Deep vein thrombosis landmark trials in treatment

Revision as of 17:56, 14 June 2012 by C Michael Gibson (talk | contribs) (/* Meta-analysis of Home versus inpatient treatment of DVT{{cite journal |author=Schraibman IG, Milne AA, Royle EM |title=Home versus in-patient treatment for deep vein thrombosis |journal=Cochrane Database Syst Rev |volume= |issue=2 |pages=CD0030...)
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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.

Trials Comparing Different Formulations of Heparin in the Treatment of DVT

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[1]

  • 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.

2. Fixed-Dose Heparin (FIDO) trial[2]

  • 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.

3. Polish Multi Center Trial[3]

  • 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.

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

1. Cochrane Meta-Analysis[4]

  • 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.

Trials Evaluating Fondaparinux

1. Matisse Investigators[5]

  • 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.

Meta-Analysis Evaluating LMWH Dosing[6]

  • 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.

Meta-Analysis of Home Versus Inpatient Treatment of DVT[7]

  • 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 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 UFH in hospital with LMWH at home. The trials showed that home treatment was no more liable to complications than hospital treatment. Initial results from a smaller trials comparing LMWH treatment in both home and hospital arms came to the same conclusion.
  • Conclusions: Limited evidence suggested that home treatment of DVT is preferred by patients and more cost-effective, without any major complications.

Catheter-directed thrombolysis[8]

  • 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 CDT or standard treatment alone, in a open multi center, randomized controlled trial. Patients were followed after 6 months with duplex ultrasound and air-plethysmography.
  • Results: Compared with standard treatment alone, patients who underwent CDT had significantly increased ileofemoral potency (RR 28%, 95% CI 9.7%-46.7%, p=0.004). Femoral venous insufficiency was similar in both groups.
  • Conclusions: Additional treatment with CDT in the early course of DVT is associated with increased iliofemoral vein potency at 6 months.


Meta-analysis assessing Thromblysis[9]

  • 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 on occurrence of 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. PREPIC (Prevention du Risque d'Embolie Pulmonaire par Interruption Cave) study[10]

  • 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 a 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). Postthrombotic syndrome and mortality rates were almost similar in both groups.
  • Conclusions: IVC filter reduced the risk of P, but increased that of DVT and had no effect on survival.

Newer anticoagulants

Rivaroxaban

EINSTEIN Study[11]

  • 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, noninferiority 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 antagonit 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). Nonmajor bleeding was also similar in both groups (HR 0.97, 95% CI 0.76-1.22). In the continued-treatment study, rivaroxaban had 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 for 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[12]

  • 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.

References

  1. ↑ Prandoni P, Carnovali M, Marchiori A (2004). "Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism". Arch. Intern. Med. 164 (10): 1077–83. doi:10.1001/archinte.164.10.1077. PMID 15159264. Unknown parameter |month= ignored (help)
  2. ↑ Kearon C, Ginsberg JS, Julian JA; et al. (2006). "Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism". JAMA. 296 (8): 935–42. doi:10.1001/jama.296.8.935. PMID 16926353. Unknown parameter |month= ignored (help)
  3. ↑ Lopaciuk S, Meissner AJ, Filipecki S; et al. (1992). "Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial". Thromb. Haemost. 68 (1): 14–8. PMID 1325076. Unknown parameter |month= ignored (help)
  4. ↑ Erkens PM, Prins MH (2010). "Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism". Cochrane Database Syst Rev (9): CD001100. doi:10.1002/14651858.CD001100.pub3. PMID 20824828.
  5. ↑ Büller HR, Davidson BL, Decousus H; et al. (2004). "Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial". Ann. Intern. Med. 140 (11): 867–73. PMID 15172900. Unknown parameter |month= ignored (help)
  6. ↑ van Dongen CJ, MacGillavry MR, Prins MH (2005). "Once versus twice daily LMWH for the initial treatment of venous thromboembolism". Cochrane Database Syst Rev (3): CD003074. doi:10.1002/14651858.CD003074.pub2. PMID 16034885.
  7. ↑ Schraibman IG, Milne AA, Royle EM (2001). "Home versus in-patient treatment for deep vein thrombosis". Cochrane Database Syst Rev (2): CD003076. doi:10.1002/14651858.CD003076. PMID 11406067.
  8. ↑ Enden T, Kløw NE, Sandvik L; et al. (2009). "Catheter-directed thrombolysis vs. anticoagulant therapy alone in deep vein thrombosis: results of an open randomized, controlled trial reporting on short-term patency". J. Thromb. Haemost. 7 (8): 1268–75. doi:10.1111/j.1538-7836.2009.03464.x. PMID 19422443. Unknown parameter |month= ignored (help)
  9. ↑ Watson LI, Armon MP (2004). "Thrombolysis for acute deep vein thrombosis". Cochrane Database Syst Rev (4): CD002783. doi:10.1002/14651858.CD002783.pub2. PMID 15495034.
  10. ↑ "Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d'Embolie Pulmonaire par Interruption Cave) randomized study". Circulation. 112 (3): 416–22. 2005. doi:10.1161/CIRCULATIONAHA.104.512834. PMID 16009794. Unknown parameter |month= ignored (help)
  11. ↑ Bauersachs R, Berkowitz SD, Brenner B; et al. (2010). "Oral rivaroxaban for symptomatic venous thromboembolism". N. Engl. J. Med. 363 (26): 2499–510. doi:10.1056/NEJMoa1007903. PMID 21128814. Unknown parameter |month= ignored (help)
  12. ↑ Schulman S, Kearon C, Kakkar AK; et al. (2009). "Dabigatran versus warfarin in the treatment of acute venous thromboembolism". N. Engl. J. Med. 361 (24): 2342–52. doi:10.1056/NEJMoa0906598. PMID 19966341. Unknown parameter |month= ignored (help)

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