EINSTEIN DVT: efficacy and safety of rivaroxaban in the treatment of deep vein thrombosis
EINSTEIN DVT met its primary efficacy endpoint and showed that a single-drug approach with oral rivaroxaban was at least as effective as (non-inferior to) conventional dual-drug therapy (subcutaneous enoxaparin plus vitamin K antagonist [VKA] followed by VKA alone), with a similar safety profile, for the treatment of acute, symptomatic deep vein thrombosis (DVT).96
There was a significant improvement in the net clinical benefit for rivaroxaban compared with enoxaparin/VKA, achieved via a reduction in recurrent venous thromboembolism and similar rates of bleeding.
In conclusion, EINSTEIN DVT demonstrated that a fixed-dose regimen of oral rivaroxaban offers an effective and convenient single-drug alternative to the current standard of care of dual-drug therapy for the treatment of acute DVT.
Patient demographics
Patients were well matched in both study arms, with similar demographic and clinical characteristics:
- Mean age: ~56 years
- ~57% were men
- ~83% had a body weight of >50 to 100 kg
- ~69% had creatinine clearance ≥80 ml/min, with a further 23% classified as having moderate renal impairment (creatinine clearance 50–79 ml/min)
- ~19% had experienced a previous venous thromboembolic event before the acute, symptomatic DVT that qualified them for inclusion in the study
Primary efficacy endpoint: single-drug therapy with rivaroxaban was non-inferior to dual-drug therapy with enoxaparin plus VKA for the treatment of acute DVT96
The primary efficacy outcome occurred in 36/1731 (2.1%) patients treated with rivaroxaban, compared with 51/1718 (3.0%) patients treated with enoxaparin/VKA (p<0.001 for non-inferiority); there was a trend towards superiority for rivaroxaban.
Clinical outcomes in each study group
CI, confidence interval; DVT, deep vein thrombosis; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism.
Safety outcome: similar rates of bleeding with rivaroxaban and enoxaparin/VKA96
Rivaroxaban was well tolerated by patients in EINSTEIN DVT, and the rate of major or non-major clinically relevant bleeding was similar to enoxaparin plus VKA followed by VKA alone).
Rivaroxaban provides superior net clinical benefit96
A key secondary endpoint in the study was net clinical benefit; defined as the composite of the primary efficacy endpoint and major bleeding.
- Rivaroxaban provided a significantly improved net clinical benefit compared with enoxaparin/VKA, the current standard of care.
- The net clinical benefit outcome occurred in 51/1731 (2.9%) patients who received rivaroxaban compared with 73/1718 (4.2%) patients who received enoxaparin/VKA (hazard ratio 0.67; 95% confidence interval 0.47–0.95; p=0.03)
Adverse events rates were similar in the two treatment groups during the treatment period96
EINSTEIN EXT: efficacy and safety of rivaroxaban for prevention of recurrent venous thromboembolism96
EINSTEIN EXT met its primary efficacy endpoint and showed that extended-duration rivaroxaban (20 mg once daily for 6–12 months) was superior – when 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 (VKA).97
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.
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 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 with a VKA or rivaroxaban. Extended anticoagulation with rivaroxaban was superior to placebo for the long-term prevention of recurrent symptomatic VTE.
- To prevent one venous thromboembolic event, only 15 patients need to be treated with rivaroxaban97
Clinical outcomes in each study group
CI, confidence interval; DVT, deep vein thrombosis; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism.
Safety outcome: incidence of major bleeding was low in the rivaroxaban arm96
The primary safety outcome was major bleeding, which occurred in 4/598 (0.7%) patients in the rivaroxaban group and in none of the patients in the placebo group (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 benefit96
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.
- 1 - Xarelto® (rivaroxaban) Summary of Product Characteristics as approved by the European Commission.
- 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.
- 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.
- 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.
- Venous thromboembolism
- A disease process beginning with a blood clot occurring within the venous system, including deep vein thrombosis and pulmonary embolism.
- 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.
