Fixed-dose low-molecular-weight heparin, bemiparin, in the long-term treatment of venous thromboembolism in patients with transient risk factors in standard clinical practice: the FLEBUS study.

Abstract

Treatment for deep vein thrombosis (DVT) usually includes two stages: an initial treatment period of the acute event, using unfractionated heparin (UFH) or a low‐molecular‐weight heparin (LMWH) for 5–10 days, and a long‐term treatment phase of oral anticoagulation (OA) with a vitamin K antagonist (VKA) for at least 3 months. OA does not completely eliminate the risk of venous thromboembolism (VTE) recurrence, is associated with a significant rate of bleeding complications and requires laboratory monitoring of its anticoagulant effect. Thus, in recent years there has been a growing interest in searching for an alternative to OA in order to reduce clinical complications without the need for laboratory monitoring. LMWH has been shown to be at least as effective and safe as VKA for long‐term treatment of VTE [1Iorio A. Guercini F. Pini M. Low‐molecular‐weight heparin for the long‐term treatment of symptomatic venous thromboembolism: meta‐analysis of the randomized comparisons with oral anticoagulants.J Thromb Haemost. 2003; 1: 1906-13Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 2Van Der Heijden J.F. Hutten B.A. Buller H.R. Prins M.H. Vitamin K antagonists or low‐molecular‐weight heparin for the long term treatment of symptomatic venous thromboembolism.Cochrane Database Syst Rev. 2002; 1: CD002001PubMed Google Scholar, 3Lecumberri R. Feliu J. Rocha E. Nuevas estrategias en la prevención secundaria de la recurrencia de la tromboembolia venosa.Med Clin (Barc). 2005; 125: 748-55Crossref Google Scholar], especially in cancer patients [4Meyer G. Marjanovic Z. Valcke J. Lorcerie B. Gruel Y. Solal‐Celigny P. Le Maignan C. Extra J.M. Cottu P. Farge D. Comparison of low‐molecular‐weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study.Arch Intern Med. 2002; 162: 1729-35Crossref PubMed Scopus (755) Google Scholar, 5Lee A.Y. Levine M.N. Baker R.I. Bowden C. Kakkar A.K. Prins M. Rickles F.R. Julian J.A. Haley S. Kovacs M.J. Gent M. for the Randomized Comparison of Low‐Molecular‐Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent VenousThromboembolism in Patients with Cancer (CLOT) Investigators. Low‐molecular‐weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.N Engl J Med. 2003; 349: 146-53Crossref PubMed Scopus (2266) Google Scholar, 6Monreal M. Zacharski L. Jimenez J.A. Roncales J. Vilaseca B. Fixed‐dose low‐molecular‐weight heparin for secondary prevention of venous thromboembolism in patients with disseminated cancer: a prospective cohort study.J Thromb Haemost. 2004; 2: 1311-5Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar], and may be an alternative when OA is either contraindicated or inconvenient [3Lecumberri R. Feliu J. Rocha E. Nuevas estrategias en la prevención secundaria de la recurrencia de la tromboembolia venosa.Med Clin (Barc). 2005; 125: 748-55Crossref Google Scholar, 7Buller H.R. Agnelli G. Hull R.D. Hyers T.M. Prins M.H. Raskob G.E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 401S-28SAbstract Full Text Full Text PDF PubMed Scopus (1309) Google Scholar]. Bemiparin is a second‐generation LMWH [8Planes A. Review on bemiparin sodium – a new second generation low‐molecular‐weight heparin – and its applications in venous thromboembolism.Expert Opin Pharmacother. 2003; 4: 1551-61PubMed Google Scholar] that in a previous clinical trial was as effective and safe as VKA for secondary prevention of VTE recurrences [9Kakkar V.V. Gebska M. Kadziola Z. Saba N. Carrasco P. Bemiparin Investigators. Low‐molecular‐weight heparin in the acute and long‐term treatment of deep vein thrombosis.Thromb Haemost. 2003; 89: 674-80Crossref PubMed Scopus (81) Google Scholar]. We report here the results of a prospective, observational, phase IV, open label, multicenter study, designed to assess the effectiveness and safety of a LMWH, bemiparin, administered for 3 months in standard clinical practice, for secondary prophylaxis in patients with a first VTE event associated with transient risk factors. Eligible patients were informed of the study characteristics before inclusion. The study protocol was approved by the clinical research ethics committees of Hospital Universitario Puerta del Mar and Hospital de Mataró. Thirty‐eight investigators from 36 Spanish centers participated in the study. Consecutive patients of both sexes, aged 18 years or older, with a first DVT event with or without pulmonary embolism (PE) documented by objective methods, with transient risk factors for VTE and who had received an initial treatment for acute VTE with bemiparin or other LMWH at therapeutic doses for 7 ± 2 days, were recruited into the study. Patients were excluded if they had known congenital thrombophilia, antiphospholipid antibodies, vena cava filter, hypersensitivity to heparin, history of immune‐mediated heparin‐induced thrombocytopenia (HIT), active hemorrhage or increased risk of bleeding because of impaired hemostasis or organ lesion, acute or sub‐acute endocarditis, impossibility for the patient to be adequately followed‐up, life expectancy of fewer than 3 months, pregnancy, or participation in another study in the past month. All patients receiving at least one dose of study medication and with at least one outcome assessment were included in the intention‐to‐treat (ITT) population. Patients with poor treatment compliance, concomitant cancer or previous history of VTE were excluded from the per‐protocol (PP) population. Patients who had received bemiparin or other LMWH for treatment of acute VTE were scheduled to receive s.c. bemiparin at the fixed high prophylactic dose of 3500 IU once daily for secondary prophylaxis of VTE recurrences for 90 ± 7 days. The primary effectiveness outcome was the incidence of documented symptomatic recurrent VTE, up to 3 and 6 months after the start of long‐term treatment with bemiparin. Symptomatic recurrent VTE had to be confirmed by objective methods or by necropsy in fatal cases. The primary safety outcome was the incidence of major bleeding complications, and the secondary included the incidence of minor bleeding complications, total bleeding complications, thrombocytopenia, spontaneous fractures, death from any cause, and other adverse events. Treatment compliance, VTE recurrences, bleeding and other adverse events were assessed during follow‐up visits at 6 weeks and at 3 and 6 months. Patient and physician satisfaction with bemiparin use during secondary VTE prevention was assessed at the 3‐month visit using a questionnaire based on a 5‐point scale: excellent, very good, good, fair, or poor. Finally, rates of recurrent VTE, bleeding events and deaths were analyzed in different patient subgroups: elderly patients (age ≥ 70 years), obese patients (body mass index ≥ 30 kg m−2 in men and ≥ 28.6 kg m−2 in women), and patients with extreme body weights (> 100 kg or < 50 kg). The primary statistical analysis was performed on the ITT population. A secondary effectiveness analysis was performed in the PP population. Ninety‐five per cent confidence intervals were calculated for rates of clinical outcomes. From June 2002 to April 2004, 445 consecutive patients with a suspected first episode of VTE associated with transient risk factors were screened for study entry. Of these, 25 patients were excluded because an objective test documenting the initial DVT was not available. Sixty‐eight additional patients were excluded because they did not have at least one outcome assessment. Thus, 352 patients were included in the ITT analysis (DVT was documented by Doppler ultrasound in 342 patients and by venography in 10 patients). Additionally, 33 patients were excluded from the PP analysis (15 patients with poor treatment adherence, 10 patients with cancer, and eight patients with a history of VTE). Therefore, the PP population consisted of 319 patients. Demographic and other baseline characteristics of the 352 assessable patients are shown in Table 1.Table 1Demographics and other baseline characteristics in the intention‐to‐treat populationCharacteristicPatients (n = 352)Demographic dataAge (years), mean (SD)64.7 (15.5)Range (years)19–98Sex, n (%)Male149 (42.3)Female203 (57.7)Weight (kg), mean (SD)73.7 (16.6)Range (kg)40–140Body mass index, mean (SD)27.6 (8.2)Characteristics of acute VTEDVT only, n (%)340 (96.6)DVT plus PE, n (%)12 (3.4)Proximal DVT, n (%)186 (52.8)Distal DVT, n (%)166 (47.1)Risks factors of VTEImmobilization, n (%)209 (59.4)Age ≥ 70 years, n (%)150 (42.6)Previous major surgery, n (%)84 (23.9)Estrogen‐containing medications, n (%)16 (4.5)Other, n (%)44 (12.5)Patients with ≥ 2 risk factors, n (%)134 (38.1)Treatment of acute VTEBemiparin, n (%)110 (31.3)Other LMWH, n (%)242 (68.7)DVT, deep vein thrombosis; LMWH, low‐molecular‐weight heparin; PE, pulmonary embolism; VTE, venous thromboembolism. Open table in a new tab DVT, deep vein thrombosis; LMWH, low‐molecular‐weight heparin; PE, pulmonary embolism; VTE, venous thromboembolism. Only one (0.3%) recurrence (proximal DVT on day 37) occurred during the 3‐month secondary prophylaxis with bemiparin (Table 2). During the whole study period (days 1–180) there were four (1.1%) VTE recurrences (two proximal DVTs on days 37 and 93 and two distal DVTs on days 96 and 136). No PE or VTE related deaths were recorded. Similar results were seen in the PP population (data not shown). Recurrent VTE rates during secondary prophylaxis were similar in the patient cohorts receiving acute VTE treatment with bemiparin or other LMWH (data not shown). During the 3‐month period of secondary prophylaxis with bemiparin, one (0.3%) major bleeding and three (0.9%) minor bleedings occurred (Table 2). During the 3‐month follow‐up period (days 91–180), four additional patients had minor bleeding complications not related to bemiparin (Table 2). A total of 150 patients were aged 70 years or older, 82 patients were obese, nine patients weighed > 100 kg, and four patients weighed < 50 kg. No significant differences were found in the rates of VTE or bleeding complications when each subgroup was compared with the remaining study population (data not shown).Table 2Clinical outcomes during the study in the intention‐to‐treat populationPeriodEvents (%) (n = 352)95% CI (%)Secondary prophylaxis period (up to day 90)Documented symptomatic recurrent VTE1 (0.3)0.0–1.6Proximal DVT1 (0.3)0.0–1.6Distal DVT0 (0)0.0–1.0Pulmonary embolism (PE)0 (0)0.0–1.0Death because of VTE0 (0)0.0–1.0Total bleeding4 (1.1)0.3–2.9Major bleeding1 (0.3)0.0–1.6Minor bleeding3 (0.9)0.2–2.5Deaths2 (0.6)0.1–2.0Follow‐up period (days 91–180)Documented symptomatic recurrent VTE3 (0.9)0.2–2.5Proximal DVT1 (0.3)0.0–1.6Distal DVT2 (0.6)0.1–2.0PE0 (0)0.0–1.0Death because of VTE0 (0)0.0–1.0Total bleeding4 (1.1)0.3–2.9Major bleeding0 (0)0.0–1.0Minor bleeding4 (1.1)0.3–2.9Deaths3 (0.9)0.2–2.5DVT, deep vein thrombosis; VTE, venous thromboembolism. Open table in a new tab DVT, deep vein thrombosis; VTE, venous thromboembolism. Two deaths occurred during the first 3 months and three additional patients died during the 3‐month follow‐up. No death was considered to be drug‐related. No spontaneous bone fractures were seen. Three patients developed mild to moderate thrombocytopenia (platelet counts were 146 000, 135 000 and 77 000 μL−1 respectively) that did not require treatment discontinuation during long‐term treatment with bemiparin. Treatment was rated as ‘excellent’, ‘very good’ or ‘good’ by 97.3% of patients and 97.8% of physicians. Only 2.7% of patients and 2.2% of physicians rated bemiparin treatment as ‘fair’ or ‘poor’. The results of this observational study suggest that a LMWH (bemiparin) administered once daily for 3 months at fixed s.c. doses (3500 IU) without laboratory monitoring is a valid therapeutic option for long‐term treatment of patients with a first VTE event associated with transient risk factors. It is common practice to treat DVT initially with LMWH, followed by OA to prevent delayed recurrence. One of the main disadvantages of VKA therapy is the need for continuous laboratory monitoring, because of intra‐subject variability. Several factors may lead to over‐ or under‐anticoagulation in patients receiving VKA. In addition, OA with VKA increases the risk of bleeding complications, which are sometimes fatal [10Ansell J. Hirsh J. Poller L. Bussey H. Jacobson A. Hylek E. The pharmacology and management of the vitamin K antagonists.Chest. 2004; 126: 204S-33SAbstract Full Text Full Text PDF PubMed Scopus (1080) Google Scholar]. UFH and LMWH have been used as an alternative to OA. Adjusted UFH doses were as effective as VKA and probably safer [11Hull R.D. Delmore T. Carter C. Hish J. Genton E. Gent M. Turpie G. McLaughlin D. Adjusted subcutaneous heparin versus warfarin sodium in the long‐term treatment of venous thrombosis.N Engl J Med. 1982; 306: 189-94Crossref PubMed Scopus (379) Google Scholar]. However, UFH still requires laboratory monitoring and twice‐daily injections for secondary prevention of VTE. LMWH is at least as effective as UFH for long‐term treatment of patients with DVT [12Monreal M. Lafoz E. Olive A. Del Rio L. Vedia C. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin.Thromb Haemost. 1994; 71: 7-11Crossref PubMed Scopus (405) Google Scholar], does not require routine laboratory monitoring, may be given once daily, and also appears to involve a lower risk of causing HIT and osteoporosis as compared with UFH [12Monreal M. Lafoz E. Olive A. Del Rio L. Vedia C. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin.Thromb Haemost. 1994; 71: 7-11Crossref PubMed Scopus (405) Google Scholar, 13Levine M.N. Hirsh J. Horsewood P. Roberts R.S. Gent M. Kelton J.G. Heparin‐induced thrombocytopenia in patients treated with low‐molecular‐weight heparin or unfractionated heparin.N Engl J Med. 1995; 332: 1330-5Crossref PubMed Google Scholar]. Several clinical trials [3Lecumberri R. Feliu J. Rocha E. Nuevas estrategias en la prevención secundaria de la recurrencia de la tromboembolia venosa.Med Clin (Barc). 2005; 125: 748-55Crossref Google Scholar] and meta‐analyses [1Iorio A. Guercini F. Pini M. Low‐molecular‐weight heparin for the long‐term treatment of symptomatic venous thromboembolism: meta‐analysis of the randomized comparisons with oral anticoagulants.J Thromb Haemost. 2003; 1: 1906-13Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 2Van Der Heijden J.F. Hutten B.A. Buller H.R. Prins M.H. Vitamin K antagonists or low‐molecular‐weight heparin for the long term treatment of symptomatic venous thromboembolism.Cochrane Database Syst Rev. 2002; 1: CD002001PubMed Google Scholar] have also shown LMWH to be at least as effective and safe as VKA for long‐term treatment of VTE. In our study, only one patient (0.3%) experienced a recurrent VTE event during the 3‐month treatment with bemiparin. This incidence is lower than the overall incidence found in previous clinical studies on secondary prophylaxis of VTE [1Iorio A. Guercini F. Pini M. Low‐molecular‐weight heparin for the long‐term treatment of symptomatic venous thromboembolism: meta‐analysis of the randomized comparisons with oral anticoagulants.J Thromb Haemost. 2003; 1: 1906-13Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 2Van Der Heijden J.F. Hutten B.A. Buller H.R. Prins M.H. Vitamin K antagonists or low‐molecular‐weight heparin for the long term treatment of symptomatic venous thromboembolism.Cochrane Database Syst Rev. 2002; 1: CD002001PubMed Google Scholar, 3Lecumberri R. Feliu J. Rocha E. Nuevas estrategias en la prevención secundaria de la recurrencia de la tromboembolia venosa.Med Clin (Barc). 2005; 125: 748-55Crossref Google Scholar], which reported recurrence rates of 5.0% (46 of 913) in patients treated with VKA and 4.2% (35 of 831) in patients treated with LMWH for up to 3 months. However, it cannot be ruled out that these differences may be related to a lower risk of VTE in our study population, from which patients with idiopathic VTE, thrombophilia, or DVT associated with persistent risk factors, were excluded. These patients are known to have a higher recurrence risk than patients with transient risk factors [14Pini M. Aiello S. Manotti C. Pattacini C. Quintavalla R. Poli T. Tagliaferri A. Dettori A.G. Low‐molecular‐weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis.Thromb Haemost. 1994; 72: 191-7Crossref PubMed Scopus (243) Google Scholar, 15Lopaciuk S. Bielska‐Falda H. Noszczyk W. Bielawiec M. Witkiewicz W. Filipecki S. Michalak J. Ciesielski L. Mackiewicz Z. Czestochowska E. Zawilska K. Cencora A. Low molecular weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis.Thromb Haemost. 1999; 81: 26-31Crossref PubMed Scopus (154) Google Scholar]. In addition, almost half of the patients in our study had distal DVT, while most previous studies mainly included patients with proximal DVT. The low event rate recorded might also be due to the open study design in standard clinical practice, with a significant number (16%) of patients lost at follow‐up. However, the incidence of recurrent VTE in our study is in agreement with that reported by Kakkar et al. [9Kakkar V.V. Gebska M. Kadziola Z. Saba N. Carrasco P. Bemiparin Investigators. Low‐molecular‐weight heparin in the acute and long‐term treatment of deep vein thrombosis.Thromb Haemost. 2003; 89: 674-80Crossref PubMed Scopus (81) Google Scholar], using bemiparin 3500 IU day−1 for 3 months, and also similar to that found with bemiparin (median daily dose 5000 IU) in patients with a higher risk of recurrence (> 50% of patients having idiopathic DVT or with a history of VTE, cancer or thrombophilia) [16Santamaria A. Juarez S. Reche A. Gomez‐Outes A. Martinez‐Gonzalez J. Fontcuberta J. ESFERA InvestigatorsLow‐molecular‐weight heparin, bemiparin, in the outpatient treatment and secondary prophylaxis of venous thromboembolism in standard clinical practice: the ESFERA Study.Int J Clin Pract. 2006; 60: 518-25Crossref PubMed Scopus (23) Google Scholar]. During the 3‐month extended follow‐up period after bemiparin treatment had ended, three (0.9%) additional VTE recurrences were recorded. Again, this recurrence rate is lower than that found in seven of the nine studies included in previously published meta‐analyses and reviews [1Iorio A. Guercini F. Pini M. Low‐molecular‐weight heparin for the long‐term treatment of symptomatic venous thromboembolism: meta‐analysis of the randomized comparisons with oral anticoagulants.J Thromb Haemost. 2003; 1: 1906-13Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 2Van Der Heijden J.F. Hutten B.A. Buller H.R. Prins M.H. Vitamin K antagonists or low‐molecular‐weight heparin for the long term treatment of symptomatic venous thromboembolism.Cochrane Database Syst Rev. 2002; 1: CD002001PubMed Google Scholar, 3Lecumberri R. Feliu J. Rocha E. Nuevas estrategias en la prevención secundaria de la recurrencia de la tromboembolia venosa.Med Clin (Barc). 2005; 125: 748-55Crossref Google Scholar], with a follow‐up of 9 months, in patients treated with LMWH (5.0%) or OA (2.1%). As stated above, these differences could be related to a lower risk of VTE recurrence in our study population. In addition, the total observation period was only 6 months in our study, as compared with 12 months in the above‐mentioned studies. Therefore, the incidence of recurrent VTE in our study could have been similar to that found in previous studies if a longer follow‐up period had been used. The incidence of major bleeding complications in our study was lower (0.3%) than the overall incidence reported in previous studies [1Iorio A. Guercini F. Pini M. Low‐molecular‐weight heparin for the long‐term treatment of symptomatic venous thromboembolism: meta‐analysis of the randomized comparisons with oral anticoagulants.J Thromb Haemost. 2003; 1: 1906-13Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 2Van Der Heijden J.F. Hutten B.A. Buller H.R. Prins M.H. Vitamin K antagonists or low‐molecular‐weight heparin for the long term treatment of symptomatic venous thromboembolism.Cochrane Database Syst Rev. 2002; 1: CD002001PubMed Google Scholar, 3Lecumberri R. Feliu J. Rocha E. Nuevas estrategias en la prevención secundaria de la recurrencia de la tromboembolia venosa.Med Clin (Barc). 2005; 125: 748-55Crossref Google Scholar], in which major bleeding occurred in 5.4% (50 of 926) of patients receiving OA and in 2.4% (20 of 834) of patients treated with long‐term LMWH, but is similar to the incidence seen in previous studies of bemiparin in long‐term treatment of VTE [9Kakkar V.V. Gebska M. Kadziola Z. Saba N. Carrasco P. Bemiparin Investigators. Low‐molecular‐weight heparin in the acute and long‐term treatment of deep vein thrombosis.Thromb Haemost. 2003; 89: 674-80Crossref PubMed Scopus (81) Google Scholar, 16Santamaria A. Juarez S. Reche A. Gomez‐Outes A. Martinez‐Gonzalez J. Fontcuberta J. ESFERA InvestigatorsLow‐molecular‐weight heparin, bemiparin, in the outpatient treatment and secondary prophylaxis of venous thromboembolism in standard clinical practice: the ESFERA Study.Int J Clin Pract. 2006; 60: 518-25Crossref PubMed Scopus (23) Google Scholar]. These observations agree with those of a recent meta‐analysis showing that LMWH is probably safer than VKA for the long‐term treatment of VTE [1Iorio A. Guercini F. Pini M. Low‐molecular‐weight heparin for the long‐term treatment of symptomatic venous thromboembolism: meta‐analysis of the randomized comparisons with oral anticoagulants.J Thromb Haemost. 2003; 1: 1906-13Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar]. Clinical studies evaluating LMWHs for long‐term treatment have used different doses, ranging from a prophylactic dose to intermediate or full therapeutic doses, for 3 or 6 months [3Lecumberri R. Feliu J. Rocha E. Nuevas estrategias en la prevención secundaria de la recurrencia de la tromboembolia venosa.Med Clin (Barc). 2005; 125: 748-55Crossref Google Scholar]. A recent meta‐analysis has shown a direct linear correlation between LMWH dose and bleeding complications. This correlation was not statistically significant for efficacy, but the meta‐regression analysis showed an inverse relationship suggesting that a prophylactic LMWH dose may be too low [1Iorio A. Guercini F. Pini M. Low‐molecular‐weight heparin for the long‐term treatment of symptomatic venous thromboembolism: meta‐analysis of the randomized comparisons with oral anticoagulants.J Thromb Haemost. 2003; 1: 1906-13Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar]. Patients with idiopathic DVT, thrombophilia or cancer [4Meyer G. Marjanovic Z. Valcke J. Lorcerie B. Gruel Y. Solal‐Celigny P. Le Maignan C. Extra J.M. Cottu P. Farge D. Comparison of low‐molecular‐weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study.Arch Intern Med. 2002; 162: 1729-35Crossref PubMed Scopus (755) Google Scholar, 5Lee A.Y. Levine M.N. Baker R.I. Bowden C. Kakkar A.K. Prins M. Rickles F.R. Julian J.A. Haley S. Kovacs M.J. Gent M. for the Randomized Comparison of Low‐Molecular‐Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent VenousThromboembolism in Patients with Cancer (CLOT) Investigators. Low‐molecular‐weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.N Engl J Med. 2003; 349: 146-53Crossref PubMed Scopus (2266) Google Scholar, 6Monreal M. Zacharski L. Jimenez J.A. Roncales J. Vilaseca B. Fixed‐dose low‐molecular‐weight heparin for secondary prevention of venous thromboembolism in patients with disseminated cancer: a prospective cohort study.J Thromb Haemost. 2004; 2: 1311-5Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar] may need an intermediate to full therapeutic dose; further studies comparing different LMWHs and doses are needed to fully address this issue. Nevertheless, according to our results, long‐term treatment with bemiparin 3500 IU day−1 (high prophylactic dose) for 3 months is adequate for most low‐risk patients with a first VTE event associated with transient risk factors. No cases of HIT or spontaneous bone fractures were seen. These data support previous reports of a lower risk of thrombocytopenia and osteoporosis when LMWH is used instead of UFH [12Monreal M. Lafoz E. Olive A. Del Rio L. Vedia C. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin.Thromb Haemost. 1994; 71: 7-11Crossref PubMed Scopus (405) Google Scholar, 13Levine M.N. Hirsh J. Horsewood P. Roberts R.S. Gent M. Kelton J.G. Heparin‐induced thrombocytopenia in patients treated with low‐molecular‐weight heparin or unfractionated heparin.N Engl J Med. 1995; 332: 1330-5Crossref PubMed Google Scholar], and are in agreement with previous reports on the use of bemiparin for long‐term treatment of VTE in which no cases of severe thrombocytopenia or osteoporosis were detected [9Kakkar V.V. Gebska M. Kadziola Z. Saba N. Carrasco P. Bemiparin Investigators. Low‐molecular‐weight heparin in the acute and long‐term treatment of deep vein thrombosis.Thromb Haemost. 2003; 89: 674-80Crossref PubMed Scopus (81) Google Scholar, 16Santamaria A. Juarez S. Reche A. Gomez‐Outes A. Martinez‐Gonzalez J. Fontcuberta J. ESFERA InvestigatorsLow‐molecular‐weight heparin, bemiparin, in the outpatient treatment and secondary prophylaxis of venous thromboembolism in standard clinical practice: the ESFERA Study.Int J Clin Pract. 2006; 60: 518-25Crossref PubMed Scopus (23) Google Scholar]. There are few data regarding long‐term administration of LMWH, without laboratory monitoring, in special populations such as elderly or obese patients. In our study, administration of a fixed bemiparin dose for 3 months in elderly and obese patients was as effective and safe as in the remaining study patients. This study is the first prospective study including a significant number of consecutive patients with a first episode of acute DVT, with or without PE, associated with transient risk factors in which long‐term treatment was administered as a fixed dose of LMWH (bemiparin) for 3 months. Our study has several limitations, mainly derived from its observational nature. However, observational studies may provide a more accurate ‘real life’ picture than phase III randomized clinical trials, in which the study population is usually much more selected. In a daily clinical practice setting, patients show a more variable profile, with frequent concurrent conditions and concomitant treatments. Some authors think that the need for daily s.c. injections, with the attendant increase in pharmacy costs, may be a drawback in the replacement of OA by LMWH in most situations in which secondary prevention of VTE is required [12Monreal M. Lafoz E. Olive A. Del Rio L. Vedia C. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin.Thromb Haemost. 1994; 71: 7-11Crossref PubMed Scopus (405) Google Scholar, 15Lopaciuk S. Bielska‐Falda H. Noszczyk W. Bielawiec M. Witkiewicz W. Filipecki S. Michalak J. Ciesielski L. Mackiewicz Z. Czestochowska E. Zawilska K. Cencora A. Low molecular weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis.Thromb Haemost. 1999; 81: 26-31Crossref PubMed Scopus (154) Google Scholar]. However, in our study, physician and patient satisfaction with long‐term bemiparin treatment was very high, which is consistent with the results of a recent bemiparin study in standard clinical practice [16Santamaria A. Juarez S. Reche A. Gomez‐Outes A. Martinez‐Gonzalez J. Fontcuberta J. ESFERA InvestigatorsLow‐molecular‐weight heparin, bemiparin, in the outpatient treatment and secondary prophylaxis of venous thromboembolism in standard clinical practice: the ESFERA Study.Int J Clin Pract. 2006; 60: 518-25Crossref PubMed Scopus (23) Google Scholar]. Moreover, two pharmacoeconomic studies have shown bemiparin to be a cost‐neutral alternative to VKA for long‐term treatment of VTE [16Santamaria A. Juarez S. Reche A. Gomez‐Outes A. Martinez‐Gonzalez J. Fontcuberta J. ESFERA InvestigatorsLow‐molecular‐weight heparin, bemiparin, in the outpatient treatment and secondary prophylaxis of venous thromboembolism in standard clinical practice: the ESFERA Study.Int J Clin Pract. 2006; 60: 518-25Crossref PubMed Scopus (23) Google Scholar, 17Gomez‐Outes A. Rocha E. Martinez Gonzalez J. Kakkar V.V. Cost effectiveness of bemiparin versus unfractionated heparin and oral anticoagulants in the acute and long‐term treatment of deep vein thrombosis.Pharmacoeconomics. 2006; 24: 81-92Crossref PubMed Scopus (22) Google Scholar]. Based on all these data from various previously published studies [9Kakkar V.V. Gebska M. Kadziola Z. Saba N. Carrasco P. Bemiparin Investigators. Low‐molecular‐weight heparin in the acute and long‐term treatment of deep vein thrombosis.Thromb Haemost. 2003; 89: 674-80Crossref PubMed Scopus (81) Google Scholar, 16Santamaria A. Juarez S. Reche A. Gomez‐Outes A. Martinez‐Gonzalez J. Fontcuberta J. ESFERA InvestigatorsLow‐molecular‐weight heparin, bemiparin, in the outpatient treatment and secondary prophylaxis of venous thromboembolism in standard clinical practice: the ESFERA Study.Int J Clin Pract. 2006; 60: 518-25Crossref PubMed Scopus (23) Google Scholar] and on the results of our study, long term treatment of VTE using a fixed, once‐daily bemiparin dose may be considered to be simpler, equally effective and probably safer than standard therapy with VKA. In conclusion, our study shows that the LMWH bemiparin, administered s.c. at a fixed dose of 3500 IU once daily for 3 months in standard clinical practice, is associated with a low incidence of recurrent VTE, bleeding and other adverse events. Moreover, long‐term treatment with bemiparin is well‐accepted by both patients and physicians, and provides an alternative to VKA for the prevention of recurrences after a first episode of VTE associated with transient risk factors, without the need for routine laboratory monitoring. The study was supported by Laboratorios Farmacéuticos Rovi, SA. We thank Medicus Spain for performing the entire data analysis. We thank J. Martínez González, A. Gómez Outes, R. Maeso Martín and G. Monteagudo Ruíz for their help with this project. FLEBUS investigators: E. Rocha (Coordinator Investigator), R. Lecumberri (Clínica Universitaria de Navarra, Pamplona); E. Rosario, G. Soler (H. Clínico Universitario, Málaga); J. Pacho (H. Central de Asturias, Oviedo); A. Santamaría (H. de Sant Pau, Barcelona); J. Rodríguez (Clínica Plató, Barcelona); G. Pia (H. Arquitecto Marcide‐Novoa Santos, Ferrol); J. O. Pastor (H. Gral. de Granollers, Barcelona); J. M. Reuss (RPPMM Manoteras, Madrid); E. de Ramón, C. Díaz (H. Carlos Haya, Málaga); A. J. Trujillo (H. Costa del Sol, Marbella); J. M. Buisan (H. C. U. Lozano Blesa, Zaragoza); J Soles (Clínica Bofia, Gerona); F. Minguela (H. La Paz, Madrid); A. Marín (H. de Molina de Segura, Murcia); I. Antigues (H. Gral. Universitario, Valencia); M. M. Nieto (H. Neurotraumatológico, Jaén); R. Otero (H. Virgen del Rocío, Sevilla); E. Ramos (H. Clínico Universitario, Santiago de Compostela); F. Vázquez (H. Da Costa, Burela); I. M. Domínguez (C. H. Torrecárdenas, Almería); A. Baloira (C. H. de Pontevedra, Pontevedra); M. Cardona (H. Creu Roja, Barcelona), A. J. González (H. San Agustín, Avilés); J. L. de Frutos, R. Fernández‐Paredes (H. Arnau de Vilanova, Lérida); P. Gallego (H. Jerez de la Frontera, Cádiz); F. Vidal‐Barraquer (H. del Mar, Barcelona); F. Gamboa (H. Valme, Sevilla); J. A. Todolí (H. Universitario La Fe, Valencia); A. Cerveró (H. Gral. de Valencia, Valencia); A. Pineda (H. de Barcelona, Barcelona); P. Llamas (Fundación Jiménez Díaz, Madrid); C. M. Abad (H. Sagrat Cor, Barcelona); P. Rodríguez (Clínica San Miguel, Pamplona); J. L. Royo (H. Universitario Virgen Macarena, Sevilla); F. López (H. Arnau de Vilanova, Valencia), F. Molina (H. Ciudad de Jaén, Jaén).