Deep vein thrombosis landmark trials in treatment

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Editor(s)-In-Chief: The APEX Trial Investigators, C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] Ujjwal Rastogi, MBBS [3]; Kashish Goel, M.D.; Assistant Editor(s)-In-Chief: Justine Cadet

Overview

Landmark trials have compared different formulations and routes of antithrombin administration to treat and prevent deep vein thrombosis.

Landmark Trials

Trials Comparing Low-Molecular-Weight Heparin With Subcutaneous Unfractionated Heparin

1. Fixed dose subcutaneous LMWH compared to adjusted dose unfractionated heparin for the treatment of VTE

• Methods: A total of 720 patients (including those with PE and recurrent VTE) were randomly assigned to subcutaneous LMWH or fixed-dose subcutaneous unfractionated heparin.
• Results: Subcutaneous LMWH and unfractionated heparin groups had similar incidence of recurrent thromboembolic events (4.2% and 3.9%), mortality (3.3% and 3.3%) and major bleeding (0.8% and 1.1%) during 3-months of follow-up.
• Conclusions: Fixed dose subcutaneous LMWH is as effective and safe as adjusted dose unfractionated heparin for treatment of VTE.

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2. Fixed-Dose Heparin (FIDO) trial

• Objective: Compare subcutaneous unfractionated heparin with LMWH for treatment of VTE
• Methods: Randomized, open-label, adjudicator-blinded, noninferiority trial of 708 patients with VTE, who were randomized to unfractionated heparin at an initial dose of 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours and LMWH at a fixed dose of 100 U/kg every 12 hours. Both treatments were administered as outpatient regimens.
• Results: The rate of recurrent VTE (3.8% and 3.4%) and major bleeding (1.1% and 1.4%) was similar in the UFH and LMWH groups respectively.
• Conclusions: Fixed dose subcutaneous UFH is as effective and as safe as LMWH for treatment of VTE in an outpatient setting.

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3. Polish Multi Center Trial

• Methods: A total of 149 patients with DVT were randomly assigned to subcutaneous LMWH or subcutaneous UFH for 10 days.
• Results: One symptomatic nonfatal PE, two rethromboses and one major leading was noted in the UFH group, compared to none in LMWH group.
• Conculusions: Subcutaneous fixed-dose LMWH is as effective and safe as subcutaneous UFH in treatment of DVT.

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Trials Comparing Low-Molecular-Weight Heparin With Intravenous Unfractionated Heparin

1. Cochrane Meta-Analysis

• Objective: To compare the effectiveness of LMWH with IV UFH for VTE treatment.
• Methods: A cochrane collaboration meta-analysis of randomized controlled trials comparing the fixed dose subcutaneous LMWH with adjusted dose intravenous or subcutaneous UFH for treatment of VTE was performed.
• Results: A total of 23 studies were included in the meta-analysis. Thrombotic complications (3.6% vs. 5.3%; OR, 0.70, 95% CI 0.57-0.85), major hemorrhages (1.1% vs. 1.9%; OR, 0.58, 95% CI 0.40-0.83) and mortality (4.3% vs. 5.8%; OR, 0.77, 95% CI 0.63-0.93) was significantly lower in subjects treated with LMWH compared with UFH.
• Conclusions: Subcutaneous LMWH signficantly reduced the incidence of thrombotic complications, major bleeding and mortality in patients with acute VTE. It is more effective and safer than IV UFH for the initial treatment of VTE.

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Trials Evaluating Fondaparinux

1. Matisse Investigators

• Objective: To compare fondaprinux with LMWH for initial treatment of DVT
• Methods: A randomized double-blind study randomizing 2205 patients with acute DVT to fondaparinux 7.5 mg subcutaneously once daily or enoxaparin for at least 5 days.
• Results: The rate of recurrent thromboembolic events were similar in the fondaparinux (3.9%) and enoxaparin (4.1%) groups. Major bleeding occurred in 1.1% of patients receiving fondaparinux compared with 1.2% in patients receiving enoxparin.
• Conclusions: Fondaparinux was as effective and safe as Enoxaparin for treatment of acute DVT.

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Meta-Analysis Evaluating LMWH Dosing

• Objective: To compare the efficacy and safety of once versus rice daily administration of LMWH
• Methods: A cochrane collaboration meta-analysis of randomized clinical trials assessing the dosing of LMWH.
• Results: A total of 5 studies enrolling 1508 subjects with acute VTE were included in this meta-analysis. There was no significant difference between the two groups for the risk of recurrent VTE (OR 0.77, 95% CI 0.40-1.45), in the risk of major hemorrhagic events (OR 1.14, 95% CI 0.62-2.08) or in mortality rates (OR 0.82, 95% CI 0.49-1.39),
• Conclusions: Once daily LMWH was as effective and safe as twice daily dosing. However, the increased 95% CI limits imply that there may be a higher risk of recurrent VTE in patients treated with once daily dosing.

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Meta-Analysis of Home Versus Inpatient Treatment of DVT

• Objective: To compare the safety, efficacy, patient acceptability and cost implications of home versus in-patient treatment.
• Methods: A cochrane collaboration meta-analysis was conducted including all randomized controlled trials of home versus in-hospital treatment of DVT. The patients were treated with either LMWH or UFH.
• Results: Only 2 trials were found, with some inherent limitations including high exclusion rates, partial hospital treatment of many in the LMWH arms, and comparison of in-hospital UFH with home-based LMWH. The trials showed that home treatment was not associated with excess complications when compared to hospital treatment. Initial results from smaller trials comparing LMWH treatment in both the home and hospital arms came demonstrated similar findings.
• Conclusions: Limited data suggests that home treatment of DVT is preferred by patients, it may be more cost-effective, and it may not be associated with an excess of major complications.

Catheter-Directed Thrombolysis

• Objective: To assess the efficacy of catheter-directed thrombolysis compared with standard treatment alone.
• Methods: A total of 103 patients with iliofemoral DVT and symptoms <21 days were randomized to additional catheter directed thrombolysis (CDT) or standard treatment alone, in a open multi center, randomized controlled trial. Patients were followed for 6 months with duplex ultrasound and air-plethysmography.
• Results: Compared with standard treatment alone, patients who underwent CDT had significantly increased iliofemoral vein patency (vessel opening) (RRR 28%, 95% CI 9.7%-46.7%, p=0.004). Venous insufficiency was similar in both groups.
• Conclusions: Additional treatment with CDT in the early course of DVT is associated with increased iliofemoral vein patency at 6 months.

Meta-Analysis Evaluating Thrombolysis

• Objective: To determine the efficacy and safety of systemic thrombolysis for treatment of DVT.
• Methods: A cochrane meta-analysi was conducting including all the randomized controlled trials examining the role of thrombolysis versus anticoagulation for treatment of acute DVT or calf vein thrombosis.
• Results: Twelve studies were included in the meta-analysis. Patients who received thrombolysis had a significantly higher rate of clot lysis (RR 0.24, 95% CI 0.07-0.82), lesser incidence of post-thrombotic syndrome (RR 0.66, 95% CI 0.47-0.94), but significantly higher rate of major bleeding complications (RR 1.73, 95% CI 1.04-2.88). Data regarding the occurrence of pulmonary embolism (PE) and recurrent DVT were inconclusive.
• Conclusions: Thrombolysis appears to offer advantages in terms of reducing post-thrombotic syndrome and maintaining venous patency after DVT. Use of strict eligibility criteria has improved the safety and acceptability of this treatment.

Use of IVC filters

1. A Clinical Trial of IVC Filters in the Prevention of PE in Patients with Proximal DVT

• Objective: Test the efficacy and safety of IVC filters in PE prevention using a high risk population of patients with proximal DVT.
• Methods: Dr. Decousus and his team, led a two-by-two factorial design was used to randomize 400 patients with proximal DVT who were at risk for PE to receive either an IVC filter (200 patients) or no filter (200 patients), and to receive enoxaparin (195 patients) or unfractioned heparin (205 patients). The outcomes were the recurrent VTE rate, death rate, and major bleeding rate at day 12 and at 2 years.
• Results: At day 12; 1.1% of patients assigned to the IVC filter arm and 4.8% of patients without a filter had a symptomatic or asymptomatic PE, with an odds ratio of 0.22 and a 95% confidence interval from 0.05 to 0.90. At two years 20.8% of patients assigned to the IVC filter arm and 11.6% % without the filter had a recurrent DVT, with an odds ratio of 1.87, and 95 % confidence interval from 1.10 to 3.20. There were no significant differences in mortality or other outcomes. 1.6% of patients who received low molecular heparin group (enoxaparin) and 4.2% of the unfractioned heparin group had a symptomatic or asymptomatic PE with an odds ratio of 0.38 and a 95% confidence interval from 0.10 to 1.38. DVT
• Conclusions: This study concluded that IVC filters had an initial benefit preventing PE, but there is an excess of recurrent DVT

without any difference in mortality. On the other hand; enoxaparin was similar in terms of effectiveness and safety as unfractioned heparin in the prevention of (PE).

2. PREPIC (Prevention du Risque d'Embolie Pulmonaire par Interruption Cave) study

• Objective: Eight-year follow-up study to assess the long-term effect of IVC filters.
• Methods: Four hundred patients with proximal deep-vein thrombosis with or without pulmonary embolism were randomized either to receive or not receive an IVC filter in addition to standard anticoagulant treatment for at least 3 months. Data on vital status, venous thromboembolism, and post-thrombotic syndrome were obtained once a year for up to 8 years.
• Results: Symptomatic PE occurred less frequently in the IVC filter group (6.2%) compared with the no-filter group (15.1%, p=0.008). However, DVT was more frequent in the filter group (35.7%) compared with the no-filter group (27.5%, p=0.042). Post-thrombotic syndrome and mortality rates were almost similar in both groups.
• Conclusions: Placement of an IVC filter reduced the risk of pulmonary embolism (PE), but increased the risk of DVT and had no effect on survival.

Newer Anticoagulants

Rivaroxaban

EINSTEIN Study

• Objective: To determine the safety and efficacy of Rivaroxaban for treatment of acute VTE as compared to warfarin.
• Methods: An open-label, randomized, event-driven, non-inferiority study comparing oral rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by vitamin K antagonist. The investigators also conducted a superiority study, that randomized patients to rivaroxaban (20 mg once daily) or placebo for an additional 6-12 months, after completing 6 to 12 months of VTE treatment.
• Results: Rivaroxaban was non-inferior to enoxaparin and vitamin K antagonist in terms of primary outcome of recurrent VTE (2.1% in rovaroxaban group vs. 3.0% in other group, p<0.0001 for non-inferiority). Major bleeding occurred in 0.8% of the patients on rivaroxaban versus 1.2% in the warfarin group (HR 0.65, 95% CI 0.33-1.30). Non-major bleeding was also similar in both groups (HR 0.97, 95% CI 0.76-1.22). In the continued-treatment study, rivaroxaban demonstrated superior efficacy (1.3% vs. 7.1% in placebo group; HR 0.18, 95% CI 0.09-0.39).
• Conclusions: Rivaroxaban was non-inferior to warfarin in the initial treatment of acute VTE, with a similar safety profile. It is also safe and effective for continued treatment of VTE.

Dabigatran

RE-COVER Study

• Objective: To compare the effectiveness and safety of Dabigatran with warfarin therapy for treatment of VTE.
• Methods: A randomized, double-blind, non-inferiority trial was conducted, involving patients with acute VTE who were initially given parenteral anticoagulation for 8-11 days, and then randomized to dabigatran 150 mg twice daily or warfarin with a therapeutic INR range of 2.0-3.0.
• Results: A total of 1274 patients were randomized to dabigatran and 1265 received warfarin therapy. The number of recurrent thromboembolism was almost similar (2.4% with dabigatran vs. 2.1% with warfarin, non-inferiority p <0.001). Major bleeding occurred in 1.6% of patients on dabigatran compared with 1.9% on warfarin (HR for dabigatran 0.82, 95% CI 045-1.48). The number of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in both groups. Adverse events occurred in 9% patients on dabigatran vs. 6.8% on warfarin (p=0.05), leading to discontinuation of the drug.

• Conclusions: Dabigatran is as effective and safe as warfarin for the treatment of acute VTE. This drug does not need monitoring as compared to warfarin.