebo-controlled trial of Chinese patients, the LMWH nadroparin was also effective in improving outcome at 6 months when given within 48 h of the onset of ischemic stroke symptoms. 35 LMWH in pregnancy Heparin is the anticoagulant of choice during pregnancy both for preventive and therapeutic purposes. Because of the pharmacologic advantages and convenience of LMWH, especially in cases requiring prolonged administration (months), many clinicians are using LMWH during pregnancy although these compounds are merely mentioned in the guidelines on the prevention, investigation, and management of thrombosis associated with pregnancy, published in 1993. 36 Nonetheless, their use should be considered particularly because transplacental passage has been excluded (at least for enoxaparin during the second trimester 37 and nadroparin during the third trimester of pregnancy 38 ). This attitude is further supported by two recently published series. In 34 pregnancies (32 patients) at high risk of DVT who received prophylactic dalteparin during a mean period of 20 weeks, 39 there was no thromboembolic event, thrombocytopenia, or excessive hemorrhage, but one patient had osteoporotic vertebral collapse postpartum. Safe and effective prophylaxis with nadroparin was also recently demonstrated in seven patients with familial thrombophilia during their entire pregnancies. 40 Conclusions For a given antithrombotic efficacy, the novel LMWH compounds are safer than unfractionated heparin both in the prophylactic and therapeutic indications of venous thrombosis. Whether this improved benefit-to-risk ratio is the consequence of the increased anti-factor Xa to antithrombin activity ratio or from other, yet undefined characteristics, remains unclear. The most important practical advantage of LMWH consists of particular pharmacologic properties that allow the drug to be administered in one (prophylactic setting) or one to two (therapeutic setting) subcutaneous injections instead of two to three for UFH. Although LMWH fractions exhibit a more favorable profile, they are not devoid of risk with respect to complications such as bleeding or immuno-allergic thrombo- cytopenia. Thus, objective indications for prophylaxis and treatment are still mandatory. As an additional advantage, no laboratory control is required with LMWH in most patients except for a mandatory weekly platelet count. However, for some indications, such as treatment of arterial thrombosis or myocardial infarction, data are still needed before LMWH can definitely replace UFH. References 1 Choay J, Petitou M, Lormeau JC, Sinay P, Casu B, Gatti G. Structure activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. Biochem Biophys Res Commun 1983; 116: 492 99. 2 Rosenberg RD, Damus PS. The purification and mechanism of action of human antithrombin-heparin cofactor. J Biol Chem 1973; 248: 6490 505. 3 Kakkar VV, Murray WJG. Efficacy and safety of low-molecularweight heparin (CY216) in preventing postoperative venous thromboembolism: a co-operative study. Br J Surg 1985; 72: 786 91. 4 Hemker HC, Béguin S. 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