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20 Oral Rivaroxaban for the Treatment of Symptomatic Venous Thromboembolism: A Pooled Analysis of the EINSTEIN DVT and EINSTEIN PE Studies

Program: Oral and Poster Abstracts
Type: Oral
Session: 332. Antithrombotic Therapy I
Saturday, December 8, 2012: 12:15 PM
B405-B407, Level 4, Building B (Georgia World Congress Center)

Harry Roger Buller, MD, PhD

Dept of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands

Harry R. Büller, MD, PhD on behalf of the EINSTEIN Investigators

Background

The EINSTEIN DVT and EINSTEIN PE studies showed that a fixed-dose regimen of rivaroxaban was non-inferior to standard therapy of subcutaneous enoxaparin followed by vitamin K antagonist (VKA) for the treatment of symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), with similar occurrence of clinically relevant bleeding (The EINSTEIN Investigators. N Engl J Med 2010;363:2499–510; The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–97). This prespecified pooled analysis compared rivaroxaban with the standard therapy for the primary efficacy and safety outcomes, including subgroup analyses for body weight, age, and renal function.

Methods

This data pool included all patients and events from EINSTEIN DVT (patients with acute symptomatic DVT without PE) and EINSTEIN PE (patients with acute symptomatic PE with or without DVT). Both studies shared an open-label, randomized, non-inferiority design and compared oral, fixed-dose rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous body weight-adjusted enoxaparin followed by warfarin or acenocoumarol (international normalized ratio 2–3) for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism (the composite of recurrent DVT or nonfatal or fatal PE); safety outcomes included the composite of major and clinically relevant non-major bleeding, and major bleeding alone. Adjudication was done by a single committee. Subgroup analyses for efficacy and safety were performed.

Results

The intention-to-treat population included 4150 rivaroxaban patients and 4131 enoxaparin/VKA patients. Rivaroxaban demonstrated non-inferior efficacy to enoxaparin/VKA for the primary efficacy outcome (rivaroxaban: 86 events [2.1%], enoxaparin/VKA: 95 events [2.3%]; hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.66–1.19; p<0.0001 for non-inferiority). Major and clinically relevant non-major bleeding occurred in 388 patients (9.4%) in the rivaroxaban group and 412 patients (10.0%) in the enoxaparin/VKA group (HR=0.93; 95% CI 0.81–1.06; p=0.272), and major bleeding occurred in 40 (1.0%, 3 fatal) and 72 (1.7%, 8 fatal) of the rivaroxaban and enoxaparin/VKA recipients, respectively (HR=0.54; 95% CI 0.37–0.79; p=0.002). Efficacy was consistent for rivaroxaban compared with enoxaparin/VKA among the various subgroups, whereas increasing age and declining renal function were associated with a strong reduction in major bleeding in favor of rivaroxaban (Table). Major bleeding was consistently lower in the rivaroxaban recipients for all body weight categories.

Conclusion

This analysis demonstrates that the simple, single-drug approach with oral rivaroxaban has an improved benefit–risk profile compared with standard therapy for the treatment of symptomatic venous thromboembolism. The reduction in major bleeding in favor of rivaroxaban was most pronounced in elderly patients and those with moderate renal impairment (creatinine clearance <50 mL/min), and was consistent among various body weight categories, thereby obviating the need for a rivaroxaban dose adjustment in these subgroups.

Table. Subgroup analyses of the primary efficacy outcome and major bleeding

 

Primary efficacy outcome

Major bleeding

 

Rivaroxaban
n/N (%)

Enoxaparin/VKA
n/N (%)

HR
(95% CI)

Rivaroxaban
n/N (%)

Enoxaparin/VKA
n/N (%)

HR
(95% CI)

Age, years

 

 

 

 

 

<65

55/2606
(2.1)

53/2590
(2.0)

1.01
(0.69–1.47)

19/2592
(0.7)

24/2579
(0.9)

0.76
(0.41–1.38)

65–75

16/888
(1.8)

19/914
(2.1)

0.87
(0.45–1.69)

13/883
(1.5)

20/913
(2.2)

0.68
(0.34–1.37)

>75

15/656
(2.3)

23/627
(3.7)

0.61
(0.32–1.17)

8/655
(1.2)

28/624
(4.5)

0.26
(0.12–0.56)

Weight, kg

 

 

 

 

 

≤70

29/1147
(2.5)

31/1145
(2.7)

0.92
(0.55–1.52)

17/1141
(1.5)

25/1140
(2.2)

0.65
(0.35–1.20)

>70–90

33/1821
(1.8)

43/1826
(2.4)

0.75
(0.47–1.18)

15/1811
(0.8)

32/1824
(1.8)

0.47
(0.26–0.87)

>90

24/1174
(2.0)

21/1158
(1.8)

1.14
(0.63–2.05)

8/1171
(0.7)

15/1151
(1.3)

0.49
(0.21–1.16)

Creatinine clearance, mL/min

≥80

49/2748
(1.8)

52/2787
(1.9)

0.94
(0.64–1.39)

23/2739
(0.8)

29/2776
(1.0)

0.79
(0.46–1.37)

50–<80

24/1030
(2.3)

30/992
(3.0)

0.76
(0.44–1.30)

14/1024
(1.4)

30/993
(3.0)

0.44
(0.24–0.84)

<50

11/332
(3.3)

11/322
(3.4)

0.95
(0.41–2.20)

3/329
(0.9)

13/320
(4.1)

0.21
(0.06–0.73)

 

Disclosures: Buller: Bayer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sanofi-aventis: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Isis: Consultancy, Research Funding; Thrombogenics: Consultancy, Research Funding.

*signifies non-member of ASH