EINSTEIN PE: efficacy and safety of rivaroxaban in the treatment of pulmonary embolism
EINSTEIN PE demonstrated that oral rivaroxaban was at least as effective as (non-inferior to) standard dual-drug therapy with subcutaneous enoxaparin plus vitamin K antagonist (VKA) followed by VKA alone for the treatment of acute, symptomatic pulmonary embolism (PE) with or without symptomatic deep vein thrombosis (DVT). It also demonstrated that rivaroxaban had a similar rate of clinically relevant bleeding to standard therapy but significantly reduced the incidence of major bleeding.121
In conclusion, EINSTEIN PE demonstrates that oral rivaroxaban is a simple and effective, single-drug solution for the treatment of acute PE with or without symptomatic DVT, with an improved benefit–risk profile compared with the standard of care.
Patient demographics
Patients were well matched in both study arms, with similar demographic and clinical characteristics:
- Mean age: ~58 years
- ~53% were male
- ~83% had a body weight of >50 to 100 kg
- ~66% had creatinine clearance ≥80 ml/min, with a further 25% classified as having mild renal impairment (creatinine clearance 50–79 ml/min)
- ~24% had extensive PE (involving multiple lobes and >25% of entire pulmonary vasculature)
- ~25% had concurrent symptomatic DVT
- ~19% had experienced a previous venous thromboembolic event before the acute, symptomatic and objectively confirmed PE 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 PE
The primary efficacy outcome (composite of non-fatal or fatal PE or DVT) occurred in 50/2419 (2.1%) patients treated with rivaroxaban, compared with 44/2413 (1.8%) patients treated with standard therapy (p=0.003 for non-inferiority).
Clinical outcomes in each study group
| Clinical outcomes in each study group | ||||
|---|---|---|---|---|
| Efficacy outcome | Rivaroxaban (n=2419) n (%) |
Enoxaparin/VKA (n=2413) n (%) |
Hazard ratio (95% CI) |
p-value (for non-inferiority) |
| Recurrent VTE* | 50 (2.1) | 44 (1.8) | 1.12 (0.75-1.68) | 0.003 |
| Fatal PE | 2 | 1 | ||
| Death in which PE could not be ruled out |
8 | 5 | ||
| Non-fatal PE | 22 | 19 | ||
| Recurrent DVT plus PE | 0 | 2 | ||
| Recurrent DVT | 18 | 17 | ||
Rivaroxaban had similar rates of clinically relevant bleeding compared with standard therapy but reduced major bleeding by 51%
In EINSTEIN PE, the rate of major or non-major clinically relevant bleeding in patients receiving rivaroxaban was similar to that for standard therapy. Importantly, major bleeding was significantly reduced in patients receiving rivaroxaban compared with those receiving standard therapy (p=0.003) and the rates of critical site bleeding were markedly lower for rivaroxaban.
| Safety outcome | Rivaroxaban (N=2412) n (%) |
Enoxaparin/VKA (N=2405) n (%) |
Hazard ratio (95% CI) |
p-value |
|---|---|---|---|---|
| First major or non-major clinically relevant bleeding event occurring during treatment | 249 (10.3) | 274 (11.4) | 0.90 (0.76-1.07) |
0.23 |
| Major bleeding | 26 (1.1) | 52 (2.2) | 0.49 (0.31-0.79) |
0.003 |
| Contributing to death | 2 (<0.1) | 3 (0.1) | ||
| In a critical site | 7 (0.3) | 26 (1.1) | ||
| Associated with a decrease in haemoglobin of ≥2 g/dl, transfusion of ≥2 units, or both | 17 (0.7) | 26 (1.1) | ||
| Non-major clinically relevant bleeding | 228 (9.5) | 235 (9.8) | ||
| Total deaths up to the end of intended treatment period | 58 (2.4) | 50 (2.1) | 1.13 (0.77-1.65) |
0.53 |
| Cause of death | ||||
| PE, or PE not ruled out | 11 | 7 | ||
| Bleeding | 5 | 4 | ||
| Cancer | 20 | 23 | ||
| Myocardial infarction | 2 | 1 | ||
| Ischaemic stroke | 2 | 1 | ||
| Other cardiac or respiratory failure | 4 | 4 | ||
| Infectious disease or septicemia | 10 | 6 | ||
| Other | 4 | 4 | ||
Rivaroxaban provides comparable net clinical benefit to standard therapy
Net clinical benefit, defined as the composite of the primary efficacy endpoint and major bleeding, was a key secondary endpoint in EINSTEIN PE.
In EINSTEIN PE, rivaroxaban had a similar net clinical benefit compared with enoxaparin plus VKA followed by VKA alone, with numerically fewer events.
- The net clinical benefit outcome occurred in 83/2419 (3.4%) patients who received rivaroxaban compared with 96/2413 (4.0%) patients who received standard therapy (hazard ratio 0.85; 95% confidence interval 0.63–1.14; p=0.28)
Adverse event rates were similar in the two treatment groups during the treatment period
| Adverse event | Rivaroxaban (n=2412) n (%) |
Enoxaparin/VKA (n=2405) n (%) |
||
|---|---|---|---|---|
| Any on-treatment adverse event | 1941 (80.5) | 1903 (79.1) | ||
| Any serious on-treatment adverse event | 476 (19.7) | 470 (19.5) | ||
| Any event leading to or prolonging hospitalization | 475 (19.7) | 430 (17.9) | ||
| Any event resulting in permanent discontinuation of study drug | 123 (5.1) | 99 (4.1) | ||
- 121 - The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–1297.
- Subcutaneous
- Introduced beneath the skin.
- Thrombosis
- Formation of a clot inside a blood vessel.
- 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.
- 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.
- 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.
