EINSTEIN DVT: single-drug therapy with oral rivaroxaban versus dual-drug therapy with subcutaneous enoxaparin and oral VKA
Acute DVT is a common disorder. The current standard of care is dual-drug therapy with a parenteral agent (such as unfractionated heparin, low molecular weight heparin or fondaparinux) plus a vitamin K antagonist (VKA) followed by international normalized ratio (INR)-adjusted VKA alone.97 Although short-term treatment with the current standard of care is effective, management of acute DVT with VKA therapy in the outpatient setting remains challenging. Many of these challenges relate to the limitations of VKA therapy, which include:123
- Narrow therapeutic window
- Requirement for regular coagulation monitoring and dose adjustment
- Multiple food and drug interactions
- Lifestyle limitations
Rivaroxaban, as a newer oral anticoagulant, overcomes many of these limitations. It has a rapid onset of action and so does not require bridging therapy with parenteral agents. 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 objective of EINSTEIN DVT was to determine whether a single-drug approach with oral rivaroxaban was at least as effective as (non-inferior to) dual-drug therapy with enoxaparin/VKA and to compare the safety of these two approaches for the treatment of patients with acute symptomatic DVT without symptomatic PE.
Study design
EINSTEIN DVT was an randomized, open-label, event-driven, non-inferiority study of 3449 patients with a predefined treatment duration of 3, 6 or 12 months. The patients were randomly assigned to receive one of the following regimens:96
- Oral rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily for the remaining treatment period
- Subcutaneous, body weight-adjusted enoxaparin twice daily for at least 5 days plus a VKA, followed by dose-adjusted VKA only (target INR of 2.0–3.0) for the remaining treatment period
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 clinically relevant bleeding, defined as the composite of major bleeding or non-major clinically relevant bleeding; major bleeding was 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, such as intracranial or retroperitoneal
- Death
- A decrease in haemoglobin of 2 g/dl or more
- 97 - Buller HR. Oral rivaroxaban for the acute and continued treatment of symptomatic venous thromboembolism: the EINSTEIN-DVT and EINSTEIN-Extension Study. Blood (ASH Annual Meeting Abstracts) 2010;116:86. Abstract 187.
- 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.
- 96 - The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–2510.
- 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.
- Low molecular weight heparin
- An anticoagulant used to prevent new clots forming and existing clots from getting larger. It is injected subcutaneously (under the skin).
- 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.
- 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.
- 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.
