Low molecular weight heparins. Drug selection by means of the SOJA method
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Summary In the Netherlands, four low molecular weight heparins (dalteparin, enoxaparin, nadroparin and tinzaparin) are available on the market. This strengthens the need for a rational selection of the best low molecular weight heparin for formulary purposes. The available low molecular weight heparins were evaluated by means of the System of Objectified Judgement Analysis (SOJA) method. Separate scores were made for prophylaxis in orthopaedic surgery, non-orthopaedic surgery and for the treatment of deep venous thrombosis (DVT). The following selection criteria were used (relative weight): approved indications (20); number of formulations (60); variability of the AUC (20); drug interactions (60); clinical efficacy (295); side effects (220); dosage frequency (115); acquisition cost (110); and documentation (100). Despite many differences in their physicochemical properties, few major clinically relevant differences are observed between the various low molecular weight heparins. Overall, dalteparin shows the highest scores for all indications, mainly due to its good documentation and the large number of available formulations. The differences are small in comparison with other SOJA scores. No relevant differences between the drugs are apparent for the major criteria, such as clinical efficacy, tolerability and drug interactions; the only major differences between the drugs are observed in the extent of clinical documentation. In general, dalteparin and enoxaparin are better documented than nadroparin or tinzaparin. The differences in acquisition cost are generally limited.Keywords:
Tolerability
Formulary
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Niedermolekulare Heparine, deren Einsatz zur Thromboseprophylaxe heute praktisch zum Standard geworden ist, können seit kurzem auch für die Behandlung von tiefen Venenthrombosen verwendet werden. In dieser Übersichtsarbeit wird dargelegt, welche Gründe es dafür gibt und insbesondere welche Vorteile sich daraus im klinischen Alltag ergeben. Nach einer Beschreibung der verschiedenen prinzipiellen Ansätze zum therapeutischen Einsatz niedermolekularer Heparine werden die wesentlichen Ergebnisse bisher durchgeführter Studien angeführt. Sie zeigen, daß das bisher übliche Schema der initialen Behandlung mit intravenös gegebenem unfraktioniertem Heparin durch subkutane Gaben niedermolekularer Heparine ersetzt werden kann, wobei eine mindestens gleich gute Wirksamkeit bei besserer Verträglichkeit zu erwarten ist. Außerdem ermöglicht die Einfachheit dieses therapeutischen Regimes die ambulante Durchführung, die sowohl aus Sicht des Patienten als auch aus Kostengründen beträchtliche Vorteile bietet.
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Traditionally, it has been recommended that the prevention of venous thromboembolic disease (VTD) be treated, subcutaneously, with heparins, be they fractionated (UH) or low molecular weight (LMWH). While it has been expected that the latter would prove the more effective, numerous clinical studies have confirmed that there are no appreciable differences between either, given the results obtained in the prevention of VTD, or of bleeding, or of death. It therefore appears logical to think that the moment has arrived to consider substituting the old, conventional heparins, for the new LMWH. In order to attempt to answer this question, we have undertaken a revision of the main meta-analysis published, wherein both heparins have been comparatively employed; thus we analyze their mechanisms of action, their pharmacokinetics differences, and their adverse effects, as well as the type of patients, both at the time of initiation and continuation of tromboprophylaxis with heparins. Using currently available data, it can be inferred that LMWH are as safe and effective as the UH in the prevention of VTD. Moreover, there are a series or added advantages, such as no unnecessary laboratory controls, and the easy dosification and administration, both to patient as well as nursing staff.
Venous thromboembolic disease
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Background: In major orthopedic surgery, prevention of venous thromboembolism has been based on Unfractionated Heparins (UFHs) over the past decades, then on LowMolecular Weight Heparins (LMWHs), and on New Oral Anticoagulants (NOACs) more recently. To summarize the comparative effectiveness of UFHs, LMWHs, and NOACs in this clinical indication, we applied Bayesian network meta-analysis to the clinical material (randomized studies) published in two previous reviews focused on this issue. Objectives: Our end-point was a composite of venous thromboembolism and pulmonary embolism. Materials and Methods: Our analysis was based on standard Bayesian network metaanalysis (random-effect model). Results: The analysis included 21 randomized trials for a total of 21,805 patients. Our results showed that the degree of effectiveness did not differ among UFHs, LMWHs, and NOACs. Although some trends emerged from an in-depth analysis of these data (e.g. according to the histogram of rankings), no significant differences were found (P > 0.05). Moreover, two agents among LMWHs proved to be adequately supported by randomized trials (enoxaparin and dalteparin), while limited evidence was available for other agents of this class. Conclusions: Our synthesis of the effectiveness data can be useful as an overall reference in this area and can also contribute to defining the place of further innovative treatments for this clinical indication.
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Low molecular weight heparins are derived from unfractionated heparin by chemical or enzymatic depolymerization; as a result, the mean molecular weight of unfractionated heparin is reduced by about one third and its biochemical and pharmacologic properties are improved. Demonstrated advantages of low molecular weight heparins over unfractionated heparin are the greater bioavailability at low doses, the longer half-life, and the more predictable dose response, which allows for fixed doses to be administered without laboratory monitoring; a potential advantage is the reduced hemorrhagic-to-thrombotic ratio observed in experimental animals. Clinical studies in the prevention of venous thromboembolism have shown that whereas the advantages offered by low molecular weight heparin over unfractionated heparin are modest in general surgery, they are substantial when compared with these and other agents in orthopedic surgery. In addition, low molecular weight heparins are at at least as safe and effective as unfractionated heparin in the treatment of established deep vein thrombosis, but have the advantage that they can be administered once or twice daily without laboratory monitoring and can be used to treat uncomplicated deep venous thrombosis on outpatient basis.
Depolymerization
Therapeutic index
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In the past few years, several clinical trials with low–molecular-weight heparins in acute coronary syndromes without ST-segment elevation have been published. In the acute phase of treatment, enoxaparin obtained better results than unfractionated heparin, but dalteparin and nadroparin did not. Enoxaparin also obtained better results than tinzaparin. From these results, it can be assumed that the efficacy of enoxaparin is higher than that of dalteparin and nadroparin. However, because low–molecular-weight heparins have not been compared head to head (except in the case of enoxaparin and tinzaparin), and given the differences between studies in patient selection criteria, design, treatment strategies, and efficacy variables, it cannot be concluded that one low–molecular-weight heparin is superior to another in the acute phase of treatment. Prolonged dalteparin treatment suggests a benefit, particularly for patients at high risk (defined as those with high troponin levels), and it can also be useful in patients waiting for invasive procedures.
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Some 10 low molecular weight heparin products are currently available for commercial use. Enoxaparin and fraxiparin appear to be the most developed low molecular weight heparins. Many well-designed clinical trials have been carried out for different clinical indications with both of these products. As shown in both experimental and clinical settings, the prophylactic antithrombotic efficacy of enoxaparin is distinct from other low molecular weight heparins. Enoxaparin has provided consistently impressive clinical results. Moreover, at comparable dosages, other products have exhibited safety/efficacy profiles different from that of enoxaparin. The clinical performance of each low molecular weight heparin is characteristic of only that particular agent. Besides the commercially available low molecular weight heparin preparations, some 14 other agents are under development at this time. Although each product has similar basic characteristics, their biological actions should be studied carefully. Apart from differences in the physicochemical properties, the pharmacologic actions of these agents may differ significantly. Only results from valid clinical trials will show similarities or differences between the low molecular weight heparins. Other manufacturers should follow the lead of enoxaparin and conduct their own clinical trials on each of their products.
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Enoxaparin sodium
Clinical efficacy
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In numerous clinical studies, the antithrombotic effect and tolerance of low-molecular-weight heparins (LMWHs) were compared to those of unfractionated heparin (UFH). Based on our own experience and on a review of the literature the following conclusions can be drawn. In the field of prophylaxis of thromboembolism, including high-risk patients with major bone surgery, the antithrombotic efficacy of a single daily dose of LMWH is at least equivalent to two or three injections of UFH per day. It should, however, be noted that the margin between thromboembolic and bleeding complications has not become bigger, although this had been derived from experimental results. In order to avoid bleeding complications, it is absolutely necessary to take note of the manufacturers' recommendations. This is particularly important when a change of various preparations is considered, because the standardization of LMWH preparations is different and the units are not comparable. The main advantage of LMWH results from an improved practicability. The single daily dose leads to an improved compliance of patients and the nursing staff is spared a great deal of work.
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Current guidelines recommend low-molecular-weight-heparins (LMWH) monotherapy for 3 to 6 months as first-line treatment for cancer-associated venous thromboembolism (VTE). In clinical practice, enoxaparin and nadroparin are common agents used. However, differences in therapy adherence between these LMWHs have never been reported. Therefore, our aim was to compare adherence to enoxaparin and nadroparin in patients with cancer-associated VTE. Consecutive patients with active cancer and objectively confirmed VTE, treated at a Dutch or a Spanish hospital, were followed during LMWH therapy with a maximum of 180 days. Cumulative incidences of discontinuation of both LMWHs were estimated and compared according to the Kaplan-Meier method, applying a competing risk analysis to correct for mortality. A total of 366 patients were analyzed during LMWH treatment, of whom 284 patients (78%) were treated with enoxaparin and 82 (22%) with nadroparin. The cumulative incidence of discontinuation of enoxaparin and nadroparin treatment because of side effects was 30% (95% confidence interval [CI] 24-36) and 8.8% (95% CI 1.1-15), respectively. Competing risk analysis revealed a higher number of patients discontinuing enoxaparin due to side effects (adjusted hazard ratio [HR]: 2.8; 95% CI 1.06-7.2). Pain at the injection site was the most common reason of discontinuation in patients using enoxaparin, occurring in 32 patients, while it occurred in 1 patient using nadroparin (adjusted HR: 4.0; 95% CI 0.52-31). This analysis reveals that enoxaparin was associated with a higher risk of discontinuation because of side effects compared to nadroparin. However, given the nature of the patient groups, these findings should be followed by future studies.
Discontinuation
Enoxaparin sodium
Cumulative incidence
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Objective. To evaluate the pharmacokinetic, safety, and effectiveness data of dosing low-molecular-weight heparins (LMWHs) for prophylaxis of venous thromboembolic events (VTEs) in obese people. Data Sources. A PubMed search (1966 to September 2015) was performed of published English articles using the following keywords: low-molecular-weight heparin, prophylaxis, and obesity. Study Selection and Data Extraction. In all, a total of 11 articles were included in this review. The search was conducted to identify pharmacokinetic studies, clinical trials (phases I-IV), or retrospective evaluations of the impact of weight and/or obesity on anti-Xa levels as well as the safety and effectiveness of LMWHs used for VTE prophylaxis. Data Synthesis. The vast majority of the available data focus on enoxaparin. Pharmacokinetic, effectiveness, and safety data all support increased enoxaparin dosing in obese patients. However, the optimal adjustment remains uncertain. For now, we recommend using 40 mg twice daily as the data for effectiveness use this regimen. Dalteparin dosing should not be adjusted in class I-II obese (body mass index 30.0-39.9 kg/m 2 ) patients. Data regarding the impact of class III obesity (body mass index ≥40 kg/m 2 ) on dalteparin effectiveness is needed. Total body weight dosing of tinzaparin can be used to optimize anti-Xa levels, but safety and effectiveness data are needed before weight-based tinzaparin dosing is routine medical practice for obese patients. Conclusions. The data regarding dosing of LMWHs for VTE prophylaxis are quite limited. High-quality studies are needed to help optimize dosing for obese adults requiring LMWH prophylaxis.
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