EINSTEIN EXT: efficacy and safety of rivaroxaban for prevention of recurrent venous thromboembolism
EINSTEIN EXT met its primary efficacy endpoint and showed that extended-duration rivaroxaban (20 mg once daily for 6–12 months) was superior – compared with placebo – for prevention of recurrent venous thromboembolism (VTE) in patients who had previously completed 6–12 months of treatment for VTE with either rivaroxaban or a vitamin K antagonist 96
Rivaroxaban showed a favourable benefit–risk profile, as demonstrated by a significant improvement in the net clinical benefit, which was defined as the composite of the primary efficacy outcome and major bleeding.
In conclusion, EINSTEIN EXT demonstrated that rivaroxaban offers effective long-term prevention of recurrent VTE with reassuring safety.
Patient demographics
At study entry, patients in the rivaroxaban and placebo groups had similar demographic and clinical characteristics:
- Mean age: ~58 years
- ~58% were male
- ~82% had a body weight of >50 to 100 kg
- ~62% had creatinine clearance ≥80 ml/min, with a further 22% classified as having mild renal impairment (creatinine clearance 50–79 ml/min)
- ~16% had experienced a previous venous thromboembolic event before the deep vein thrombosis (DVT) or pulmonary embolism (PE) that qualified them for inclusion in the study
Primary efficacy endpoint: 82% relative risk reduction with rivaroxaban
The EINSTEIN EXT study included patients about whom there is clinical uncertainty whether to continue or stop anticoagulant therapy after initial prophylaxis for 6–12 months with a VKA or rivaroxaban. This study showed that anticoagulation with rivaroxaban for a further 6 or 12 months was superior to placebo for the long-term prevention of recurrent symptomatic VTE. It also showed that there is still a sustained risk of recurrence in patients with symptomatic DVT or PE after the initial anticoagulant therapy for 6–12 months.
- To prevent one venous thromboembolic event, only 15 patients need to be treated with rivaroxaban97
Safety outcome: incidence of major bleeding was low in the rivaroxaban arm
The primary safety outcome was major bleeding, which was low and occurred in 4/598 (0.7%) patients in the rivaroxaban group and in none of the patients in the placebo group resulting in a non-significant difference (p=0.11). All cases of major bleeding in the rivaroxaban arm did not occur in a critical site, but were associated with a fall in haemoglobin of ≥2 g/dl, transfusion of ≥2 units, or both. The most common non-major clinically relevant bleeding events in the rivaroxaban arm were haematuria (9/32), epistaxis (8/32) and rectal bleeding (7/32); one event of gastrointestinal bleeding occurred (1/32).
Rivaroxaban provides superior net clinical benefit
Compared with placebo, rivaroxaban provided a significantly improved net clinical benefit; a prespecified secondary endpoint defined as the composite of the primary efficacy endpoint and major bleeding. This outcome occurred in 12/602 (2.0%) patients receiving rivaroxaban and in 42/594 (7.1%) patients receiving placebo (hazard ratio 0.28; 95% CI 0.15–0.53; p<0.001).
- 96 - The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–2510.
- 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.
- 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.
- Thrombosis
- Formation of a clot inside a blood vessel.
- 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.
