EINSTEIN PE: single-drug therapy with oral rivaroxaban versus dual-drug therapy with subcutaneous enoxaparin and oral VKA

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 The current standard of care is initial parenteral therapy (with unfractionated heparin, low molecular weight heparin or fondaparinux) plus a VKA, followed by long-term management with INR-adjusted VKA alone.122, 113 Short-term treatment with conventional anticoagulant therapy is effective, but long-term management with VKA therapy is challenging. Many of these challenges relate to the 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, 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 was 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 and to compare the safety of these two approaches in the treatment of patients with confirmed acute symptomatic PE with or without symptomatic DVT.

Study design

EINSTEIN PE was an randomized, open-label, event-driven, non-inferiority study of 4833 patients with a predefined treatment duration of 3, 6 or 12 months. The patients were randomly assigned to receive one of the following regimens:121
  • 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 PE121
  • 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:121
    • 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


  • 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.
  • 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.
  • 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.
  • 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.
  • 121 - The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–1297.
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.
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.
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.

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PE kills more people in the Western hemisphere than breast cancer, prostate cancer, AIDS, and traffic accidents combined.47

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