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Fondaparinux, LMWH, or UFH for PE?
Edith Nutescu, Pharm.D.
February, 2004
Review: Subcutaneous Fondaparinux versus Intravenous Unfractionated Heparin in the Initial Treatment of Pulmonary Embolism. The Matisse Investigators. N Engl J Med 2003;349:1695-702.
Current State of Therapy for Pulmonary Embolism:
Intravenous, unfractionated heparin (UFH) is still considered as the standard of anticoagulant therapy for patients with pulmonary embolism (PE).1 In recent years several studies evaluated low-molecular-weight heparins (LMWHs) as alternatives to UFH for this indication. However, due to the small number of PE patients in most of these trials, many clinicians have been reluctant to adopt LMWHs for treatment of acute symptomatic PE. A recent meta-analysis combined data from 12 studies that included 1,951 patients with PE and demonstrated that LMWHs are as safe and as effective as intravenous UFH in the treatment of non-massive PE.2 (Table)
Fondaparinux as a novel therapeutic option for PE:
In recent years, various novel anticoagulants have emerged that may offer benefit over traditional anticoagulants in the treatment of patients with venous thrombosis. Fondaparinux, one of these novel agents, is obtained by chemical synthesis and acts by selective inhibition of factor-Xa. A recent randomized, open-label study evaluated the efficacy of fondaparinux compared to intravenous UFH in 2213 patients with acute symptomatic PE.3 This is the largest randomized study published to date that evaluated a novel anticoagulant "specifically" in the treatment of patients with acute symptomatic PE. The study demonstrated that once daily, subcutaneous fondaparinux is at least as effective and as safe as UFH in treatment of patients with hemodynamically stable PE. (Table) There was an absolute difference in favor of fondaparinux of -1.2% compared to UFH with regards to the primary outcome of recurrent venous thromboembolism, however this did not reach statistical significance. Safety and mortality were similar in both groups. An additional, interesting observation was reported in a subgroup analysis of patients with active cancer. Recurrent venous thromboembolism occurred in 10 of 112 patients in the fondaparinux group (8.9%) and in 22 of 128 patients in the UFH group (17.2%). Approximately 15% of the patients received fondaparinux in part on an outpatient basis, offering a more convenient and more economical option to in-hospital administered UFH.
Fondaparinux versus LMWH in treatment of PE?
At this time there are no direct head to head trials that compare LMWH and fondaparinux in the treatment of PE. The table below makes an indirect comparison of the efficacy and safety results of fondaparinux and LMWH as compared to UFH. Overall, the efficacy, safety, and mortality results are comparable for fondaparinux, LMWH, and UFH. Therefore, both LMWH and fondaparinux seem to be reasonable alternatives to UFH in the treatment of patients with PE.
Summary:
The Matisse study presents the largest randomized database to date to suggest that a novel anticoagulant such as fondaparinux is a safe and effective alternative to UFH in the treatment of PE. As "direct" evidence from large randomized clinical trials on the efficacy of LMWH in the treatment of acute symptomatic PE is still limited, fondaparinux will be a welcomed addition to the armamentarium of currently available anticoagulants used for this indication.
References:
1. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2001;119:Suppl:176S-193S.
2. Qunilan DJ, McQuillan A, Eikelboom JW. Low-Molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism. A meta-analysis of randomized, controlled trials. Ann Intern Med 2004;140:175-183.
3. The Matisse Investigators. Subcutaneous Fondaparinux versus Intravenous Unfractionated Heparin in the Initial Treatment of Pulmonary Embolism. N Engl J Med 2003;349:1695-702.
Table: Clinical Outcomes of Fondaparinux and LMWH versus UFH in the treatment of PE*
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Outcome
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Matisse Investigators: Randomized trial of Fondaparinux vs. UFH3
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Quinlan DJ, et.al: Meta-analysis of LMWH vs. UFH2
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Fondaparinux n/n (%)
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UFH n/n (%)
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LMWH n/n (%)
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UFH n/n (%)
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VTE initial treatment
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14/1103 (1.3)
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19/1110 (1.7)
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14/1023 (1.4)
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22/928 (2.4)
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VTE entire study (3 months)
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42/1103 (3.8)
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56/1110 (5.0)
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30/988 (3.0)
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39/895 (4.4)
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DVT entire study
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12/1103 (1)
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17/1103 (1.5)
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15/891 (1.7)
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19/792 (2.4)
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PE entire study
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30/1103 (2.7)
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39/1103 (3.5)
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16/891 (1.8)
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20/792 (2.5)
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Major bleeding initial treatment
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14/1092 (1.3)
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12/1092 (1.1)
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14/1023 (1.4)
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21/928 (2.3)
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Mortality initial treatment
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9/1092 (0.8)
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12/1092 (1.1)
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14/1023 (1.4)
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11/928 (1.2)
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Mortality entire study (3 months)
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57/1092 (5.2)
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48/1092 (4.4)
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46/988 (4.7)
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55/895 (6.1)
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Adapted from N Engl J Med 2003;349:1695-702 and Ann Intern Med 2004;140:175-183.
*None of the differences reached statistical significance
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