EINSTEIN EXT: rivaroxaban in the long-term prevention of recurrent, symptomatic VTE
Effective treatment of an acute venous thromboembolic event reduces the risk of recurrence dramatically, from an estimated 25% to approximately 3% during the first 6–12 months.96 However, the optimal duration of anticoagulation therapy after an acute event remains a matter of debate. Treatment with VKAs beyond 1 year is associated with an annual risk of major bleeding of 1–2%,122 and clinicians must balance the long-term risks of recurrent VTE if anticoagulation is halted versus the risk of bleeding with further therapy and the healthcare burden of managing this therapy. Long-term management with VKA therapy is challenging and many of these challenges relate to limitations of VKA therapy, which include:123
- Narrow therapeutic window
- Requirement for frequent coagulation monitoring and dose adjustments
- Multiple food and drug interactions
- Lifestyle limitations
Rivaroxaban, as a newer oral anticoagulant, simplifies DVT treatment and prevention of recurrent DVT and PE. It does not require routine coagulation monitoring and has minimal interactions with commonly prescribed drugs; therefore, rivaroxaban provides a convenient, simplified treatment option for patients, with a consequent positive impact on daily life.96
Objective
The main efficacy objective of the EINSTEIN EXT study was to demonstrate that fixed-dose oral rivaroxaban (20 mg once daily) was superior to placebo in the long-term secondary prevention of recurrent VTE in patients with symptomatic DVT or PE who had already completed 6–12 months of VTE treatment with either a VKA or rivaroxaban and in whom there was clinical uncertainty as to whether to continue anticoagulation. Safety was also evaluated.96
Study design
EINSTEIN EXT was a double-blind, randomized, placebo-controlled, event-driven superiority study of 1197 patients who were at clinical equipoise regarding the need for continued VKA therapy. Patients who had completed the EINSTEIN DVT or EINSTEIN PE studies could be recruited in to EINSTEIN EXT. In addition, patients who had not participated in these studies were also enrolled, if they had received treatment with a VKA up to randomization after an initial diagnosis of DVT or PE. The patients were randomly assigned to one of the following regimens:96
- Rivaroxaban 20 mg tablet once daily
- Placebo once daily
In both arms, the treatment duration was either 6 or 12 months.96
Endpoints
- The primary efficacy endpoint was symptomatic, recurrent VTE – the composite of recurrent DVT or fatal or non-fatal PE96
- The principal safety outcome was major bleeding, defined as overt bleeding associated with any of the following:96
- A decrease in haemoglobin of 2 g/dl or more
- A transfusion of two or more units of packed red blood cells or whole blood
- Occurrence at a critical site: intracranial or retroperitoneal
- Death
- 96 - The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–2510.
- 122 - Kearon C, Akl EA, Comerota AJ et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th Ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e419S–e494S.
- 123 - Ageno W, Gallus AS, Wittkowsky A et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines (9th Edition). Chest 2012;141:e44S–e88S.
- Venous thromboembolism
- A disease process beginning with a blood clot occurring within the venous system, including deep vein thrombosis and pulmonary embolism.
- 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.
- 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.
