Oral treatment of acute pulmonary embolism with a fixed dose of rivaroxaban is non-inferior to standard treatment
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
- Correspondence to: Professor Alexander Niessner
Waehringer Guertel 18–20, Vienna 1090, Austria;
Pulmonary embolism (PE) is a common disease with potentially life-threatening consequences. Current guidelines1 recommend immediate start of anticoagulation with heparin for at least 5 days. Thereafter, heparin may be replaced by vitamin K antagonists (VKAs). The EINSTEIN-PE study tested rivaroxaban for the treatment of acute PE. Rivaroxaban, an oral anti-Xa antagonist, has the major advantage of oral administration with a fixed dose. This drug has been tested so far for thromboprophylaxis after orthopaedic surgery and for patients with atrial fibrillation. The applied therapeutic regimen of rivaroxaban was also already tested for acute deep-vein thrombosis (DVT) in the EINSTEIN-DVT trial.2
A total of 4832 adult patients with acute symptomatic PE were included in a randomised open-label trial. The study was an event-driven, non-inferiority one. The primary efficacy analysis was based on an intention-to-treat analysis using a Cox proportional-hazards model, stratified by the intended duration of treatment (3, 6, 12 months) and adjusted for cancer.
Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily was compared with enoxaparin followed by a VKA with a target international normalised ratio of 2 to 3. Administration of antiplatelet agents except for aspirin up to 100 mg per day and/or clopidogrel 75 mg per day was discouraged. Patients who received a fibrinolytic agent were excluded. Another important exclusion criterion was renal dysfunction with a creatinine clearance below 30 ml per minute. With regard to bleeding risk, patients with active bleeding, with a known high risk of bleeding or a blood pressure of more than 180/110 mm Hg, were excluded.
The primary efficacy outcome was symptomatic recurrent venous thromboembolism including DVT and PE. The principal safety outcome was clinically relevant and major bleeding, which encompassed a decrease in haemoglobin of at least 2.0 g per decilitre, transfusion of at least 2 units of red cells, intracranial or retroperitoneal bleeding, bleeding at another critical site, bleeding contributing to death and overt bleeding leading to medical intervention, unscheduled contact with a physician, discontinuation of a study drug, or discomfort or impairment of activities in daily life.
Patients with standard care received enoxaparin for a median of 8 days. The percentage of time with VKAs in the therapeutic range was 63%. The mean study duration was 9 months. The primary efficacy endpoint was observed in 2.1% of patients with rivaroxaban and in 1.8% in the standard therapy group corresponding to an HR of 1.12 (p for non-inferiority=0.003 and p for superiority=0.57). The primary safety outcome occurred in 10.3% in the rivaroxaban group and in 11.4% in the standard care group equivalent to an HR of 0.9 (p=0.23). Major bleeding was significantly different with 1.1% in patients with rivaroxaban and 2.2% in patients in the standard care group, corresponding to an HR of 0.49 (p=0.003). The primary endpoints were consistent with respect to important clinical characteristics such as age, body weight and gender. There was no evidence for increased liver toxicity.
The EINSTEIN-PE trial achieved its primary goal of showing non-inferiority with regard to efficacy between oral administration of rivaroxaban and standard care treatment in patients with acute PE. These results are consistent with the EINSTEIN-DVT trial.2 The EINSTEIN-PE study was not powered to detect a moderate difference in efficacy (such as a relative 10% risk change) due to the low number of events. With regard to safety the study showed that rivaroxaban may reduce the number of major bleeding events by up to 50%.
One major limitation of the study is the open-label design potentially introducing an observer bias, in particular, with regard to the rather soft definition of the primary bleeding endpoint. The results cannot be applied to patients with severe renal dysfunction and high-risk patients who receive fibrinolytic therapy. General limitations of new oral anticoagulants are the lack of clinically validated antagonists in emergency situations and missing data about the combination with new antithrombotic drugs.
In summary, this is the first study for the treatment of PE with a new oral anticoagulant administered with a fixed dose showing a non-inferior efficacy to standard treatment and a potential advantage with regard to safety. Future analyses should weigh the drug costs of rivaroxaban against reduced costs due to potentially shorter hospital stays and less bleeding.
Competing interests AN has received lecture fees from Boehringer Ingelheim, served on an advisory board for Boehringer Ingelheim and received travel fees from Boehringer Ingelheim, Daiichi Sankyo and Pfizer.