Treatment of Venous Thromboembolism: the EINSTEIN Programme
The EINSTEIN clinical trial programme comprises three randomized phase III studies of rivaroxaban for the treatment of venous thromboembolism (VTE) and the long-term prevention of recurrent VTE. It is the only clinical programme that has investigated a new oral anticoagulant for the treatment of acute deep vein thrombosis (DVT) and treatment for acute pulmonary embolism (PE) in separate trials.
- EINSTEIN DVT : rivaroxaban versus enoxaparin plus a vitamin K antagonist (VKA) in the treatment of acute DVT96
- EINSTEIN PE : rivaroxaban versus enoxaparin plus a VKA in the treatment of acute PE [This study is completed (www.clinicaltrials.gov; NCT00439777); results are planned to be reported in 2012]
- EINSTEIN EXT : rivaroxaban in the long-term prevention of recurrent, symptomatic VTE in patients who had already received 6–12 months of anticoagulant treatment for DVT or PE96
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.86 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:30
- Narrow therapeutic window
- Requirement for frequent 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 for the treatment of patients with acute symptomatic DVT without symptomatic PE.
Study design
EINSTEIN DVT was an open-label, event-driven, non-inferiority, randomized 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
EINSTEIN PE: single-drug therapy with oral rivaroxaban versus dual-drug therapy with subcutaneous enoxaparin and oral VKA
This study is completed and the results are planned to be reported in 2012 (www.clinicaltrials.gov; NCT00439777)
PE is the most severe complication of DVT. It is associated with significant mortality and is often undiagnosed.46 Up to 26% of patients with untreated, clinically diagnosed PE die within 2 weeks.49 For patients with confirmed PE, evaluation of the benefit–risk profile of thrombolytic therapy is recommended.86 In patients who are unable to receive thrombolytic therapy because of the risk of bleeding, or whose critical status does not allow sufficient time for systemic thrombolytic therapy to be effective, the recommended immediate treatment strategy is an intravenous bolus of unfractionated heparin with or without an embolectomy.86, 113 In addition, short-term treatment with conventional anticoagulant therapy (parenteral heparin plus a VKA followed by international normalized ratio [INR]-adjusted VKA alone) is effective, but long-term management with VKA therapy is challenging. Many of these challenges relate to the limitations of VKA therapy, which include.30
- Narrow therapeutic window
- Requirement for frequent coagulation monitoring and dose adjustments
- 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 objective of EINSTEIN PE is to determine whether a single-drug approach with oral rivaroxaban is at least as effective as (non-inferior to) dual-drug therapy with enoxaparin/VKA in the treatment of patients with confirmed acute symptomatic PE with or without symptomatic DVT.
Study design
EINSTEIN PE was an open-label, event-driven, non-inferiority, randomized study of 4845 enrolled patients with a predefined treatment duration of 3, 6 or 12 months. The patients were randomly assigned to receive one of the following regimens:
- 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 the combination of major and 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 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
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%,86 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:30
- 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.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.
- 86 - Kearon C, Kahn SR, Agnelli G et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:454S–545S.
- 30 - Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):160S-198S.
- 46 - Cohen AT, Agnelli G, Anderson FA, et al; VTE Impact Assessment Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost. 2007;98(4):756-764.
- 49 - Kearon C. Natural history of venous thromboembolism. Circulation. 2003;107(23 suppl 1):I22-I30.
- 113 - Torbicki A, Perrier A, Konstantinides S et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008;29:2276–2315.
- Thrombosis
- Formation of a clot inside a blood vessel.
- Venous thromboembolism
- A disease process beginning with a blood clot occurring within the venous system, including deep vein thrombosis and pulmonary embolism.
- 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.
- 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.
- 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).
- Efficacy
- The ability of a drug to produce the desired effect.
