EINSTEIN’s CHOICE for Treatment of Venous Thromboembolism

Dakota T. Craft, Mercer University College of Pharmacy

Venous thromboembolism (VTE) is a blood clot that starts in a vein and includes deep vein thrombosis (DVT) and pulmonary embolism (PE).  The development of VTE may be provoked or idiopathic in origin.  This condition can occur at any age, but is most common in adults over 60. [1]  A history of VTE is the main risk factor for recurrent VTE, with a risk of recurrence as high as 53% in 10 years. [2]

Goals of therapy include decreasing mortality and preventing thrombus embolization and recurrence.  Per the American College of Chest Physicians 2016 guidelines for the treatment of VTE, first line treatment options for VTE include dabigatran, rivaroxaban, apixaban or edoxaban, while vitamin K antagonists are second line.  Duration of therapy often depends on the patient’s calculated risk of recurrence, with some indications for indefinite anticoagulation treatment. [3]  Physicians may choose to treat with aspirin rather than anticoagulants after 6- 12 months due to concerns of bleeding. [4]

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism (EINSTEIN’s CHOICE) [5]
Design Randomized, double-blind, phase 3 study; N= 3,365
Objective To assess the safety and efficacy of rivaroxaban and aspirin for the extended treatment of VTE
Study Groups Rivaroxaban 10 mg (n= 1,127); rivaroxaban 20 mg (n= 1,107); aspirin 100 mg (n= 1,131)
Methods This study included patients with a history of confirmed DVT or PE who had previously completed 6 to 12 months of anticoagulation therapy.  Study drugs were then administered for up to 12 months.  Patients were enrolled at least 24 hours after the last dose of a direct oral anticoagulant or when INR was less than 2.5 in those receiving a vitamin K antagonist.  Patient assessments occurred in clinic or by telephone at days 30, 90, 180, 270, and 360. The final patient assessment was completed 30 days after stopping the study medication.  Efficacy and safety analyses were determined by intention-to-treat population.  It was determined that 80 primary efficacy events would provide 90% power to show superiority of rivaroxaban over aspirin.
The composite primary efficacy outcome included unexplained death for which pulmonary embolism could not be ruled out.  
Duration March 2014 to March 2016
Primary Outcome Measure Incidence and comparison of recurrent VTE, PE, or unexplained death, and major bleeding between interventions
Baseline Characteristics Rivaroxaban

20 mg

Rivaroxaban

10 mg

Aspirin

100 mg

Male, n (%) 602 (54.4) 620 (55.0) 643 (56.9)
Mean age, yrs ± SD yrs 57.9 ± 14.7 58.8 ± 14.7 58.8 ±14.7
Weight, n (%)
< 70 kg 276 (24.9) 283 (25.1) 277 (24.5)
70-90 kg 471 (42.5) 480 (42.6) 508 (44.9)
> 90 kg 360 (32.5) 364 (32.3) 346 (30.6)
Creatinine clearance, n (%)
< 30 mL/min 1 (0.1) 2 (0.2) 1 (0.1)
30- 49 mL/min 40 (3.6) 49 (4.3) 63 (5.6)
50 to < 80 mL/min 279 (25.2) 302 (26.8) 277 (24.5)
≥ 80 mL/min 787 (71.1) 774 (68.7) 790 (69.8)
Results Rivaroxaban 20 mg Rivaroxaban 10 mg Aspirin 100 mg
Recurrent VTE, n (%) 17 (1.5) 13 (1.2) 50 (4.4)
PE or unexplained death, n (%) 2 (0.2) 0 2 (0.2)
Major bleeding, n (%) 6 (0.5) 5 (0.4) 3 (0.3)
Rivaroxaban 20 mg vs. Aspirin Rivaroxaban 10 mg vs. Aspirin Rivaroxaban 20 mg vs. 10 mg
HR (95% CI) p-

value

HR (95% CI) p-

value

HR (95% CI) p-

value

Recurrent VTE 0.34 (0.20- 0.59) < 0.001 0.26 (0.14-  0.47) < 0.001 1.34 (0.65- 2.75) 0.42
Major bleeding 2.01 (0.50- 8.04) 0.32 1.64 (0.39- 6.84) 0.50 1.23 (0.37- 4.03) 0.74
Adverse Events Any unspecified adverse events, n (%):

Rivaroxaban 20 mg= 194 (17.5)

Rivaroxaban 10 mg= 196 (17.4)

Aspirin 100 mg= 193 (17.1)

Serious Adverse Events, n (%):

Rivaroxaban 20 mg Rivaroxaban 10 mg Aspirin 100 mg
Nonmajor bleeding associated with study drug interruption for more than 14 days, n (%) 17 (1.9) 12 (1.3) 12 (1.3)
Major or clinically relevant nonmajor bleeding, n (%) 36 (4.1) 27 (3.0) 23 (2.6)
Clinically relevant nonmajor bleeding 30 (3.4) 22 (2.4) 20 (2.3)
Percentage that Discontinued due to Adverse Events:

Rivaroxaban 20 mg: 4.5%

Rivaroxaban 10 mg: 4.5%

Aspirin 100 mg: 4.2%

Study Author Conclusions Rivaroxaban was more effective than aspirin for the prevention of recurrent VTE and was associated with a similar risk of bleeding.

The EINSTEIN CHOICE study provides evidence for the use of extended treatment with rivaroxaban that provides physicians with a balance between VTE protection and bleeding risk.  The prophylactic rivaroxaban dose of 10 mg was associated with less bleeding, and this may ease further prescribing concerns.  Cost will likely continue to be a factor in reduced utilization of this medication. A younger patient population was enrolled compared to those expected to develop VTE; thus results may not be generalizable to the older patient population.

References

[1] American Heart Association: What is Venous Thromboembolism (VTE)? http://www.heart.org/HEARTORG/Conditions/More/What-is-Venous-Thromboembolism-VTE_UCM_479052_Article.jsp#.WNMVlBiZPBJ. Accessed March 21, 2017.

[2] Galioto NJ, Danley DL, Maanen RJV. Recurrent Venous Thromboembolism. Am Fam Physician. 2011 Feb 1;83(3):293-300.

[3] Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-52.

[4] Brighton TA, Eikelboom JW, Mann K, et al. Low-dose aspirin for preventing re- current venous thromboembolism. N Engl J Med 2012;367:1979-87.

[5] Weitz JI, Lensing AW, Prins MH, et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med. 2017.

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