Pooled EINSTEIN DVT and EINSTEIN PE analysis: efficacy and safety of rivaroxaban in the treatment of deep vein thrombosis and pulmonary embolism in over 8000 patients
The results of the pooled EINSTEIN DVT and EINSTEIN PE analysis confirmed the results of the individual studies in over 8000 patients: single-drug oral rivaroxaban was at least as effective as (non-inferior to) conventional standard-of-care dual-drug therapy (subcutaneous enoxaparin plus oral vitamin K antagonist [VKA] followed by VKA alone) for the treatment and secondary prevention of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) with no increase in clinically relevant bleeding, regardless of age, sex, body weight, renal function or fragility (defined as being older than 75 years or renally compromised [creatinine clearance (CrCl) <50 ml/min] or underweight [body weight ≤50 kg]).124, 125 Overall, rivaroxaban significantly reduced the risk of major bleeding, with fewer fatal bleeding and intracranial bleeding events than standard of care. Rivaroxaban was also associated with significantly lower rates of major bleeding in high-risk patients, such as elderly (>75 years), renally impaired and fragile patients.124, 125
Rivaroxaban had superior net clinical benefit compared with standard of care (hazard ratio [HR]=0.77; 95% confidence interval [CI] 0.61–0.97; p=0.02), achieved via non-inferiority for efficacy, similar rates for the principal safety outcome, and significantly fewer events of major bleeding, including those in older patients (≥75 years) and patients with renal impairment.
In conclusion, the pooled analysis 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 and acute PE and prevention of recurrent DVT and PE, even in high-risk subgroups.
Patient demographics
Patients were well matched in both treatment groups, with similar demographic and clinical characteristics:
- Mean age: ~57 years
- ~55% were male
- ~ 2% had a body weight of ≤50 kg and ~83% had a body weight of >50–100 kg
- ~67% had CrCl ≥80 ml/min, with a further 24% classified as having mild renal impairment (CrCl 50–79 ml/min) and ~ 8% had CrCl <50 ml/min
- ~19% had experienced a previous venous thromboembolic event before the acute, symptomatic DVT or 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 standard of care for the treatment of acute DVT and acute PE
The primary efficacy outcome occurred in 86/4150 (2.1%) patients treated with rivaroxaban, compared with 95/4131 (2.3%) patients treated with standard of care (p<0.0001 for non-inferiority).
Clinical outcomes in each study group
| Efficacy outcome | Rivaroxaban (N=4150) n(%) |
Enoxaparin/VKA (N=4131) n(%) |
Hazard ratio (95% CI) |
p-value (for non- inferiority) |
|---|---|---|---|---|
|
* Composite of DVT or non-fatal or fatal PE. ** CI, confidence interval; DVT, deep vein thrombosis; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism. |
||||
| First symptomatic recurrent VTE* | 86 (2.1) | 95 (2.3) | 0.89 (0.66 - 1.19) | <0.0001 |
| Fatal PE | 2 (<0.1) | 1 (<0.1) | ||
| Death (PE could not be ruled out) | 10 (0.2) | 11 (0.3) | ||
| Symptomatic DVT and PE | 1 (<0.1) | 2 (<0.1) | ||
| Symptomatic recurrent DVT only | 32 (0.8) | 45 (1.1) | ||
| Symptomatic recurrent PE only | 41 (1.0) | 36 (0.9) | ||
Principal safety outcome: similar rates of bleeding with rivaroxaban and standard of care
Rivaroxaban was well-tolerated by patients in EINSTEIN DVT and EINSTEIN PE, and the rate of major or non-major clinically relevant bleeding was similar to that for standard of care.
Significant reductions in major bleeding events with rivaroxaban
Rivaroxaban demonstrated significant reductions in major bleeding events compared with standard of care (HR=0.54; 95% CI 0.37–0.79; p=0.002)
VKA, vitamin K antagonist.
| Outcome |
Rivaroxaban (N=4130) |
Enoxaparin/VKA (N=4116) |
HR (95% CI) p-value |
||
| n | % | n | % | ||
| * Some patients had >1 event. | |||||
| Major bleeding* | 40 | 1.0 | 72 | 1.7 | 0.54 (0.37 - 0.79) p=0.002 |
| Fatal | 3 | <0.1 | 8 | 0.2 | |
| Retroperitoneal | 0 | 0 | 1 | <0.1 | |
| Intracranial | 2 | <0.1 | 4 | <0.1 | |
| Gastrointestinal/thorax | 1 | <0.1 | 3 | <0.1 | |
| In a critical site | 10 | 0.2 | 29 | 0.7 | |
| Retroperitoneal | 1 | <0.1 | 8 | 0.2 | |
| Intracranial | 3 | <0.1 | 10 | 0.2 | |
| Intraocular | 3 | <0.1 | 3 | <0.1 | |
| Pericardial | 0 | 0 | 2 | <0.1 | |
| Intra-articular | 0 | 0 | 4 | <0.1 | |
| Adrenal/pulmonary/abdominal | 3 | <0.1 | 2 | <0.1 | |
|
Fall in haemoglobin ≥2 g/dl and/or transfusions ≥2 units |
27 | 0.7 | 37 | 0.9 | |
Rivaroxaban was associated with lower rates of fatal bleeding and intracranial bleeding compared with standard of care.
Key secondary and other outcomes: rivaroxaban provides superior net clinical benefit
As in the individual EINSTEIN DVT and EINSTEIN PE studies, net clinical benefit was defined as the composite of the primary efficacy outcome plus major bleeding. Rivaroxaban had a superior net clinical benefit compared with standard of care (incidence of symptomatic recurrent VTE plus major bleeding: 3.2% vs 4.1%, respectively; HR=0.77; 95% CI 0.61–0.97; p=0.02). Cerebrovascular events (0.2% vs 0.3%, respectively) and liver abnormalities (0.2% vs 0.2%, respectively) occurred at a low and similar rate between treatment groups.
Subgroup analyses of the primary efficacy outcome
Rivaroxaban was non-inferior to standard therapy for the primary efficacy outcome in all subgroups analysed, including age, weight, sex and renal function. In fragile patients (defined as being older than 75 years or renally compromised [creatinine clearance (CrCl) <50 ml/min] or underweight [body weight ≤50 kg]) there was a trend to lower rates of recurrent VTE in those treated with rivaroxaban compared with standard of care (2.7% vs 3.8%, HR 0.68 95% CI 0.39–1.18).
Subgroup analyses of major bleeding events
Rivaroxaban was associated with a significantly lower incidence of major bleeding events compared with standard of care in elderly, renally impaired and fragile patients:
- Aged >75 years: 74% risk reduction ( 1.2% vs 4.5%; HR=0.26; 95% CI 0.12–0.56)
- With mild renal impairment (CrCl 50–<80 ml/min): 54% risk reduction (1.4% vs 3.0%; HR=0.44; 95% CI 0.24–0.84)
- With moderate/severe renal impairment (CrCl <50 ml/min): 79% risk reduction (0.9% vs 4.1%; HR=0.21; 95% CI 0.06–0.73)
- Fragile patients: 73% risk reduction (1.3% vs 4.5%; HR=0.27; 95% CI 0.13–0.54)
| Rivaroxaban n/N (%) |
Enoxaparin/VKA n/N (%) |
HR (95% CI) |
|
|---|---|---|---|
| Age, years | |||
| <65 |
19/2592 (0.7) |
24/2579 (0.9) |
0.76 (0.41-1.38) |
| 65-75 |
13/883 (1.5) |
20/913 (2.2) |
0.68 (0.34-1.37) |
| >75 |
8/655 (1.2) |
28/624 (4.5) |
0.26 (0.12-0.56) |
| Weight, kg | |||
| ≤70 |
17/1141 (1.5) |
25/1140 (2.2) |
0.65 (0.35-1.20) |
| >70-90 |
15/1811 (0.8) |
32/1824 (1.8) |
0.47 (0.26-0.87) |
| >90 |
8/1171 (0.7) |
15/1151 (1.3) |
0.49 (0.21-1.16) |
| Creatinine clearance, ml/min | |||
| ≥80 |
23/2739 (0.8) |
29/2776 (1.0) |
0.79 (0.46-1.37) |
| ≥80 |
23/2739 (0.8) |
29/2776 (1.0) |
0.79 (0.46-1.37) |
| 50≤80 |
14/1024 (1.4) |
30/993 (3.0) |
0.44 (0.24-0.84) |
| <50 |
3/329 (0.9) |
13/320 (4.1) |
0.21 (0.06-0.73) |
| Sex | |||
| Male |
18/2294 (0.8) |
35/2206 (1.6) |
0.49 (0.7-0.86) |
| Male |
18/2294 (0.8) |
35/2206 (1.6) |
0.49 (0.7-0.86) |
| Female |
22/1836 (1.2) |
37/1910 (1.9) |
0.6 (0.84-1.02) |
| Fragile patients | |||
| Fragile |
10/788 (1.3) |
35/779 (4.5) |
0.27 (0.13-0.54) |
|
Non- fragile |
30/3342 (0.9) |
37/3337 (1.1) |
0.80 (0.49-1.29) |
- 124 - Büller HR, for the EINSTEIN Investigators. Oral rivaroxaban for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies. Blood (ASH Annual Meeting Abstracts) 2012: In press. Abstract 20.
- 125 - Büller HR, for the EINSTEIN Investigators. Oral rivaroxaban for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies. American Society of Hematology 54th Annual Meeting and Exposition. Atlanta, GA, USA, 8–11 December 2012; Oral presentation 20.
- 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.
- 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.
