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Subcutaneous Fondaparinux Versus Intravenous Unfractionated Heparin in the Initial Treatment of Pulmonary Embolism - Matisse
Description:
The goal of this trial was to compare the efficacy and safety of the synthetic antithrombotic agent fondaparinux versus unfractionated heparin (UFH) in patients with pulmonary embolism.
Hypothesis:
Treatment with fixed-dose, once-daily, subcutaneous administration of fondaparinux is at least as effective as UFH for the initial treatment of symptomatic pulmonary embolism.
Study Design
Study Design:
Patients Screened: 5,993
Patients Enrolled: 2,213
Mean Follow Up: 3 months
Mean Patient Age: mean age 62-63 years
Female: 56
Patient Populations:
Age ≥18 years; acute symptomatic pulmonary embolism requiring antithrombotic therapy, documented by intraluminal filling defect on spiral computed tomography or pulmonary angiography, a high-probability ventilation–perfusion lung scan, or a nondiagnostic lung scan with documentation of DVT either by compression ultrasonography or by venography
Exclusions:
Treatment with therapeutic doses of low molecular weight heparin or oral anticoagulants for >24 hours; need for thrombolysis, embolectomy, or a vena cava filter; contraindication for anticoagulant therapy; serum creatinine >2.0 mg/dl or uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg); pregnancy; or life expectancy <3 months
Primary Endpoints:
Composite of symptomatic, recurrent pulmonary embolism (nonfatal or fatal) and new or recurrent DVT at three months
Drug/Procedures Used:
Patients with acute symptomatic pulmonary embolism were randomized open-label to fondaparinux (subcutaneously 5.0, 7.5, or 10.0 mg/day in patients weighing <50, 50-100, or >100 kg, respectively; n=1,103) or intravenous UFH (activated partial-thromboplastin time 1.5-2.5 times control; n=1,110). Patients were treated for at least five days and until the use of vitamin K antagonists resulted in an international normalized ratio (INR) >2.0.
Concomitant Medications:
Vitamin K antagonist, started within at least 72 hours after initiation of study treatment
Principal Findings:
In the fondaparinux arm, 14.5% of patients received treatment on an outpatient basis. Mean duration of treatment was 6.5 days in the fondaparinux arm and 6.9 days in the UFH arm. Recurrent thromboembolic events occurred in 3.8% of patients in the fondaparinux arm versus 5.0% in the UFH arm (absolute difference –1.2%, 95% confidence interval [CI] –3.0 to 0.5), demonstrating the noninferiority of fondaparinux.
Major bleeding occurred in 1.3% of patients in the fondaparinux arm versus 1.1% in the UFH arm. There was no difference in mortality at three months in the two treatment arms (5.2% with fondaparinux vs. 4.4% with UFH, absolute difference 0.8%, 95% CI –1.0 to 2.6).
Interpretation:
Among patients with acute symptomatic pulmonary embolism, treatment with fondaparinux was noninferior compared with UFH for the primary endpoint of recurrent pulmonary embolism and new or recurrent deep-vein thrombosis (DVT).
Fondaparinux is a synthetic antithrombotic agent with specific antifactor Xa activity. The fondaparinux regimen allows for fixed-dose, once-daily subcutaneous injection without the need for monitoring, unlike UFH, which requires continuous intravenous infusion with laboratory monitoring and dose titration. Further studies comparing fondaparinux with low molecular weight heparins are warranted.
References:
Buller HR, Davidson BL, Decousus H, et al., for the Matisse Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003;349:1695-702.
Keywords: Vitamin K, Polysaccharides, Documentation, Pulmonary Embolism, Heparin, Low-Molecular-Weight, Fibrinolytic Agents, Tomography, Spiral Computed, International Normalized Ratio, Thrombosis, Injections, Subcutaneous, Phlebography, Thromboplastin, Confidence Intervals, Probability, Infusions, Intravenous
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