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Siste oppdatering 08 april 2016
L.NO.MKT.03.2016.1478

VTE Treatment: EINSTEIN Programme

EINSTEIN-DVT/PE: Xarelto® versus enoxaparin/vitamin K antagonist in VTE treatment

EINSTEIN-DVT and EINSTEIN-PE are 2 independent studies integrated into a single protocol to compare Xarelto® with enoxaparin/vitamin K antagonist (VKA) in patients with acute symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE).18, 19

Objectives and endpoints

The main objective in these 2 related studies is to determine whether Xarelto® is at least as effective as enoxaparin/VKA in the treatment of patients with:
  • Acute symptomatic DVT without symptomatic PE (EINSTEIN-DVT)
  • Acute symptomatic PE with or without symptomatic DVT (EINSTEIN-PE)
The primary efficacy endpoint is symptomatic, recurrent venous thromboembolism (VTE) — the composite of recurrent DVT or fatal or non-fatal PE.
The main safety endpoint is the combination of major and clinically relevant non-major bleeding.18, 19

Study design

EINSTEIN-DVT/EINSTEIN-PE is a randomised, open-label, assessor-blind pair of independent evaluations in about 6,200 patients with a predefined study treatment duration of 3, 6, or 12 months. The patients are randomly assigned to receive either:
  • Xarelto® 15 mg tablet twice daily for 3 weeks followed by 20 mg once daily for the remaining treatment period
  • Subcutaneous body weight–adjusted enoxaparin (1 mg/kg) twice daily for at least 5 days plus VKA, target INR 2.5 (INR range 2-3), for the entire treatment period
After the last dose of the study drug the patients undergo a 30-day observation period.18, 19



 

EINSTEIN-Extension: Xarelto® in the long-term prevention of recurrent, symptomatic VTE

The EINSTEIN-Extension study takes patients with symptomatic DVT or PE who have already completed 6 or 12 months of treatment with Xarelto® or a VKA to evaluate whether one-tablet, once-daily Xarelto® is effective in the long-term secondary prevention of recurrent VTE.17

Objectives and endpoints

The main efficacy objective of the EINSTEIN-Extension study is to demonstrate that one 20 mg tablet once daily of Xarelto® is superior to placebo in the long-term prevention of recurrent VTE in patients with symptomatic DVT or PE who have already completed 6 or 12 months of treatment with a VKA or Xarelto®.
The primary efficacy endpoint is symptomatic, recurrent VTE — the composite of recurrent DVT or fatal or non-fatal PE.
The main safety endpoint is major bleeding and clinically relevant non-major bleeding.17

Study design

EINSTEIN-Extension is a randomised, double-blind, placebo-controlled study in approximately 1,300 patients. Potential patients for inclusion in the study are those who participated in the EINSTEIN-VTE programme, but also patients from outside this study who received treatment with a VKA following an initial diagnosis of PE or DVT and who continued on treatment up to randomisation. The patients are randomly assigned to one of the following regimens:
  • Xarelto® 20 mg tablet once daily
  • A matching placebo tablet once daily
In both arms the treatment duration is either 6 or 12 months. After the last dose of the study drug or placebo is administered, the patients undergo a 30-day observation period.17



 

  • 18 - Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep-Vein Thrombosis Without Symptomatic Pulmonary Embolism: Einstein-DVT Evaluation. Available at http://clinicaltrials.gov/ct2/show/NCT00440193. Accessed 13 August 2008.
  • 19 - Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism With Or Without Symptomatic Deep-Vein Thrombosis: Einstein-PE Evaluation. Available at http://clinicaltrials.gov/ct2/show/NCT00439777. Accessed 13 August 2008.
  • 17 - Once-Daily Oral Direct Factor Xa Inhibitor Rivaroxaban in the Long-Term Prevention of Recurrent Symptomatic Venous Thromboembolism in Patients With Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism. The Einstein-Extension Study. Available at http://clinicaltrials.gov/ct2/show/NCT00439725. Accessed 13 August 2008.
Thrombosis
Formation of a clot inside a blood vessel.
Deep vein thrombosis
A blood clot in a deep vein, usually resulting from damage to the vein or blood flow slowing down or stopping. Usually DVTs are found in the leg, but can also be in the arm. Distal DVTs are found in deep veins of the calf, and are the most common type of DVT. Proximal DVTs are found in the legs above the calf muscle up to the waist.
Pulmonary embolism
A potentially fatal condition caused by a blood clot blocking a vessel in the lung: usually the clot originates from a DVT in the legs. PE can result in permanent lung damage.
Efficacy
The ability of a drug to produce the desired effect.
Venous thromboembolism
A disease process beginning with a blood clot occurring within the venous system, including deep vein thrombosis and pulmonary embolism.
International Normalized Ratio
A system for assessing the clotting tendency of blood in patients receiving anticoagulant therapy. For patients with atrial fibrillation, the recommended target INR range is between 2 and 3. If the INR is higher than 3, patients are at risk of serious bleeding. If the INR is less than 2, patients are at risk of a blood clotting event.
Vitamin K antagonist
An anticoagulant that inhibits multiple steps in the blood clotting process. Administered orally, the dose varies by patient, and regular monitoring and dose adjustment is required. Vitamin K antagonists have interactions with food and other drugs. Due to the many limitations of this drug, many patients are actually not treated and many of those who are treated are outside of the required target INR range, which can be the cause for increased bleeding or a greater risk of stroke.

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The clinical phase III landmark study RECORD2 has been published in The Lancet. 3

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