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Fondaparinux as Monotherapy for DVT and/or Pulmonary Embolism

2014-08-27 03:41:01 | BioPortfolio

Summary

To determine whether fondaparinux as monotherapy without warfarin is effective and safe for long-term (90 days) treatment of DVT and/or PE, thus gaining new long-term experience and data using fondaparinux.

Description

Background and Significance:

Warfarin is usually prescribed to manage long-term anticoagulation of deep vein thrombosis (DVT) and pulmonary embolism (PE). However about 5% of patients are unable to tolerate warfarin or to be safely or effectively anticoagulated. Some of the reasons for discontinuing warfarin anticoagulation and switching patients to parenteral anticoagulation are as follows:

1. Recurrent venous thromboembolism despite anticoagulation with warfarin

2. Clinically important bleeding complications due to warfarin

3. Inability to achieve target International Normalized Ratio (INR) on warfarin

4. Nonbleeding side effects of warfarin, such as hair loss or rash.

These patients who cannot tolerate or respond adequately to warfarin are usually managed with "off-label" twice-daily enoxaparin injections as monotherapy. The approved duration of treatment of DVT and PE with fondaparinux is 5 to 9 days as a "bridge" to warfarin. Until now, no studies have investigated the use of fondaparinux for more than 26 days for the treatment of PE and more than 10 days for the treatment of DVT.

Treatment doses of twice-daily enoxaparin are only Food and Drug Administration (FDA) approved for 5 to 14 days for "bridging" for the treatment of acute DVT and/or PE patients to warfarin.

Fondaparinux is a synthetic antithrombotic agent with specific anti-factor Xa activity. Its pharmacokinetic properties allow for a simple, fixed-dose, once daily regimen of subcutaneous injection, without the need for dose adjustment based on laboratory monitoring.

Fondaparinux is available only in 3 treatment doses and is prescribed once every 24 hours based on patient's weight: 5 mg for patients weighing less than 50 kg, 7.5 mg for patients weighing between 50 to 100 kg, and 10 mg for patients weighing more than 100 kg and is available in prefilled syringes. Also, fondaparinux does not cross react with heparin-induced platelet antibodies, and heparin-induced thrombocytopenia has never been documented with fondaparinux.

The MATISSE Investigators showed that once-daily, subcutaneous administration of fondaparinux for at least 5 days and until 2 consecutive INRs were greater than 2.0 as a "bridge" to warfarin is at least as effective and safe as adjusted-dose, intravenous administration of unfractionated heparin as a "bridge" to warfarin in the initial treatment of hemodynamically stable patients with pulmonary embolism. During the 3-month follow up, 42 of the 1103 patients randomly assigned to receive fondaparinux (3.8 percent) had recurrent thromboembolic events, as compared with 56 of the 1110 patients randomly assigned to receive unfractionated heparin (5.0 percent). Major bleeding occurred in 1.3 percent of the patients treated with fondaparinux and 1.1 percent of those treated with unfractionated heparin. Mortality rates at three months were similar in the two groups.

In another randomized double-blinded trial by the MATISSE Investigators, patients were randomized to fondaparinux once daily versus enoxaparin twice daily for at least 5 days and until 2 consecutive INRs were greater than 2.0 as a "bridge" to warfarin for initial treatment of acute symptomatic DVT. Fondaparinux was found to be as effective and safe as twice-daily enoxaparin during the 3-month follow up period. 43 (3.9%) of 1098 patients randomly assigned to fondaparinux had recurrent thromboembolic events compared with 45 (4.1%) of 1107 patients randomly assigned to enoxaparin. Major bleeding occurred in 1.1% of patients receiving fondaparinux and 1.2% of patients receiving enoxaparin. Mortality rates were 3.8% and 3.0%, respectively.

These two MATISSE trial totaled 4418 patients and led to the FDA approval of fondaparinux in the treatment of acute symptomatic DVT and PE as a "bridge" to warfarin.

In this investigator-initiated trial, we will conduct a cohort study with once daily fondaparinux as monotherapy without warfarin for 90-day management of DVT and/or PE in patients who are unable to tolerate or respond adequately to warfarin.

Research Design and Methods:

This is a cohort study with a sample size of 30 patients at Brigham and Women's Hospital with history of DVT and/or PE who are intolerant to warfarin or not responding to warfarin.

During the study there will be 3 visits at day zero, week 6, and at day 90. Patients will be monitored closely for any bleeding complications.

During these visits, blood will be drawn for platelet counts, renal function, hematocrit, and transaminase level.

Primary endpoints

1. Recurrent acute symptomatic DVT confirmed by venous ultrasound and/or CT scan

2. Recurrent acute symptomatic PE confirmed by chest CT scan

3. Major hemorrhage defined as spinal, retroperitoneal or intracranial bleeding, drop in hemoglobin ≥2g/dl or transfusion ≥2U or surgical or medical intervention, death related to bleeding

Secondary endpoints

Comparison of Day Zero, 6 week, and Day 90 platelet counts, renal function, hematocrit and transaminase level

Drug Dose:

Patients enrolled in the study will receive a weight-based dose of fondaparinux as monotherapy for 90 days for the treatment of DVT and/or PE.

Weight < 50 kg - 5 mg daily Weight 50 - 100 kg - 7.5 mg daily Weight > 100 kg - 10 mg daily

Biostatistical Analysis:

Descriptive statistics will be performed using age, gender, and indication for long-term anticoagulation.

Study Design

Allocation: Non-Randomized, Control: Uncontrolled, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Deep Vein Thrombosis

Intervention

Fondaparinux

Location

Brigham and Women's Hospital
Boston
Massachusetts
United States
02115

Status

Completed

Source

Brigham and Women's Hospital

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:41:01-0400

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Medical and Biotech [MESH] Definitions

DEEP VEIN THROMBOSIS of an upper extremity vein (e.g., AXILLARY VEIN; SUBCLAVIAN VEIN; and JUGULAR VEINS). It is associated with mechanical factors (Upper Extremity Deep Vein Thrombosis, Primary) secondary to other anatomic factors (Upper Extremity Deep Vein Thrombosis, Secondary). Symptoms may include sudden onset of pain, warmth, redness, blueness, and swelling in the arm.

A compression of ILIAC VEIN that results in a decreased flow in the vein and in the left LOWER EXTREMITY due to a vascular malformation. It may result in left leg EDEMA, pain, iliofemoral DEEP VENOUS THROMBOSIS and POSTTHROMBOTIC SYNDROME. Compression of the left common ILIAC VEIN by the right common ILIAC ARTERY against the underlying fifth LUMBAR VERTEBRA is the typical underlying malformation.

Congenital arteriovenous malformation involving the VEIN OF GALEN, a large deep vein at the base of the brain. The rush of arterial blood directly into the vein of Galen, without passing through the CAPILLARIES, can overwhelm the heart and lead to CONGESTIVE HEART FAILURE.

Tight coverings for the foot and leg that are worn to aid circulation in the legs and prevent the formation of EDEMA and DEEP VEIN THROMBOSIS. PNEUMATIC COMPRESSION STOCKINGS serve a similar purpose especially for bedridden patients and following surgery.

Instruments that generate intermittent forces, uniformed or graduated, to facilitate the emptying of VEINS. These devices are used to reduce limb EDEMA and prevent venous THROMBOEMBOLISM, such as deep vein thrombosis in the legs.

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