Vascular Pharmacology 62 (2014) 32–37

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Vascular Pharmacology

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Review

Bemiparin, an effective and safe low molecular weight heparin: A review

Marco Matteo Ciccone a,⁎, Francesca Cortese a, Filomena Corbo b, Noel Ernesto Corrales c,Abdul Kareem Al-Momen d, Antonio Silva e, Annapaola Zito a, Mariangela Pinto a,Michele Gesualdo a, Pietro Scicchitano a

a Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation, University of Bari, School of Medicine, Policlinico, Bari, Italyb Department of Pharmacy-Pharmaceutical Sciences, University of Bari, Bari, Italyc Cirurgia vascular y flebologia, cirurgia general y laparoscopica, Guatemalad College of Medicine, King Saud University, Riyadh, Saudi Arabiae Ochsner Clinic LLC–Cardiology Department, Slidell, LA, USA

⁎ Corresponding author at: Piazza G. Cesare, Bari 11-70E-mail address: marcomatteo.ciccone@uniba.it (M.M.

http://dx.doi.org/10.1016/j.vph.2014.03.0011537-1891/© 2014 Elsevier Inc. All rights reserved.

a b s t r a c t

a r t i c l e i n f o

Article history:Received 19 November 2013Received in revised form 13 February 2014Accepted 11 March 2014Available online 19 March 2014

Chemical compounds studied in this article:Acenocoumarol (PubChem CID: 54676537)Bemiparin (PubChem CID: 25244225)Dabigatran (PubChem CID: 216210)Enoxaparin (PubChem CID: 772)Fondaparinux (PubChem CID: 5282448)Heparin (PubChem CID: 444410)Idraparinux (PubChem CID: 3083445)Rivaroxaban (PubChem CID: 9875401)Warfarin (PubChem CID: 54678486)

Keywords:BemiparinLow molecular weight heparinVenous thromboembolismPrevention

Bemiparin is a lowmolecular weight heparin (LMWH) indicated for the acute treatment of deep vein thrombosiswith or without pulmonary embolism, for the prophylaxis of venous thromboembolism in surgical and non-surgical patients and for the prevention of clotting in the extracorporeal circuit during hemodialysis. Due to itsexcellent pharmacological profile—the second-generation LMWHwith the lowest molecular weight, the longesthalf-life and the highest anti-Factor Xa/anti-Factor IIa activity ratio—it can be safely used in special categories ofpatients (children, elderly, patients with renal impairment and congestive heart failure).Several studies demonstrated its safety and efficacy, while cost analyses show the economic benefits ofbemiparin treatment as compared to other heparins.Recent evidences suggested the application of bemiparin even in the management of diabetic foot ulcers.The aim of this narrative review was to evaluate literature according to results coming from studies involvingbemiparin administration in various clinical conditions.

© 2014 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322. Bemiparin: an overview on its features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323. Bemiparin and fondaparinux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324. Prophylaxis and acute treatment of VTE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

4.1. Prophylaxis of VTE: in general surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334.2. Prophylaxis of VTE: in orthopedic surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334.3. Acute treatment of VTE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334.4. Long-term treatment of VTE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

5. Treatment of VTE in special populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336. Bemiparin: other applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347. The economic impact in bemiparin administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

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124, Italy. Tel.: +39 080 5478791; fax: +39 080 5478796.Ciccone).

33M.M. Ciccone et al. / Vascular Pharmacology 62 (2014) 32–37

1. Introduction

Bemiparin is a lowmolecular weight heparin (LMWH) already usedin Europe during the last 10 years. It is administered in case of acutedeep vein thrombosis (DVT) with or without pulmonary embolism(PE), 115 IU anti-Xa activity/kg bodyweight once daily. Furthermore, itis used as prophylactic drug in venous thromboembolism (VTE) afterorthopedic surgical events, in patients obliged to rest positions [1].Themain characteristics of this LMWHare its lowanti-factor IIa (throm-bin) anti-Xa activity and its skill in increasing the release and activity oftissue factor pathway inhibitor from endothelial cells under both staticand shear stress conditions [1,2].

The European consensus on the prevention of VTE indicated 160cases of DVT and 60 of PE for every 100000 people per year [3]. VTE isalso associated with a high mortality risk [4].

These considerations underlined the importance of thrombo-prophylaxis in patients at moderate or high risk for VTE.

Several studies have beenperformed in order to establish the correctapproach for the prevention and treatment of VTE in terms of drugs'efficacy, dosages and time of administration. Previous studies suggestedthe importance of UFH (Heparin) use [5]. The synthesis of LMWHsimproved pharmacological profile of heparin family and efficacy andtolerability of thromboprophylactic regimens. [6].

This review tried to consider the most relevant aspects aboutbemiparin use in prophylaxis, in acute and long-term treatment ofVTE, both in outpatients and special populations [pregnant women,children, elderly, subjects with renal impairment and congestive heartfailure (CHF)]. Moreover, we tried to analyze the pharmaco-economicimpact of bemiparin use on public economy.

2. Bemiparin: an overview on its features

Bemiparin is structurally formed by repeating disaccharide unitscomposed of uronic acid residue and D-glycosamine residue, with thenon-reducing end formed by 4-enopyranosyluronate group [1]. Thesulfo-groups are fundamental for the pharmacological features of thecompound because they allow bemiparin, and other heparin-derivedmolecules, to interact with several basic proteins thanking the anionproperties that such chemical groups confer to the molecule [7,8].

Bemiparin was synthesized by alkaline depolymerization of medical-grade sodium unfractionated heparin (UFH) obtained from porcineintestinal mucosa [1]. Chemical or enzymatic process are effectivelyable to depolymerize heparin into lower molecular compounds: thisgenerates low molecular weight heparins which have been developedtill the generation of recent ultra-low molecular weight heparins, agroup to which bemiparin belong [8]. The compounds so obtainedshow a longer biological half-life and are more selective in its antagonis-tic action toward Xa coagulation factor [1]. The main feature of thisultra-low molecular weight heparin can be resumed as following:lower molecular weight than other LMWHs and UFH (3.6 kDa vs. 4.5kDa of enoxaparin and 15 kDa of UFH), a higher anti-Xa–anti-IIa activityratio (8.0:1 vs. 3.3–5.3:1 of enoxaparin and 1:1 of UFH) and a longer half-life (5.2–5.4 h vs. 4–4.4 h of enoxaparin and 0.5–1 of UFH) [2].

The chains show a high affinity-specific pentasaccharide, responsi-ble for the characteristics of bemiparin [8]. The reduced number ofchain is responsible for the high anti-Xa activity of the molecule ratherthan its thrombin inhibition. Gray et al. [9] outlined that a minimumnumber of saccharides next to the pentasaccharide zone is required inorder to achieve a good thrombin binding. This number is equal to 13saccharides associated to the pentasaccharide sequence and allows thecreation of a peculiar site which is able to fit the thrombin and inhibitits function [9]. Bemiparin is not good for this action due to its reducednumber of saccharides. Nevertheless, the inhibiting action on Xa coagu-lation factor is not dependent from the steric zone formed by the sac-charides chain [9]. For this reason, a higher anti-Xa–anti-IIa activityratio could be found for bemiparin as compared to other compounds.

Thus, bemiparin has a good antithrombotic activity and a betterpharmacological profile than UFH [1]. A recent study demonstratesthat depolymerized heparins like bemiparin can exhibit a range ofbiologic activitiesmaking themunique agents [10]. It hasmultiple phar-maceutical characteristics such as anti-IIa and anti-Xa activities andseems to exert pleiotropic effects. Several preclinical studies tried toaddress and better delineate the main features of bemiparin. Da Pozzoet al. [11] carried out an in vitro study to evaluate the action ofbemiparin in vasculo-genesis process over its classic anticoagulantproperties. They treated human umbilical vein endothelial cells orhuman endothelial progenitor cells with bemiparin, fondaparinux andunfractionated heparin. Only bemiparin was able to contrast angiogen-esis: this was important for the possible role that this compound canexert in case of cancer and cancer-related thrombosis. Furthermore,the study demonstrated novel pharmacological activities of this com-pound as compared to the classic heparin and the novel pentasaccha-ride fondaparinux. An in vivo experiment performed by Dogan et al.[12] in a chick chorioallantoic membrane model confirmed a classaction of bemiparin and similar compounds (enoxaparin, nadroparinand tinzaparin sodium). When compared to the recent ULMWHRO-14, bemiparin was similarly able to inhibit the angiogenesis andendothelial cells migrations as well as the angiogenetic growth in-duced by vascular endothelial growth factor (VEGF) and fibroblastgrowth factor (FGF)-2, in an in vitro experiment involving humanleukemia, lung cancer and breast cancer cells [13].

Bemiparin is also able to play antioxidant actions in plasma. García-de-la-Asunción et al. [14] found reduced plasma levels of oxidizedglutathione and malondialdehyde in patients undergone bemiparinadministration as compared to placebo group.

It has been demonstrated that bemiparin is able to reduce thepercentage of subendothelial matrix covered by platelets under flowconditions, more than dalteparin and UFH [15].

As comparedwith other ultra-lowmolecularweight heparin such assemuloparin, bemiparin is able to better influence activated partialthromboplastin time (aPTT), activated clotting time (ACT) and anti-thrombin assays [16]. Furthermore, bemiparin seems to better reducethe aggregation of platelets induced by thrombin and to better interactwith heparin-induced thrombocytopenia antibodies than semuloparin[16]. Bemiparin is further able to decrease the messenger RNA(mRNA) PAI-1 expression by human endothelial cells more than UFHadministration could ever do [17]. Nevertheless, it increases plasmino-gen activator inhibitor-1 (PAI-1) as well as UFH: this might increasethe anticoagulant properties of this molecule and its efficiency [17].Furthermore, differently fromUFH, bemiparin is not able to increase tis-sue factor (TF) secretion [17]. Even tissue factor pathway inhibitor(TFPI) expression, release and activity is modulate in vitro by bemiparinmore than dalteparin andUFH:when endothelial cells underwent shearstress, they showed an overall higher production and activity of TFPIthan the other two compounds [18,19].

3. Bemiparin and fondaparinux

Fondaparinux and idraparinux can be considered as ultra-lowmolecular weight heparins. Nevertheless, they are chemical syntheticanalogues of the pentasaccharide thatwe can found in heparin chemicalstructure [8]. Although these compounds share similar characteristicssuch as the extreme low weight and their anticoagulant properties,some features distinguish them each other. Bemiparin is surely theLMWH with the highest anti-Xa/anti-FIIa ratio, although not fullycomparable to the high fondaparinux power in selectively blocking Xa.Nevertheless, Gerotziafas et al. [20] found that fondaparinux was moreeffective than bemiparin in decreasing all the parameter related tothrombin generation curve. Thus, like other LMWH, bemiparin, ratherthan fondaparinux, was able to block thrombin generation only via itsanti-IIa properties.

34 M.M. Ciccone et al. / Vascular Pharmacology 62 (2014) 32–37

Da Pozzo et al. [11] already outlined that, beyond anticoagulation,bemiparin is superior than fondaparinux in preventing in vitro angio-genesis. This skill is important in cancer evolution and in thrombosiscancer-related and account for a certain superiority of bemiparin overfondaparinux. Furthermore, although the mechanism are still not wellunderstood, bemiparin is able to reduce acute bronchospasm and relat-ed clinical expression in sensitized Brown–Norway rats, while no effectshas been observed with fondaparinux [21]. Nevertheless, when consid-ering the delayed-type hypersensitivity to LMWH, subcutaneous testingrevealed that bemiparin had comparable reactivity in patients sensi-tized to other similar compound, while no effect was detected in thesame patients when treated with fondaparinux [22].

4. Prophylaxis and acute treatment of VTE

Bemiparin can be used in prevention and treatment of VTE. Severalstudies compared bemiparin and UFH in the prophylaxis and acutetreatment of VTE and obtained excellent results in term of efficacy andtolerability of the former over the latter drug; its clinical use has primar-ily been tested in general and orthopedic surgery.

4.1. Prophylaxis of VTE: in general surgery

A multicenter, randomized double-blind trial, compared 7 daysadministration of bemiparin 2.500 IU/day to calcium UFH 5.000 IUtwice daily, in 100 patients undergoing elective abdominal surgery, atlow/moderate risk for VTE [23]. No cases of VTE or death were observedin the two groups. Nevertheless, UFH group showed a higher number oftransfusions and re-operations due to bleeding and a higher frequencyof wound hematoma. The number and size of hematomas at the injec-tion site were higher in UFH group as compared to bemiparin group.Only one patient under bemiparin treatment showed a moderatethrombocytopenia without clinical manifestations. Thus, bemiparindemonstrated to be as effective as UFH in reducing the incidenceof VTE and more effective than UFH in preventing major and minorbleeding episodes [23].

4.2. Prophylaxis of VTE: in orthopedic surgery

Patients undergoing orthopedic surgery are another high-risk popu-lation for VTE. Several studies tested bemiparin in this special categoryof patients [24–27]. Navarro-Quilis et al. [24] demonstrated thatbemiparin was more cost-effective than enoxaparin for thrombo-prophylaxis in total knee replacement surgery. In this multicenter, con-trolled, double-blind, randomized trial, 381 patients undergoing totalknee replacement surgery were randomly assigned to bemiparin3.500 IU (first dose 6 h after surgery) or to enoxaparin 40 mg (firstdose 12 h before surgery) for 10 + 2 days. No differences were foundas regard the primary efficacy end points (symptomatic and/orvenographic VTD detected within 10 ± 2 days after surgery, symptom-atic PE and deaths from all causes: 32.1% in the bemiparin group vs.36.9% in the enoxaparin one, p = ns), the secondary end points(individual distal andproximalDTV or PE) and the incidence of bleedingepisodes (major and minor bleeding occurring in three and four sub-jects of each group, respectively) in this prospective trial [24]. A higherincidence of hematoma on injection site was recorded in patients underenoxaparin (32.5% vs. 22.7%, p= 0.03). Thus, thromboprophylaxis withbemiparin 6 h after orthopedic surgery appeared to be safe and effec-tive. At the best of our knowledge, bemiparin is the only heparinapproved in Spain for the postoperative prevention of VTE [24,28].

Otero-Fernandez et al. [26] in their prospective, open, multicenter,observational study analyzed 7959 patients undergoing cast immobili-zation of the leg (n = 2052), knee replacement (n = 1082), hip re-placement (n = 876), hip fracture surgery (n = 437), other lowerlimb surgery (n = 1569), knee arthroscopy (n = 769) and spine sur-gery (n = 231). The study was non-randomized. Symptomatic VTE

(DVT and PE), major bleeding, death, thrombocytopenia and other ad-verse events associated with bemiparin treatment were gathered bythe authors. Another aim was to evaluate the influence of factors asbemiparin dose, concomitant medications, age and obesity on VTE andbleeding rates. Patients (6456) were evaluated after receiving bemiparinfor 28 days (median). Bemiparin 3500 IU/daily and 2500 IU/daily wereused in 84.9% and 15.1% of patients, respectively. The authors found alow rate of VTE (0.91%), non-fatal major bleeding (0.17%), deaths notrelated to PE (0.37%) and mild to moderate thrombocytopenia (0.51%).Bemiparin dose, concomitant medications, age and obesity seemed notto influence VTE and bleeding rates.

4.3. Acute treatment of VTE

Bemiparin safety and efficacy in recurrence of VTE is similar to UFH,and it can be considered as an effective alternative to warfarin [2].

Kakkar et al. [6] performed a multi-center, prospective, randomizedtrial aiming at comparing acute and long-term treatmentwith bemiparinversus intravenous UFH. At the fourteenth day, the venographic reduc-tion in thrombus size was statistically significantly higher after acutetreatment with bemiparin as compared to UFH group [6].

FLEBUS study [29] enrolled 352 patients suffering from a first VTEepisode and transient risk factors. This was an observational andnon-randomized trial. They were initially treated with bemiparin3500 IU/day for 3 months. Bemiparin was associated with a lowerincidence of recurrent VTE (only one patient, 0.3%), bleeding (onemajor and threeminor bleeding events, 1.1%) and other adverse events[29]. Finally, ESFERA trial compared bemiparin to vitamin K antagonists(VKA). In this multicenter, prospective and non-randomized cohortstudy, during the acute phase, the adverse event rate was similar inthe outpatient cohort as compared to inpatient (5.1 % outpatient vs.7.4% inpatient, p = 0.196). The overall rate of VTE was 0.5% in outpa-tients vs. 0.7% in inpatients, while only 1.4% and 2.1% of the outpatientsexperienced major and minor bleeding events, respectively. Inpatientsshowed no major events [30].

4.4. Long-term treatment of VTE

Bemiparin, as other LMWHs, is currently used for long-term treat-ment of VTE when oral anticoagulation is either contraindicated. Itdemonstrated the same efficacy and bleeding complications of oralwarfarin [31].

Bemiparin is recommended and used for the prophylaxis of VTE incancer, above all if undergoing high-risk surgery procedures (radicalcystectomy, invasive neurosurgery, total hip arthroplasty and explor-atory laparotomy) [32].

Several studies analyzed long-term treatment with bemiparin ascompared to UFH treatment [6,29,30]. Kakkar et al. [6] observed no sig-nificant differences between control and bemiparin group in recurrentVTE and bleeding events rate after long-term treatment. Moreoverheparin-associated thrombocytopenia was only observed in seven sub-jects, while an impaired liver function (elevated gamma glutamyltranspeptidase) was seen in 66% of patients receiving UFH and in 47%of those receiving bemiparin [6]. FLEBUS study [29] showed thatlong-term treatment with bemiparin was well accepted by both pa-tients and physicians and did not require routine laboratorymonitoring.Finally, ESFERA study demonstrated that bemiparin was a safer alterna-tive to VKA for long-term treatment of VTE [30].

5. Treatment of VTE in special populations

The pharmacological characteristics of bemiparin make it a reliabledrug for VTE treatment in special populations like elderly, subjectssuffering from renal impairment, pregnant women, children and heartfailure. These patients need appropriate treatment regimens due totheir fragile clinical condition. They are rarely included in conventional

35M.M. Ciccone et al. / Vascular Pharmacology 62 (2014) 32–37

clinical trials; therefore, there is a lack in the appropriate treatment pro-tocols to use. As regard bemiparin treatment in elderly patients, datasuggest its safety in this patient population: there is no evidence fordose adjustment during prophylactic or active treatments [33]. Thedata coming fromother clinical studies involving other type of anticoag-ulants revealed that elderly patients are most often undertreated withanticoagulants due to a general fear for their comorbidities and theirfragile condition [34]. LMWH and fondaparinux are more advisable inpatients not showing renal impairment due to their reduced skill ininducing heparin-induced thrombocytopenia and due to an overall re-duced incidence of bleedings' events as compared to UFH [34]. Evenclassical treatment with oral anticoagulant could be taken into accountin elderly patients. The decision to adopt or not an anticoagulation pro-tocol in old patients should not be influenced by an inner tendency ofthe physician to overrate the bleeding risk in such population. Never-theless, a more strict control should be managed. Among novel oralanticoagulants, rivaroxaban seems not to be adjusted in old patientssuffering from coronary artery disease, while dabigatran doses shouldbe reduced [35].

In patients with mild to moderate renal impairment, available datademonstrated the safety of bemiparin at prophylactic doses and noneed of dose adjustment. No data are available for patients sufferingfrom severe renal impairment; therefore, any conclusion regard its safe-ty can be expressed about its use in this category of patients [33,36].Waiting for new trials able to disclose the possible use of bemiparin insevere renal function impairment, a poor amount of drugs can be usedin such a condition as anticoagulants. UFH can be safely adopted evenin case of creatinine clearance b30 mL/min; there is no chance forfondaparinux, which is contraindicated in case of severe renal impair-ment [34]. Other LMWHs show an increased risk of systemic accumula-tion. Furthermore, results from studies with novel oral anticoagulants(dabigatran and rivaroxaban) in acute coronary syndrome patients re-vealed that these anticoagulants are contraindicated in case of severerenal impairment [35].

According to pregnantwomen, the American College of Chest Physi-cians recently developed new guidelines dedicated to the treatment ofVTE in such a category of patients [37]. In particular, the authors areunanimously convinced about the beneficial effects of LMWH in caseof VTE of pregnant women. The benefits are higher than UFH treatmentand the anticoagulation treatment could be performed during all thegestational period. No mention can be found for bemiparin. Neverthe-less, data about bemiparin use in pregnant women are promising. Asother LMWH, bemiparin is recommended for the treatment of VTE inpregnant women. Anticoagulation should be continued for at least6 weeks during post-partum period, lasting at least 3 months afterVTE diagnosis, with no need for laboratory monitoring, except in caseof high-risk women [33].

Bemiparin was recently administered with great success to a neo-natewith renal vein thrombosis, suggesting its possible role in the treat-ment of VTE in pediatric patients [33].

According to CHF, it is widely accepted that CHF is associatedwitha hypercoagulable state [38]. In patients suffering from CHF, the inci-dence of deep vein thrombosis ranges from 10% to 22% when nothromboprophylaxis was undertaken [39]. The American Collegeof Chest Physicians already approved LMWH, low-dose UFH orfondaparinux (all grade IA) as thromboprophylactic drug in patientssuffering from acute congestive heart failure admitted to intensivecare unit [31]. Poor data exist about bemiparin. A single-center,randomized, double-blind, placebo-controlled trial evaluated theinfluence of 3500 IU/daily of bemiparin (prophylactic dose) on hy-percoagulable state of 100 CHF subjects [40]. After 24 h, significantstatistical differences were found between bemiparin group ascompared to placebo, according to hemostatic factors concentrations:(a) factor VIIc: −1.7 vs. 0.0%, p = 0.04; (b) D-dimers: −14 vs. +24.3 ng/mL, p = 0.009; (c) prothrombin fragments 1 and 2: −0.11vs. + 0.11 nmol/L, p = 0.01; and (d) protein C: +3.5 vs. −4.0%, p =

0.01. Similar results were detected at patients discharge. Thus,bemiparin was effectively able to modify the hypercoagulable state ofCHF patients [40].

Nevertheless, at the moment, no significant trial demonstrated thenet predominance of bemiparin over the other compounds of its class.Further studies are needed in order to assess the predominance ofbemiparin as compared to other LMWHs in special populations'categories.

6. Bemiparin: other applications

Recent evidences suggested the use of bemiparin in the manage-ment of lower-extremity diabetic ulcers [41]. Bemiparin 3500 IU/dayfor 10 days followed by 2500 IU/day for 3 months and standard ulcercare seemed to ameliorate and improve lower-extremity diabetic ulcers(defined as a reduction in ulcer area ≥ 50% and/or any decrease inWagner's ulcer grade) as compared to placebo plus standard care(70.3% vs. 45.5%, p = 0.035) in a recent prospective, triple-blind,randomized, placebo-controlled trial [41].

Bemiparin can be considered as bridge therapy in case of VKA(acenocumarol and warfarin) interruption due to invasive proceduresuch as colonoscopy or gastroscopy [42]. In their prospective, open-label, non-randomized, observational study, Constans et al. [42] foundno thromboembolic nor bleeding complications related to bemiparinduring theprevious procedures, after VKA interruption. Thus, bemiparindemonstrated to be safe and effective as bridge therapy in patientsunder oral VKA at high thromboembolic risk who require colonoscopyor gastroscopy [42].

The association between cancer and thrombosis is widely known.Cancer cells can activate the hemostatic system through the productionof pro-coagulant factors and/or by direct or cytokines/angiogenetic fac-tors mediated by interactions between endothelial cells, platelets andleukocytes. Furthermore, thrombin is able by itself to promote cancercells proliferation, angiogenesis and metastatic spread [43]. Bemiparindemonstrated efficacy and safety in thromboembolic prophylaxis ofcancer patients, as well as angiogenesis and vasculogenesis inhibition[44]. Several studies tried to evaluate the effectiveness of bemiparin inthromboembolic prophylaxis in cancer patients, especially if at high-risk (surgery or chemotherapy), above all because of its excellentpharmacological profile that allows once-daily administration and theabsolute contraindication to VKAs use in high-risk patients.

The Cancer, Bemiparin and Surgery Evaluation study (CABENSURE)is a prospective, double-blind, placebo-controlled, randomized studyplanned to compare short and long-term post-operative prophylaxisin high-risk patients undergoing abdominal or pelvic surgery for cancer[45]. Patients received 3500 IU of bemiparin subcutaneously once dailyfor 8 days andwere then randomized to receive either bemiparin or pla-cebo for 20 additional days. By comparing 4 weeks versus 1 week pro-phylaxis treatment, bemiparin demonstrated no significantly reductionin the primary efficacy outcome (DVT events, non-fatal PE and all-causemortality), but there was an increase in major VTE without increasinghemorrhagic complications [45]. Thus, cancer patients undergoingmajor surgery should get 4 weeks thromboembolic prophylaxis withLMWHs in order to reduce VTE incidence [46–48].

Another retrospective, multicenter Spanish trial highlighted thatbemiparin 3500 IU/daily was the optimal dose in VTE prophylaxis incancer patients undergoing surgery rather than 2500 IU/daily, as itwas associated with a lower incidence of VTE without any significantincrease in complications rates. Postoperative bemiparin prophylaxisdemonstrated to be as effective and safer than preoperative one [49].

All these studies are in line with literature data about thrombo-prophylaxis in patients suffering from cancer. A review from Walengaand Lyman [50] details the main trials performed in order to clear therole of anticoagulants in cancer patients. LMWHs were all able toimprove the outcome of cancer patients: the incidence and prevalenceof VTE were reduced when LMWHs were adopted, and no increased

36 M.M. Ciccone et al. / Vascular Pharmacology 62 (2014) 32–37

risk of bleeding was detected when comparing the group of LMWHs toplacebo [50]. Ameta-analysis fromPhan et al. [51] showed that heparinsin patients suffering from solid cancers are able to reduce the risk ofdeep vein thrombosis. Nevertheless, the risk is an increasing incidenceof bleeding events.

Furthermore, LMWHs seem to have anticancer effects. Studiesalready demonstrated that they could inhibit endothelial cell prolifera-tion and organization bymeans of their skill in inactivating tissue factor/factor VIIa complex, factor Xa and thrombin: these interactions interferewith tumour cell growth, angiogenesis and metastatic process [52–54].Studies demonstrated that the combination of both LMWH and chemo-therapy drugs increases survival rate in cancer patients [52,53]. DaPozzo et al. [11] recently showed that bemiparin was the only drugable to significantly decrease angiogenesis and vasculogenesis ascompared to fondaparinux and UFH.

7. The economic impact in bemiparin administration

Subcutaneous bemiparin shows a major effectiveness in thrombusregression than intravenous UFH when administered in acute inpatientsuffering fromDVT. The importance of such a result is also based on eco-nomics: the best performance of the drug is able to shorten the durationof hospital stay. Therefore, it could be able to reduce health system costas savings in days-of-in-hospital stay [6].

Several studies were performed to investigate the costs and the im-plications of bemiparin use in VTE prophylaxis in surgical patients.Balibrea et al. [49] demonstrated that postoperative administration ofsubcutaneous bemiparin 3500 IU/day lowered bleeding and VTE rates,reducing the hospitalization time and, therefore, the total costs perpatient by reaching €909 in health care cost-savings. Thus, this meansthat the post-operative bemiparin administration is sufficient in orderto obtain primary end point achievements without any preoperativedrug administration. This is an important issue in the pharmaco-economics of bemiparin use. Not administering bemiparin before surgi-cal intervention minimize the costs related to drugs; by demonstratingthe reducing hospitalization time, even the cost of hospital stay isreduced. Thus, the net reduction in costs are really effective.

Bonal et al. [55] suggested that, due to the lower rates of complica-tions associated to the surgical wound (p = 0.003) and less blood lossthrough drainages (p= 0.046) in patients undergoing hip arthroplasty,bemiparin could reduce thehealth care costs related to hospital stay andphysician services.

Furthermore, bemiparin was associated with €144.48 moneysavings per patient and more efficacy (42 fewer VTE events per 1000patients) as compared to enoxaparin during 6 weeks postoperativefollow-up of patients undergone total knee replacement surgery [56].This study enforced the net advantage in bemiparin use in clinical prac-tice. In fact, the superiority of bemiparin in health system cost saving ascompared to thewell-established LMWH enoxaparin forces the opinionversus a better use of bemiparin in VTE prophylaxis setting. The criticalfinancial period, the great results in clinical practice use and the eco-nomic advantage over enoxaparin, improve the adoption of bemiparin.These results were confirmed by Navarro-Quilis et al. [24] who clearlyshowed that bemiparin reduced the hospitalization time as comparedto enoxaparin.

ESFERA study demonstrated thatmean total costs per patient duringbemiparin treatment of acute VTE were lower in outpatient than inpa-tient group, with a cost-saving of €3985 (p b 0.001). Nevertheless,when comparing bemiparin to VKAs, the long-term treatment costswere similar between groups [30]. In their cost-effectiveness analysis,Kakkar et al. [6] showed an overall reduction in total costs per patientof about €769 when bemiparin administration was followed by VKAs,and of about €908 when acute treatment with bemiparin was followedby a 3-months bemiparin administration.

Thus, bemiparin/VKAs and long-term bemiparin treatment demon-strated to determine a net cost savings, a greater efficacy and an increased

quality-adjusted life expectancy than UFH/VKAs [57]. Bemiparincould allow a reduction in costs of health system in patients under-going thromboprophylaxis. The studies showed a cost saving foreach patients that is extremely important in such a period of time.In fact, the superiority of bemiparin over UFH and enoxaparin in theacute setting and the reduction in hospital stay is fundamental inreduction the health system costs.

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