Vascular Medicine 1998; 3: 41–46
`
`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 unfrac-
`tionated 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 bioavail-
`ability 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 progress-
`ively 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 pentasacchar-
`ide being its minimal active fragment.1 Low-molecular-
`weight 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 ineffec-
`tive 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 replac-
`ing progressively, since the mid-1980s, UFH for prevention
`of deep venous thrombosis (DVT) and pulmonary embol-
`ism (PE) in patients at risk, especially during the perioper-
`ative 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 sub-
`cutaneous 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 large-
`scale 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, Switzer-
`land.
`(cid:211) Arnold 1998
`
`the present review compares LMWH and UFH in the set-
`tings of prophylaxis and therapy of venous thromboembol-
`ism 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 con-
`firmed in clinical trials even though the antithrombotic
`effect of LMWH, like that of UFH, occurs mainly via inhi-
`bition 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 thrombocy-
`topenia (HIT) have been reported with the low-molecular-
`weight compounds.5 Due to extensive in vitro cross-
`reactivity of the two forms of heparin, periodical monitor-
`ing 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
`
`1358-863X(98)VM213MP
`
`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
`Exhibit 1018
`
`

`

`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 (PF4), 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 PF4 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. Conse-
`quently, 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 anti-
`factor Xa activity is approximately doubled both after intra-
`venous (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 per-
`mit 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 monitoring9,10 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, pro-
`longed 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
`
`anti-Xa
`plasma
`of
`thromboembolism), measurement
`activity might be useful after 24–48 h of treatment in order
`to avoid drug accumulation with possibly increased bleed-
`ing risk.11 The target anti-Xa activity for therapeutic indi-
`cations 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 gen-
`eral surgery, orthopedic surgery and neurosurgery as well
`as in immobilized medical patients. Subsequently, meta-
`analyses 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 non-
`significant12 compared with a marginally significant13
`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 large-
`scale 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 thrombopro-
`phylactic 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).
`
`Mean molecular weight (range)
`Anti-Xa to anti-IIa activity ratio
`Half-life of anti-Xa activity
`following IV application
`following SQ application
`Bioavailability
`Elimination
`Binding to PF4 and EC
`Application
`prophylaxis
`therapy
`
`Monitoring in prophylaxis
`Monitoring in therapy
`Heparin-induced thrombocytopenia
`Heparin-induced osteoporosis
`
`LMWH
`
`UFH
`
`4500 (2000–10 000)
`2–5
`
`15 000 (4000–30 000)
`1
`
`2 h
`4 h
`.90%
`Kidney
`(+)
`
`SQ (1 inj/daya)
`SQ (1–2 inj/day)
`
`No
`No
`+
`?
`
`1 h
`2 h
`40%
`Liver
`++
`
`SQ (2–3 inj/day)
`Continuous IV infusion
`or SQ (2–3 inj/day)
`No
`Yes (APTT)
`++
`+
`
`aIn 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; PF4, platelet factor 4; EC, endothelial cell; inj, injection; APTT, activated partial thromboplastin
`time.
`(+), very low importance or absent; +, low importance; ++, major importance.
`
`Vascular Medicine 1998; 3: 41–46
`
`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
`Exhibit 1018
`
`

`

`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 al12 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 clini-
`cally 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 cost-
`effectiveness 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 one-
`fourth) of all postoperative PE following general surgery
`occurs during the month following discharge from hospi-
`tal.17 While the cost-effectiveness of prolonged prophylaxis
`was questioned by Kakkar et al,14 Sarasin and Bouna-
`meaux18 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 inter-
`ventions – to recommend.
`Following major orthopedic surgery, Planes et al19 and
`Bergqvist et al20 demonstrated that prolongation of post-
`operative prophylaxis with LMWH by 3–4 weeks was asso-
`ciated with a substantial (about 50%) diminution of post-
`operative thromboembolic events
`following total hip
`replacement. On the other hand, a cost-effectiveness analy-
`
`Vascular Medicine 1998; 3: 41–46
`
`sis could demonstrate that systematic prolongation of per-
`ioperative 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 thera-
`peutic trials with clinically relevant endpoints, Leizorovicz
`et al22 and Lensing et al23 showed that LMWH was associa-
`ted with a reduction of the risk of thromboembolic recur-
`rence and major bleeding along with a statistically signifi-
`cant 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),
`
`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
`Exhibit 1018
`
`

`

`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 al22 and Lensing et al.23 The
`odds ratios are given along with the corresponding 95% confidence interval. (VTE, venous thromboembolism.)
`
`with encouraging results26,27 (Table 2). Nonetheless, treat-
`ment 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 gen-
`eralizable 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. Wide-
`spread outpatient treatment of DVT will certainly depend
`on the possibility of a once-daily subcutaneous (SQ) injec-
`tion 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 superior28 or equivalent29 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 PE31 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 subcut-
`aneous applications) of nadroparin and in the group of
`patients treated with continuous intravenous UFH (n = 33).
`These data were recently confirmed in the multicenter
``
`
`THESEE 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 trial26
`
`Canadian trial27
`
`UFH
`
`Nadroparin
`
`UFH
`
`Enoxaparin
`
`n
`Dose
`Recurrent DVT
`Recurrent PE
`Recurrent VTEa
`Death
`Major bleeding
`Hospital stayb (days)
`
`198
`IV infusion
`12
`2
`17 (8.6%)
`16 (8.1%)
`4 (2.0%)
`8.1
`
`202
`2 · 100 IU/kg per day SQ
`10
`2
`14 (6.9%)
`14 (6.9%)
`1 (0.5%)
`2.7
`
`253
`IV infusion
`15
`5
`17 (6.7%)
`17 (6.7%)
`3 (1.2%)
`6.5 6 3.4
`
`247
`2 · 1 mg/kg per day SQ
`11
`4
`13 (5.3%)
`11 (4.5%)
`5 (2.0%)
`1.1 6 2.9
`
`aIn the Tasman trial, recurrent events at 6 months, in the Canadian Multicenter trial at 3 months.
`bMean 6 SD (when available).
`SQ, subcutaneous; IV, intravenous administration.
`
`Vascular Medicine 1998; 3: 41–46
`
`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
`Exhibit 1018
`
`

`

`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 preg-
`nancy although these compounds are merely mentioned in
`the guidelines on the prevention, investigation, and man-
`agement of thrombosis associated with pregnancy, pub-
`lished in 1993.36 Nonetheless, their use should be con-
`sidered particularly because transplacental passage has been
`excluded (at least for enoxaparin during the second trimes-
`and nadroparin during the
`third trimester of
`ter37
`pregnancy38). 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 throm-
`boembolic event, thrombocytopenia, or excessive hemorrh-
`age, but one patient had osteoporotic vertebral collapse
`postpartum. Safe and effective prophylaxis with nadroparin
`was also recently demonstrated in seven patients with fam-
`ilial thrombophilia during their entire pregnancies.40
`
`Conclusions
`
`For a given antithrombotic efficacy, the novel LMWH com-
`pounds are safer than unfractionated heparin both in the
`prophylactic and therapeutic indications of venous throm-
`bosis. Whether this improved benefit-to-risk ratio is the
`consequence of
`the increased anti-factor Xa to anti-
`thrombin activity ratio or
`from other, yet undefined
`characteristics, remains unclear. The most important practi-
`cal advantage of LMWH consists of particular pharmacol-
`ogic 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 prophy-
`laxis and treatment are still mandatory. As an additional
`
`Vascular Medicine 1998; 3: 41–46
`
`Heparin in the treatment of venous thromboembolism 45
`
`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.
`
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`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
`Exhibit 1018
`
`

`

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`
`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
`Exhibit 1018
`
`