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Antonio Gómez-outes - One of the best experts on this subject based on the ideXlab platform.
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Delayed-type hypersensitivity to low molecular weight heparins and heparinoids: cross-reactivity does not depend on molecular weight. Commentary
The British journal of dermatology, 2008Co-Authors: Antonio Gómez-outes, C Gómez De La Bárcena, J. Martínez-gonzálezAbstract:Summary Background Cross-reactivity is a widespread phenomenon in patients who develop cutaneous delayed-type hypersensitivity (DTH) reactions to low molecular weight heparins (LMWHs). As molecular weight is believed to be a key determinant of sensitization to heparins, the recently developed LMWH Bemiparin, with the lowest molecular weight of all LMWHs, appeared to be a significant improvement. Objectives To evaluate cross-reactivity between Bemiparin and several other LMWHs and heparinoids by means of subcutaneous testing. Methods Test doses of Bemiparin and several other LMWHs/heparinoids were given to eight patients with a history of local eczematous reactions after subcutaneous injection of enoxaparin. Results Seven of eight patients showed cross-reactivity following subcutaneous injection of Bemiparin. In addition, nearly all tested substances caused local eczematous reactions in at least some patients, with the exception of fondaparinux, which was well tolerated by all patients. Of all substances tested, Bemiparin had the highest cross-reactivity with enoxaparin. Substances with a lower molecular weight did not cross-react less frequently than the others. Conclusions No significant correlation was found between the molecular weight of the tested substances and the frequency of DTH reactions. In patients with DTH to enoxaparin, the LMWH Bemiparin is not a suitable alternative.
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Evaluation of the Effectiveness and Safety of Bemiparin in a Large Population of Orthopedic Patients in a Normal Clinical Practice
Clinical and applied thrombosis hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis Hemostasis, 2007Co-Authors: Rafael Otero-fernández, Antonio Gómez-outes, J. Martínez-gonzález, Eduardo Rocha, Jordi FontcubertaAbstract:The authors conducted a prospective, open, multicenter, observational study to audit the utilization patterns of Bemiparin in orthopedic patients in daily clinical practice. They analyzed rates of ...
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Optimal dosing of Bemiparin as prophylaxis against venous thromboembolism in surgery for cancer: an audit of practice.
International journal of surgery (London England), 2006Co-Authors: J.l. Balibrea, J. Altimiras, I. Larruzea, Antonio Gómez-outes, J. Martínez-gonzález, Eduardo RochaAbstract:Low-molecular-weight heparins are drugs of first choice for thromboprophylaxis in cancer surgery. We sought to determine the optimal use of Bemiparin in cancer surgery in standard clinical practice. A retrospective, multicentre audit on the use of Bemiparin in patients undergoing cancer surgery and given prophylaxis with Bemiparin was undertaken. Surgeons' assessment of venous thromboembolic (VTE) risk (moderate or high) was compared to the criteria of current Consensus Guidelines for VTE management. We assessed the incidence of documented symptomatic VTE, bleeding events, thrombocytopenia, deaths and total events related to VTE or Bemiparin prophylaxis (i.e. bleeding, thrombocytopenia). The potential economic impact of postoperative vs. preoperative Bemiparin was also analysed. Clinical records from 197 patients from 5 Spanish centres were checked. Prophylaxis was started postoperatively in 45 patients (22.8%). According to the surgeons' criteria, 73 (37.1%) patients were at high VTE risk and received Bemiparin 3500 IU/d. However, according to the criteria of current Guidelines, 189 (95.9%) patients were at high risk of VTE (heterogeneity P-value<0.0001). Three (1.5%) patients, all of them receiving Bemiparin 2500 IU/d, developed a symptomatic confirmed VTE. There were 4 major and 5 minor bleeding events during Bemiparin prophylaxis. A lower incidence of bleeding (2.2% vs. 5.3%; P=0.48) and total events (2.2% vs. 9.9%; P=0.11) was seen with Bemiparin started postoperatively as compared to preoperative Bemiparin. Bleeding rates did not significantly differ between patients given low or high Bemiparin prophylactic doses (4.0% vs. 5.5%; P=0.72). Two patients died due to cardio-respiratory failure and sepsis, respectively. Postoperative Bemiparin provided net cost savings of 909 euro per patient compared to preoperative start of prophylaxis due to shorter hospital stays (9 vs. 11 days) and lower incidence of complications in the postoperative Bemiparin group. Many cancer patients are still poorly assessed for risk of VTE. Bemiparin 3500 IU/d is associated with a lower incidence of VTE without significant increase in complications as compared with Bemiparin 2500 IU/d. Postoperative Bemiparin prophylaxis seems to be as effective and safer than preoperative start of prophylaxis. Further prospective clinical studies are needed to fully address this issue.
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A prospective observational study on the effectiveness and safety of Bemiparin, first dose administered 6 h after knee or hip replacement surgery
Archives of orthopaedic and trauma surgery, 2006Co-Authors: J. Ignacio Abad, Antonio Gómez-outes, J. Martínez-gonzález, Eduardo RochaAbstract:Introduction Bemiparin has shown to be effective and safe in clinical trials in total knee or hip replacement.
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Low-molecular-weight heparin, Bemiparin, in the outpatient treatment and secondary prophylaxis of venous thromboembolism in standard clinical practice: the ESFERA Study.
International journal of clinical practice, 2006Co-Authors: Amparo Santamaría, Antonio Gómez-outes, J. Martínez-gonzález, S. Juárez, A. Reche, J FontcubertaAbstract:The objective of this study is to assess the clinical and economic outcomes associated with outpatient treatment and secondary prophylaxis of acute venous thromboembolism (VTE) with a low-molecular-weight heparin, Bemiparin. This study was designed as an open-label, multicentre, prospective, cohort study in standard clinical practice. Sixty-three investigators from 54 Spanish centres participated in the study. Five hundred eighty-three patients (434 outpatients and 149 inpatients) with acute VTE were followed up for 98 days (median). Outcome measures were costs and adverse events during initial VTE treatment with Bemiparin (outpatient vs. inpatient cohorts) and long-term treatment [Bemiparin (BEM) vs. vitamin K antagonists (VKA) cohorts]. Mean total costs per patient were lower in the outpatient cohort as compared with those in the inpatient cohort (1206 vs. 5191 euros; difference = -3985 euros; p < 0.001), with similar rates of adverse events (5.1 outpatient vs. 7.4% inpatient; p = 0.196) over 98 days. Mean total costs per patient were similar in the BEM/BEM and BEM/VKA cohorts (3616 vs. 3831 euros; difference = -215 euros; p = 0.412), but patients on long-term Bemiparin treatment had lower rates of major bleeding (0.4 vs. 1.7%; p = 0.047), minor bleeding (1.8 vs. 6%; p = 0.032) and total adverse events (2.9 vs. 9.5%; p = 0.007) than patients in the BEM/VKA cohort. Outpatient management of VTE with Bemiparin in selected patients resulted in significant cost-savings compared to inpatient treatment, while maintaining effectiveness and safety. Bemiparin may be a safer and cost-neutral alternative to VKA for long-term treatment of VTE.
Eduardo Rocha - One of the best experts on this subject based on the ideXlab platform.
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Clinical Experience with Bemiparin
Drugs, 2010Co-Authors: José Ignacio Abad Rico, Francisco S. Lozano Sánchez, Eduardo RochaAbstract:Subcutaneous Bemiparin has been evaluated for the prevention of venous thromboembolism (VTE) in moderate to high-risk patients undergoing surgery, and for the acute and long-term treatment of established VTE. General and orthopaedic surgery is associated with VTE incidence rates of 15–60% in the absence of thromboprophylaxis and this can be reduced by over 70% with appropriate thromboembolic prophylaxis. Bemiparin was as effective as unfractionated heparin (UFH) in the prevention of VTE, when both were initiated preoperatively, but was associated with significantly fewer bleeding episodes than UFH. Bemiparin prophylaxis initiated postoperatively was at least as effective as Bemiparin initiated preoperatively and was associated with a lower incidence of bleeding complications than preoperative initiation. In terms of patients with cancer undergoing abdominal or pelvic surgery, pre-liminary results from a recent study with Bemiparin showed that extended prophylaxis for 4 weeks significantly reduced the rate of major VTE, without increasing bleeding risk, compared with prophylaxis for one week. Bemiparin, initiated postoperatively, was as effective as enoxaparin, initiated preoperatively, in the prevention of VTE in patients undergoing total knee replacement. The incidence of bleeding complications was similar between groups, although the incidence of injection site haematoma was significantly higher with enoxaparin than with Bemiparin. Postoperative initiation of Bemiparin thromboprophylaxis minimized the risk of spinal haematoma in patients using neuraxial anaesthesia (approximately 93% of patients). In addition, postoperative initiation is likely to reduce the total costs, because patients do not need to be admitted to hospital the day before surgery. Bemiparin was more effective than intravenous UFH in the acute treatment of established deep vein thrombosis (DVT) and was as effective as oral warfarin in the subsequent secondary prevention of VTE over 3 months of therapy, while bleeding complications over 3 months of therapy were similarly low. In a European study, acute treatment of DVT with Bemiparin for one week followed by 12 weeks' secondary prevention with Bemiparin (i.e. Bemiparin/Bemiparin) was associated with a cost saving of €908 per patient compared with UFH/warfarin. Similarly, Bemiparin/warfarin produced a cost saving of €769 compared with UFH/ warfarin. The savings were predominantly the result of reduced hospital stays during acute treatment with Bemiparin. Bemiparin was also associated with increased quality-adjusted life expectancy. Observational studies in routine clinical practice demonstrated that outpatient treatment of acute VTE was as effective as inpatient treatment, but with lower costs, and Bemiparin was as effective as vitamin K antagonists over 3 months for secondary prevention, with VTE recurrence rates of 0% and 0.3% over 3 months in separate studies. Bemiparin is thus an effective, well tolerated agent for thromboprophylaxis in surgery, and for the acute and long-term treatment of established VTE, having advantages over UFH and particular benefits as a result of initiating therapy postoperatively.
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Evaluation of the Effectiveness and Safety of Bemiparin in a Large Population of Orthopedic Patients in a Normal Clinical Practice
Clinical and applied thrombosis hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis Hemostasis, 2007Co-Authors: Rafael Otero-fernández, Antonio Gómez-outes, J. Martínez-gonzález, Eduardo Rocha, Jordi FontcubertaAbstract:The authors conducted a prospective, open, multicenter, observational study to audit the utilization patterns of Bemiparin in orthopedic patients in daily clinical practice. They analyzed rates of ...
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Low-Molecular-Weight Heparins: Before or After Surgery? New Concepts and Evidence
Clinical Drug Investigation, 2007Co-Authors: Eduardo Rocha, Davide Imberti, Elio PaschinaAbstract:Deep venous thrombosis (DVT) and pulmonary embolism (PE) are potentially life-threatening complications associated with orthopaedic surgery. The choice of an optimal thromboprophylaxis regimen requires full understanding of the efficacy and safety profiles associated with distinct treatments. Low-molecular-weight heparins (LMWHs) are the drugs of choice for thromboprophylaxis in orthopaedic surgery. However, there is concern regarding the timing of LMWH prophylaxis initiation. Among the LMWH molecules, Bemiparin has interesting pharmacological properties: the lowest molecular weight, the longest half-life and the highest anti-FXa/anti-FIIa activity ratio. The safety and efficacy of Bemiparin administered 6 hours after surgery has been demonstrated in several orthopaedic settings (including major orthopaedic surgery, knee arthroscopy, lower limb trauma and spinal surgery) and during prolonged prophylaxis after major orthopaedic surgery. Another factor to consider in relation to thromboprophylaxis during orthopaedic surgery is the cost effectiveness of Bemiparin. The 91st meeting of the Italian Society of Orthopaedics and Traumatology (SIOT), held in Rome, Italy, on 12–16 November 2006, provided an exciting opportunity to present new and interesting evidence, including the latest advances in thromboprophylaxis in orthopaedic surgery. Of particular interest were the issues debated during the Sigma Tau/ROVI Satellite Symposium, which focused on the optimal timing strategy for initiating thromboprophylaxis in patients undergoing orthopaedic surgery. This article highlights presentations given during that symposium.
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optimal dosing of Bemiparin as prophylaxis against venous thromboembolism in surgery for cancer an audit of practice
International Journal of Surgery, 2007Co-Authors: J.l. Balibrea, J. Altimiras, I. Larruzea, Antonio Gomezoutes, Javier Martinezgonzalez, Eduardo RochaAbstract:Abstract Aims Low-molecular-weight heparins are drugs of first choice for thromboprophylaxis in cancer surgery. We sought to determine the optimal use of Bemiparin in cancer surgery in standard clinical practice. Patients and methods A retrospective, multicentre audit on the use of Bemiparin in patients undergoing cancer surgery and given prophylaxis with Bemiparin was undertaken. Surgeons' assessment of venous thromboembolic (VTE) risk (moderate or high) was compared to the criteria of current Consensus Guidelines for VTE management. We assessed the incidence of documented symptomatic VTE, bleeding events, thrombocytopenia, deaths and total events related to VTE or Bemiparin prophylaxis (i.e. bleeding, thrombocytopenia). The potential economic impact of postoperative vs. preoperative Bemiparin was also analysed. Results Clinical records from 197 patients from 5 Spanish centres were checked. Prophylaxis was started postoperatively in 45 patients (22.8%). According to the surgeons' criteria, 73 (37.1%) patients were at high VTE risk and received Bemiparin 3500IU/d. However, according to the criteria of current Guidelines, 189 (95.9%) patients were at high risk of VTE (heterogeneity P -value P =0.48) and total events (2.2% vs. 9.9%; P =0.11) was seen with Bemiparin started postoperatively as compared to preoperative Bemiparin. Bleeding rates did not significantly differ between patients given low or high Bemiparin prophylactic doses (4.0% vs. 5.5%; P =0.72). Two patients died due to cardio-respiratory failure and sepsis, respectively. Postoperative Bemiparin provided net cost savings of €909 per patient compared to preoperative start of prophylaxis due to shorter hospital stays (9 vs. 11 days) and lower incidence of complications in the postoperative Bemiparin group. Conclusions Many cancer patients are still poorly assessed for risk of VTE. Bemiparin 3500IU/d is associated with a lower incidence of VTE without significant increase in complications as compared with Bemiparin 2500IU/d. Postoperative Bemiparin prophylaxis seems to be as effective and safer than preoperative start of prophylaxis. Further prospective clinical studies are needed to fully address this issue.
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Optimal dosing of Bemiparin as prophylaxis against venous thromboembolism in surgery for cancer: an audit of practice.
International journal of surgery (London England), 2006Co-Authors: J.l. Balibrea, J. Altimiras, I. Larruzea, Antonio Gómez-outes, J. Martínez-gonzález, Eduardo RochaAbstract:Low-molecular-weight heparins are drugs of first choice for thromboprophylaxis in cancer surgery. We sought to determine the optimal use of Bemiparin in cancer surgery in standard clinical practice. A retrospective, multicentre audit on the use of Bemiparin in patients undergoing cancer surgery and given prophylaxis with Bemiparin was undertaken. Surgeons' assessment of venous thromboembolic (VTE) risk (moderate or high) was compared to the criteria of current Consensus Guidelines for VTE management. We assessed the incidence of documented symptomatic VTE, bleeding events, thrombocytopenia, deaths and total events related to VTE or Bemiparin prophylaxis (i.e. bleeding, thrombocytopenia). The potential economic impact of postoperative vs. preoperative Bemiparin was also analysed. Clinical records from 197 patients from 5 Spanish centres were checked. Prophylaxis was started postoperatively in 45 patients (22.8%). According to the surgeons' criteria, 73 (37.1%) patients were at high VTE risk and received Bemiparin 3500 IU/d. However, according to the criteria of current Guidelines, 189 (95.9%) patients were at high risk of VTE (heterogeneity P-value<0.0001). Three (1.5%) patients, all of them receiving Bemiparin 2500 IU/d, developed a symptomatic confirmed VTE. There were 4 major and 5 minor bleeding events during Bemiparin prophylaxis. A lower incidence of bleeding (2.2% vs. 5.3%; P=0.48) and total events (2.2% vs. 9.9%; P=0.11) was seen with Bemiparin started postoperatively as compared to preoperative Bemiparin. Bleeding rates did not significantly differ between patients given low or high Bemiparin prophylactic doses (4.0% vs. 5.5%; P=0.72). Two patients died due to cardio-respiratory failure and sepsis, respectively. Postoperative Bemiparin provided net cost savings of 909 euro per patient compared to preoperative start of prophylaxis due to shorter hospital stays (9 vs. 11 days) and lower incidence of complications in the postoperative Bemiparin group. Many cancer patients are still poorly assessed for risk of VTE. Bemiparin 3500 IU/d is associated with a lower incidence of VTE without significant increase in complications as compared with Bemiparin 2500 IU/d. Postoperative Bemiparin prophylaxis seems to be as effective and safer than preoperative start of prophylaxis. Further prospective clinical studies are needed to fully address this issue.
J. Martínez-gonzález - One of the best experts on this subject based on the ideXlab platform.
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Comparison of Once-Daily Bemiparin with Twice-Daily Enoxaparin for Acute Deep Vein Thrombosis: A Multicenter, Open-Label, Randomized Controlled Trial.
Clinical drug investigation, 2017Co-Authors: Igor A. Suchkov, Sebastian M. Schellong, Toni Garbade, J. Martínez-gonzález, Michela FalcianiAbstract:Individuals with deep vein thrombosis (DVT) have an increased risk of pulmonary embolism (PE), death, and long-term thrombotic complications. To evaluate the efficacy and safety of Bemiparin once daily versus enoxaparin twice daily in the treatment of acute DVT, and to establish therapeutic non-inferiority of Bemiparin. This multicenter, randomized, open-label, active-controlled phase III clinical trial enrolled patients with acute proximal DVT confirmed by complete compression ultrasound (CCUS). Patients received Bemiparin once daily or enoxaparin twice daily subcutaneously for 7 days, in combination with warfarin 5 mg/day. Assessment of thrombotic burden was blinded and used CCUS recordings. The primary efficacy endpoint was the percentage of patients with an improvement in thrombotic burden at day 83 (end of follow-up); the secondary efficacy endpoint was the incidence of symptomatic recurrent DVT and PE. Safety endpoints included treatment-emergent adverse events. Three-hundred and twelve patients were enrolled (~ 62% male; mean age 55.2 years). At least one DVT risk factor was present in 26.1% and 28.7% of the Bemiparin and enoxaparin groups, respectively. The proportion of patients who had an improvement in thrombotic burden was similar for Bemiparin (78.2%) and enoxaparin [80.8%; difference − 2.66 (97.5% CI − 12.39; ∞)], as was mean change in thrombus score (− 8.8 and − 8.6, respectively). There were no cases of recurrent DVT, and one case of non-fatal symptomatic PE in each treatment group. No major bleeding was reported, and there was no difference in the incidence of non-major bleeding. The efficacy of Bemiparin administered once daily is non-inferior to that of enoxaparin administered twice daily with a similar safety profile. NCT01880216.
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Bemiparin Versus Unfractionated Heparin as Bridging Therapy in the Perioperative Management of Patients on Vitamin K Antagonists: The BERTA Study
Clinical drug investigation, 2013Co-Authors: Amparo Santamaría, Arantxa Ugarriza, Isabel Diego, Francisca López-chulia, Carmen Benet, Natividad Gómez, Elena Pina, Carmen Muñoz, J. Martínez-gonzález, Xavier OrtínAbstract:Background and Objective The management of patients on vitamin K antagonist therapy who require an invasive procedure is problematic. A randomised, controlled, double-blind clinical trial was designed to compare the efficacy and safety of Bemiparin, a low molecular weight heparin (LMWH), with unfractionated heparin (UFH) as bridging therapy: the BERTA (Bemiparin Randomised Trial on bridging Anticoagulants) study.
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Extended prophylaxis with Bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study
Journal of thrombosis and haemostasis : JTH, 2010Co-Authors: Vijay V. Kakkar, J.l. Balibrea, J. Martínez-gonzález, Paolo PrandoniAbstract:There is not enough clinical evidence to make a strong recommendation on the optimal duration of thromboprophylaxis using low-molecular weight heparins (LMWH) in patients undergoing major cancer surgery. CANBESURE is a randomized, double-blind study which enrolled patients admitted for abdominal or pelvic surgery for cancer. They received 3500 IU of Bemiparin subcutaneously once daily for 8 days and were then randomized to receive either Bemiparin or placebo for 20 additional days. Bilateral venography was performed after 20 days and evaluated blinded. The primary efficacy outcome was the composite of deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE) and all-cause mortality at the end of double-blind period. Major venous thromboembolism (proximal deep-vein thrombosis, non-fatal pulmonary embolism and venous thromboembolism-related deaths) was also evaluated. The primary safety outcome was major bleeding. Six hundred and twenty-five and 488 patients were included in the safety and main efficacy analyzes, respectively. The primary efficacy outcome occurred in 25 out of 248 patients (10.1%) in the Bemiparin group and 32 out of 240 (13.3%) in the placebo group (relative risk reduction 24.4%; 95% CI: -23.7-53.8%; P = 0.26). At the end of double-blind period, major venous thromboembolism occurred in 2 (0.8%) and 11 (4.6%) patients, respectively (relative risk reduction 82.4%; 95% CI: 21.5-96.1%; P = 0.010). No significant difference was found in major bleedings. Four weeks compared with 1 week of prophylaxis with Bemiparin after abdominal or pelvic cancer surgery did not significantly reduce the primary efficacy outcome, but decreased major venous thromboembolism (VTE) without increasing hemorrhagic complications.
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Comparative pharmacodynamic time-course of Bemiparin and enoxaparin in healthy volunteers.
International journal of clinical pharmacology and therapeutics, 2009Co-Authors: Rosa M. Antonijoan, J. Martínez-gonzález, S Rico, M Borrell, D Valcarcel, J Fontcuberta, M J BarbanojAbstract:Low-molecular-weight heparins (LMWHs) are antithrombotic drugs that differ on biochemical and pharmacological properties. This study was conducted to compare the pharmacodynamic time-course of two LMWHs, Bemiparin and enoxaparin, at high prophylactic doses. This was an open, randomized, single-blind, cross-over study to compare the pharmacodynamic time-course, safety and tolerability of two LMWHs, Bemiparin 3500 IU and enoxaparin 4000 IU at subcutaneous single doses in 12 healthy male volunteers. Anti-Xa activity (main biomarker of heparin activity), anti-IIa activity, total and free tissue factor pathway inhibitor (TFPI), activated partial thromboplastin time (APTT), thrombin time (TT) and thromboplastin-thrombomodulin mediated time (Tp-TmT) were investigated. Bemiparin 3500 IU achieved more anti-Xa activity than enoxaparin 4000 IU, measured by the area under the curve (geometric mean AUC0t) (Bemiparin 3.69 vs. enoxaparin 3.33 IU h/ml; p < 0.001). Maximum anti-Xa activity was reached at 3 hours and there were anti-Xa measurable levels up to 16 h after subcutaneous administration. Anti-Xa activity half-life was 5.44 hours for Bemiparin and 4.71 hours for enoxaparin. Anti-IIa activity was above the limit of quantification (0.05 IU/ml) in only 2 volunteers after Bemiparin and in 8 after enoxaparin. The "in-vivo" anti-Xa:IIa ratios were: Bemiparin 37.9 (95% CI: 28.0 - 55.3, n = 2) and enoxaparin 16.3 (95% CI: 12.2 - 23.4, n = 8). Enoxaparin induced a higher release of total TFPI, but not on free TFPI, and a longer prolongation of APTT and TT (Emax) than Bemiparin, with no differences between groups on Tp-TmT. Adverse events (one in each group) were mild and transient. Bemiparin 3500 IU showed more anti-Xa activity and higher anti-Xa: anti-IIa relationship than enoxaparin 4000 IU in healthy volunteers. Both treatments were well tolerated.
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Delayed-type hypersensitivity to low molecular weight heparins and heparinoids: cross-reactivity does not depend on molecular weight. Commentary
The British journal of dermatology, 2008Co-Authors: Antonio Gómez-outes, C Gómez De La Bárcena, J. Martínez-gonzálezAbstract:Summary Background Cross-reactivity is a widespread phenomenon in patients who develop cutaneous delayed-type hypersensitivity (DTH) reactions to low molecular weight heparins (LMWHs). As molecular weight is believed to be a key determinant of sensitization to heparins, the recently developed LMWH Bemiparin, with the lowest molecular weight of all LMWHs, appeared to be a significant improvement. Objectives To evaluate cross-reactivity between Bemiparin and several other LMWHs and heparinoids by means of subcutaneous testing. Methods Test doses of Bemiparin and several other LMWHs/heparinoids were given to eight patients with a history of local eczematous reactions after subcutaneous injection of enoxaparin. Results Seven of eight patients showed cross-reactivity following subcutaneous injection of Bemiparin. In addition, nearly all tested substances caused local eczematous reactions in at least some patients, with the exception of fondaparinux, which was well tolerated by all patients. Of all substances tested, Bemiparin had the highest cross-reactivity with enoxaparin. Substances with a lower molecular weight did not cross-react less frequently than the others. Conclusions No significant correlation was found between the molecular weight of the tested substances and the frequency of DTH reactions. In patients with DTH to enoxaparin, the LMWH Bemiparin is not a suitable alternative.
Vijay V. Kakkar - One of the best experts on this subject based on the ideXlab platform.
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Extended prophylaxis with Bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study
Journal of thrombosis and haemostasis : JTH, 2010Co-Authors: Vijay V. Kakkar, J.l. Balibrea, J. Martínez-gonzález, Paolo PrandoniAbstract:There is not enough clinical evidence to make a strong recommendation on the optimal duration of thromboprophylaxis using low-molecular weight heparins (LMWH) in patients undergoing major cancer surgery. CANBESURE is a randomized, double-blind study which enrolled patients admitted for abdominal or pelvic surgery for cancer. They received 3500 IU of Bemiparin subcutaneously once daily for 8 days and were then randomized to receive either Bemiparin or placebo for 20 additional days. Bilateral venography was performed after 20 days and evaluated blinded. The primary efficacy outcome was the composite of deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE) and all-cause mortality at the end of double-blind period. Major venous thromboembolism (proximal deep-vein thrombosis, non-fatal pulmonary embolism and venous thromboembolism-related deaths) was also evaluated. The primary safety outcome was major bleeding. Six hundred and twenty-five and 488 patients were included in the safety and main efficacy analyzes, respectively. The primary efficacy outcome occurred in 25 out of 248 patients (10.1%) in the Bemiparin group and 32 out of 240 (13.3%) in the placebo group (relative risk reduction 24.4%; 95% CI: -23.7-53.8%; P = 0.26). At the end of double-blind period, major venous thromboembolism occurred in 2 (0.8%) and 11 (4.6%) patients, respectively (relative risk reduction 82.4%; 95% CI: 21.5-96.1%; P = 0.010). No significant difference was found in major bleedings. Four weeks compared with 1 week of prophylaxis with Bemiparin after abdominal or pelvic cancer surgery did not significantly reduce the primary efficacy outcome, but decreased major venous thromboembolism (VTE) without increasing hemorrhagic complications.
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Cost effectiveness of Bemiparin sodium versus unfractionated heparin and oral anticoagulants in the acute and long-term treatment of deep vein thrombosis
PharmacoEconomics, 2006Co-Authors: Antonio Gómez-outes, Javier Martínez-gonzález, Eduardo Rocha, Vijay V. KakkarAbstract:Introduction: Low-molecular-weight heparins (LMWHs) are at least as effective and well tolerated as unfractionated heparin (UFH) in the treatment of deep vein thrombosis (DVT), offering easier administration and obviating the need for anticoagulant monitoring, but have a higher acquisition cost than UFH. Objective: To quantify the potential economic impact of two regimens of subcutaneous Bemiparin 115 IU/kg/day for 7–10 days (plus oral anticoagulants [OAC] or followed by long-term Bemiparin 3500IU) versus dose-adjusted intravenous UFH for 7 days plus OAC for 3 months in the acute and long-term treatment of DVT. The representative patient was a 62-year-old, 77kg male with proximal DVT of the lower limbs. Methods: A cost-effectiveness analysis was performed using a decision-tree modelling approach. The results were expressed in terms of costs (€, 2002 values) and incremental cost effectiveness. The treatment costs (hospital stay, physician services, drug administration) and costs incurred due to complications (pulmonary embolism, recurrent DVT, bleeding events, thrombocytopenia and deaths) during the 3-month study period were considered for the primary analysis. Life expectancy and QALYs were considered for the secondary analysis. The study was performed in the setting of the Spanish National Health System. Results: Bemiparin plus OAC or long-term Bemiparin for 3 months provided net cost savings of €769 and €908 per patient, respectively, compared with UFH plus OAC (UFH plus OAC €4128 vs Bemiparin plus OAC €3359 vs long-term Bemiparin €3220). Bemiparin plus OAC and long-term Bemiparin for 3 months were calculated to avoid 27 and 7 additional VTE events, respectively, per 1000 patients treated. Bemiparin plus OAC or long-term Bemiparin increased quality- -adjusted life expectancy by approximately 1.72 and 0.74 years, respectively, compared with UFH plus OAC. The univariate sensitivity analysis supported the cost effectiveness of Bemiparin in all the ranges tested for complications and costs. Conclusions: Our model suggests that Bemiparin plus OAC or long-term Bemiparin for 3 months may be dominant strategies over UFH plus OAC in the treatment of DVT from the Spanish National Health System perspective, offering better outcomes and cost savings. Long-term Bemiparin may be a cost-neutral alternative to Bemiparin plus OAC.
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Cost effectiveness of Bemiparin sodium versus unfractionated heparin and oral anticoagulants in the acute and long-term treatment of deep vein thrombosis.
PharmacoEconomics, 2006Co-Authors: Antonio Gómez-outes, J. Martínez-gonzález, Eduardo Rocha, Vijay V. KakkarAbstract:Low-molecular-weight heparins (LMWHs) are at least as effective and well tolerated as unfractionated heparin (UFH) in the treatment of deep vein thrombosis (DVT), offering easier administration and obviating the need for anticoagulant monitoring, but have a higher acquisition cost than UFH. To quantify the potential economic impact of two regimens of subcutaneous Bemiparin 115 IU/kg/day for 7-10 days (plus oral anticoagulants [OAC] or followed by long-term Bemiparin 3500IU) versus dose-adjusted intravenous UFH for 7 days plus OAC for 3 months in the acute and long-term treatment of DVT. The representative patient was a 62-year-old, 77 kg male with proximal DVT of the lower limbs. A cost-effectiveness analysis was performed using a decision-tree modelling approach. The results were expressed in terms of costs (euro, 2002 values) and incremental cost effectiveness. The treatment costs (hospital stay, physician services, drug administration) and costs incurred due to complications (pulmonary embolism, recurrent DVT, bleeding events, thrombocytopenia and deaths) during the 3-month study period were considered for the primary analysis. Life expectancy and QALYs were considered for the secondary analysis. The study was performed in the setting of the Spanish National Health System. Bemiparin plus OAC or long-term Bemiparin for 3 months provided net cost savings of euro 769 and euro 908 per patient, respectively, compared with UFH plus OAC (UFH plus OAC euro 4128 vs Bemiparin plus OAC euro 3359 vs long-term Bemiparin euro 3220). Bemiparin plus OAC and long-term Bemiparin for 3 months were calculated to avoid 27 and 7 additional VTE events, respectively, per 1000 patients treated. Bemiparin plus OAC or long-term Bemiparin increased quality-adjusted life expectancy by approximately 1.72 and 0.74 years, respectively, compared with UFH plus OAC. The univariate sensitivity analysis supported the cost effectiveness of Bemiparin in all the ranges tested for complications and costs. Our model suggests that Bemiparin plus OAC or long-term Bemiparin for 3 months may be dominant strategies over UFH plus OAC in the treatment of DVT from the Spanish National Health System perspective, offering better outcomes and cost savings. Long-term Bemiparin may be a cost-neutral alternative to Bemiparin plus OAC.
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Low-molecular-weight heparin in the acute and long-term treatment of deep vein thrombosis
Thrombosis and haemostasis, 2003Co-Authors: Vijay V. Kakkar, Milena A. Gebska, Zbigniew Kadziola, Neelam SabaAbstract:Low molecular weight heparins (LMWHs) are frequently used during acute treatment of deep vein thrombosis, but their utility for long-term treatment needs to be defined. In this multi-centre trial, 378 patients with acute deep vein thrombosis were randomised to intravenous unfractionated heparin (group A), once daily subcutaneous LMWH (Bemiparin) for one week (group B) or once daily Bemiparin in a therapeutic dose for one week followed by a maintenance dose for 12 weeks (group C). Fifty-two per cent of patients in group A, 72% of group B and 72% of group C showed venographic reduction in thrombus size assessed objectively on day 14; 20% greater improvement in group B and C indicates not only non-inferiority of Bemiparin (p = 0.00003) but also superiority (p = 0.004) compared to UFH. Day 84 venographic or Doppler sonographic recanalisation of the affected veins was demonstrated in 75.3%, 79.8% and 81.5% in groups A, B and C respectively. Mortality, recurrent thromboembolic events and bleeding were similar in the three groups. Both Bemiparin regimens were more effective than UFH in reducing thrombus size during the acute phase of treatment. The efficacy in terms of recurrence of venous thromboembolism and safety of Bemiparin is similar to UFH. Bemiparin is also an effective alternative to warfarin for long-term treatment.
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A Comparative, Double-blind, Randomised Trial of a New Second Generation LMWH (Bemiparin) and UFH in the Prevention of Post-operative Venous Thromboembolism
Thrombosis and haemostasis, 2000Co-Authors: Vijay V. Kakkar, J. Howes, Vikram Sharma, Z KadziolaAbstract:A randomised, prospective, double-blind trial was performed, to compare the safety and efficacy of a new low-molecular-weight heparin (LMWH) Bemiparin and standard unfractionated heparin (UFH), for the prophylaxis of postoperative venous thromboembolism. 300 patients scheduled to undergo elective hip arthroplasty were included. The principal outcome measures were the incidence of thromboembolic events and bleeding complications. 149 patients received 3,500 anti-Xa IU of Bemiparin plus a placebo injection daily and 149 patients received 5,000 IU of UFH twice a day. The two groups were similar with respect to factors likely to affect the risk of developing post-operative venous thromboembolism (VTE) and risk of bleeding events. During the post-operative period, 34 patients developed VTE complications; 9 (7.2%) in the Bemiparin group and 25 (18.7%) in the UFH group. VTE in the two groups was statistically significant (OR of 2.96; 95% CI 1.32-6.62 and p = 0.01). There were no significant differences in the frequency of bleeding complications: major bleeding requiring discontinuation of prophylaxis, (OR 1.21; 95% CI 0.36-4.05; p = 1.00), the measured median operative blood loss (p = 0.77) or the median postoperative drain loss (p = 0.97), and the number of patients who developed wound haematoma (OR 0.87; 95% CI 0.31-2.46; p = 1.00). A comparison of coagulation parameters on the preoperative day with post-operative day 2 +/- 1, day 6 +/- 1 and day of discharge showed a significantly higher AT concentration, anti-factor Xa activity and TFPI levels in the Bemiparin group when compared with UFH. This study demonstrates that Bemiparin, in a single daily subcutaneous dose of 3,500 anti-Xa IU in high risk patients undergoing hip arthroplasty is more effective than UFH administered twice daily at a dose of 5,000 IU in the prevention of postoperative VTE. Both agents are equally safe.
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Biological Activities of Two Ultra-Low Molecular Weight Heparins, Semuloparin and Bemiparin, Reveal That a Common Potency Standard Is Inadequate
Blood, 2011Co-Authors: Walter Jeske, Debra Hoppensteadt, Angel Gray, Jeanine M. Walenga, Josephine Cunanan, Lauren Myers, Jawed Fareed, Helene Rigal, Alain Bayol, Christian ViskovAbstract:Abstract Abstract 4324 Introduction: Ultra-low molecular weight heparins (U-LMWHs) are being developed to improve the safety and efficacy of antithrombotic therapy. Two of these agents, Bemiparin (Rovi, Madrid, Spain) and semuloparin (Sanofi-Aventis, Paris, France), are produced by distinct methods. Bemiparin is produced by esterification of porcine mucosal heparin followed by alkaline hydrolysis and fractionation. Semuloparin is prepared by a highly selective depolymerization reaction using a phosphazene base which preserves the AT binding sequences from destruction. While both Bemiparin and semuloparin are effective at reducing the incidence of post-surgical VTE, some biological differences have been observed in humans. The objective of this investigation was to determine whether a common standard could be used to define their potency. Methods: Activities were compared using typical clinical coagulation assays and pharmacological assays required for potency assessment. Anticoagulant activity was assessed using aPTT and ACT assays. Anti-Xa and anti-IIa activities were determined using amidolytic assays. Constrained and unconstrained curves were determined for the anti-Xa and anti-IIa data to assess parallelism of the concentration-response curves. Thrombin generation was measured using a fluorometric substrate kinetic method (Technothrombin TGA assay; Technoclone GmbH, Vienna, Austria). Platelet function was assessed using platelet aggregometry and the serotonin release assay (SRA). Results: A significantly larger prolongation of the aPTT was observed with Bemiparin at concentrations >1 μ g/ml. Differences in anticoagulant activity measured by the Heptest assay were not observed at concentrations below 2.5 μ g/ml. When supplemented to whole blood samples at higher concentrations, Bemiparin and semuloparin are able to prolong the kaolin ACT. Anti-FXa activity for Bemiparin and semuloparin was the same over the concentration range tested. Bemiparin produced more anti-FIIa activity at each concentration tested. Depletion of AT led to a complete loss of anti-FXa and anti-FIIa activities for both agents while depletion of heparin cofactor-II had minimal impact on anti-IIa activity. Parallelism assessment is used to identify similarity or difference of products in biological assays. The constrained and unconstrained models using anti-FXa concentration-response data were equivalent (p=0.422), indicating that Bemiparin and semuloparin were equivalent (IC50 ratio = 0.97, confidence interval= 0.95–0.98, CV = 0.7%). In contrast, the constrained and unconstrained models using anti-FIIa concentration-response data were not equivalent (p<0.001), indicating that the in vitro anti-FIIa activities of the two agents is not equivalent (IC50 ratio = 1.25, confidence interval = 1.17–1.34, CV = 3.4%). At clinically relevant concentrations, Bemiparin more effectively inhibited thrombin generation than semuloparin. Platelet aggregation in response to collagen, ADP and arachidonic acid was not affected by either agent at concentrations up to 10 μ g/ml. At a concentration of 5 μ g/ml, Bemiparin was able to completely inhibit thrombin-induced aggregation (0.5 U/ml), whereas no effect was observed with semuloparin. Cross-reactivity of Bemiparin and semuloparin with anti-PF4/heparin HIT antibodies was tested using platelet aggregation and the SRA. The level of maximal aggregation was comparable in the presence of Bemiparin and semuloparin, however, the rate of aggregation was significantly slower in the presence of semuloparin compared to Bemiparin. The typical bell-shaped concentration-response curve was observed with both drugs in the SRA. Although the peak release was comparable for the two drugs (65.7 ± 16.0% for semuloparin vs. 75.5 ± 6.6% for Bemiparin), the peak serotonin release was observed at lower concentrations for Bemiparin (1 μ g/ml) than for semuloparin (10 μ g/ml) suggesting a higher sensitivity of Bemiparin to (stronger interaction with) the anti-PF4/heparin antibodies. Conclusions: These data demonstrate that the molecular profiling of heparin-derived agents is insufficient to determine drug class. Additional structural characterization and multiple biologic activities relevant to clinical safety and efficacy need to be considered as well. As such, the use of a common reference standard for potency determination of ULMWH is not valid. Disclosures: Rigal: Sanofi-Aventis: Employment. Bayol:Sanofi-Aventis: Employment. Viskov:Sanofi-Aventis: Employment.
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biological activities of two ultra low molecular weight heparins semuloparin and Bemiparin reveal that a common potency standard is inadequate
Blood, 2011Co-Authors: Walter Jeske, Debra Hoppensteadt, Angel Gray, Jeanine M. Walenga, Josephine Cunanan, Lauren Myers, Jawed Fareed, Helene Rigal, Alain Bayol, Christian ViskovAbstract:Abstract 4324 Introduction: Ultra-low molecular weight heparins (U-LMWHs) are being developed to improve the safety and efficacy of antithrombotic therapy. Two of these agents, Bemiparin (Rovi, Madrid, Spain) and semuloparin (Sanofi-Aventis, Paris, France), are produced by distinct methods. Bemiparin is produced by esterification of porcine mucosal heparin followed by alkaline hydrolysis and fractionation. Semuloparin is prepared by a highly selective depolymerization reaction using a phosphazene base which preserves the AT binding sequences from destruction. While both Bemiparin and semuloparin are effective at reducing the incidence of post-surgical VTE, some biological differences have been observed in humans. The objective of this investigation was to determine whether a common standard could be used to define their potency. Methods: Activities were compared using typical clinical coagulation assays and pharmacological assays required for potency assessment. Anticoagulant activity was assessed using aPTT and ACT assays. Anti-Xa and anti-IIa activities were determined using amidolytic assays. Constrained and unconstrained curves were determined for the anti-Xa and anti-IIa data to assess parallelism of the concentration-response curves. Thrombin generation was measured using a fluorometric substrate kinetic method (Technothrombin TGA assay; Technoclone GmbH, Vienna, Austria). Platelet function was assessed using platelet aggregometry and the serotonin release assay (SRA). Results: A significantly larger prolongation of the aPTT was observed with Bemiparin at concentrations >1 μ g/ml. Differences in anticoagulant activity measured by the Heptest assay were not observed at concentrations below 2.5 μ g/ml. When supplemented to whole blood samples at higher concentrations, Bemiparin and semuloparin are able to prolong the kaolin ACT. Anti-FXa activity for Bemiparin and semuloparin was the same over the concentration range tested. Bemiparin produced more anti-FIIa activity at each concentration tested. Depletion of AT led to a complete loss of anti-FXa and anti-FIIa activities for both agents while depletion of heparin cofactor-II had minimal impact on anti-IIa activity. Parallelism assessment is used to identify similarity or difference of products in biological assays. The constrained and unconstrained models using anti-FXa concentration-response data were equivalent ( p =0.422), indicating that Bemiparin and semuloparin were equivalent (IC 50 ratio = 0.97, confidence interval= 0.95–0.98, CV = 0.7%). In contrast, the constrained and unconstrained models using anti-FIIa concentration-response data were not equivalent ( p in vitro anti-FIIa activities of the two agents is not equivalent (IC 50 ratio = 1.25, confidence interval = 1.17–1.34, CV = 3.4%). At clinically relevant concentrations, Bemiparin more effectively inhibited thrombin generation than semuloparin. Platelet aggregation in response to collagen, ADP and arachidonic acid was not affected by either agent at concentrations up to 10 μ g/ml. At a concentration of 5 μ g/ml, Bemiparin was able to completely inhibit thrombin-induced aggregation (0.5 U/ml), whereas no effect was observed with semuloparin. Cross-reactivity of Bemiparin and semuloparin with anti-PF4/heparin HIT antibodies was tested using platelet aggregation and the SRA. The level of maximal aggregation was comparable in the presence of Bemiparin and semuloparin, however, the rate of aggregation was significantly slower in the presence of semuloparin compared to Bemiparin. The typical bell-shaped concentration-response curve was observed with both drugs in the SRA. Although the peak release was comparable for the two drugs (65.7 ± 16.0% for semuloparin vs. 75.5 ± 6.6% for Bemiparin), the peak serotonin release was observed at lower concentrations for Bemiparin (1 μ g/ml) than for semuloparin (10 μ g/ml) suggesting a higher sensitivity of Bemiparin to (stronger interaction with) the anti-PF4/heparin antibodies. Conclusions: These data demonstrate that the molecular profiling of heparin-derived agents is insufficient to determine drug class. Additional structural characterization and multiple biologic activities relevant to clinical safety and efficacy need to be considered as well. As such, the use of a common reference standard for potency determination of ULMWH is not valid. Disclosures: Rigal: Sanofi-Aventis: Employment. Bayol: Sanofi-Aventis: Employment. Viskov: Sanofi-Aventis: Employment.
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a common standard is inappropriate for determining the potency of ultra low molecular weight heparins such as semuloparin and Bemiparin
Thrombosis Research, 2011Co-Authors: Walter Jeske, Debra Hoppensteadt, Angel Gray, Jeanine M. Walenga, Josephine Cunanan, Lauren Myers, Jawed Fareed, Helene Rigal, Alain Bayol, Christian ViskovAbstract:Abstract Introduction Lower low-molecular-weight heparins are being developed to improve on the safety and efficacy of antithrombotic therapy. Semuloparin and Bemiparin are two depolymerized heparins produced by distinct manufacturing processes. The objective of this investigation was to determine whether a common standard could be used to define their potency. Materials and Methods Activities were compared using typical clinical coagulation assays and pharmacological assays required for potency assessment. Results The activity of semuloparin and Bemiparin was comparable in FXa-based assays (anti-FXa, Heptest). However, Bemiparin produced a stronger effect in the aPTT, ACT and anti-thrombin assays. Assessment of the parallelism of the concentration-response curves indicated that Bemiparin and semuloparin are not equivalent in terms of anti-FIIa activity. Bemiparin had a stronger inhibitory effect on thrombin induced platelet aggregation, and a stronger interaction with HIT antibodies. Conclusions These data demonstrate that depolymerized heparins can exhibit a range of biologic activities making them unique agents. Pharmacopoeial parameters such as anti-IIa and anti-Xa potency and molecular weight are insufficient to characterize such agents.
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A common standard is inappropriate for determining the potency of ultra low molecular weight heparins such as semuloparin and Bemiparin
Thrombosis research, 2011Co-Authors: Walter Jeske, Debra Hoppensteadt, Angel Gray, Jeanine M. Walenga, Josephine Cunanan, Lauren Myers, Jawed Fareed, Helene Rigal, Alain Bayol, Christian ViskovAbstract:Lower low-molecular-weight heparins are being developed to improve on the safety and efficacy of antithrombotic therapy. Semuloparin and Bemiparin are two depolymerized heparins produced by distinct manufacturing processes. The objective of this investigation was to determine whether a common standard could be used to define their potency. Activities were compared using typical clinical coagulation assays and pharmacological assays required for potency assessment. The activity of semuloparin and Bemiparin was comparable in FXa-based assays (anti-FXa, Heptest). However, Bemiparin produced a stronger effect in the aPTT, ACT and anti-thrombin assays. Assessment of the parallelism of the concentration-response curves indicated that Bemiparin and semuloparin are not equivalent in terms of anti-FIIa activity. Bemiparin had a stronger inhibitory effect on thrombin induced platelet aggregation, and a stronger interaction with HIT antibodies. These data demonstrate that depolymerized heparins can exhibit a range of biologic activities making them unique agents. Pharmacopoeial parameters such as anti-IIa and anti-Xa potency and molecular weight are insufficient to characterize such agents. Copyright © 2011 Elsevier Ltd. All rights reserved.