Evidence in long-term prevention

Efficacy and safety of NOACs for the prevention of recurrent VTE have been assessed in randomised controlled trials. Use the tabs below to view the study designs and primary efficacy and safety outcomes for each NOAC.1–5 It should be noted that there are no head-to-head RCTs comparing the NOACs, and comparisons cannot be made between individual NOACs based on these data.

For the long-term prevention of recurrent DVT / PE, apixaban is the only NOAC to demonstrate comparable rates of both major and major / clinically relevant non-major bleeding vs. placebo2–4**††

AMPLIFY-EXT (apixaban)2 RR
(95% CI)
p-value
Primary efficacy outcome
Recurrent VTE / all-cause death*
0.33
(0.22-0.48)
<0.001
Recurrent VTE / VTE-related death
0.19
(0.11-0.33)
ns
Safety outcomes
Major / CRNM bleeding
1.20
(0.69-2.10)
ns
Major bleeding
0.49
(0.09-2.64)
ns
00.5123
Favours apixaban Favours placebo

Data shown are for the apixaban 2.5 mg BD dose only.

* Primary efficacy outcome.
† 13 patients in the 2.5 mg apixaban group and 19 patients in the placebo group who were lost to follow-up were classified as having had a primary outcome event.
‡ Primary safety outcome.

EINSTEIN-EXT (rivaroxaban)4 HR
(95% CI)
p-value
Primary efficacy outcome*
Recurrent symptomatic VTE*
0.18
(0.09-0.39)
<0.001
superiority
Safety outcomes
Major / CRNM bleeding
5.19
(2.3-11.7)
<0.001
00.5151015
Favours rivaroxaban Favours placebo

* Recurrent VTE includes fatal PE. Furthermore, PE was considered to be the cause of death if death could not be attributed to a documented cause and PE could not be confidently ruled out.
† Major bleeding was the principal safety outcome in ElNSTEIN-EXT, but HR was not estimable due to the number of events, with 0 and 4 events in the placebo and rivaroxaban groups, respectively (p=0.11).

RE-SONATE (dabigatran)3 HR
(95% CI)
p-value
Primary efficacy outcome
VTE / VTE-related death / unexplained death*
0.08
(0.02-0.25)
<0.001
superiority
Safety outcomes
Major / CRNM bleeding
2.92
(1.52-5.60)
=0.001
00.5123456
Favours dabigatran Favours placebo

* Primary efficacy outcome was recurrent symptomatic and objectively verified VTE or death associated with VTE (or unexplained death in the placebo group).
† Safety outcomes included major bleeding and CRNM bleeding. For major bleeding the HR was not estimable due to the number of events, with 0 and 2 events in the placebo and dabigatran groups, respectively (p=1.0).

EINSTEIN CHOICE (rivaroxaban)5 HR
(95% CI)
p-value
Primary efficacy outcome
rivaroxaban 10 mg* vs. aspirin Recurrent VTE
0.26
(0.14-0.47)
<0.001
rivaroxaban 20 mg* vs. aspirin Recurrent VTE
0.34
(0.20-0.59)
<0.001
Safety outcomes
rivaroxaban 10 mg* vs. aspirin Major / CRNM bleeding
1.16
(0.67-2.03)
=0.60
rivaroxaban 10 mg* vs. aspirin Major bleeding
1.64
(0.39-6.84)
=0.50
rivaroxaban 20 mg* vs. aspirin Major / CRNM bleeding
1.59
(0.94-2.69)
=0.08
rivaroxaban 20 mg* vs. aspirin Major bleeding
2.01
(0.50-8.04)
=0.32
00.51246810
Favours rivaroxaban Favours aspirin

* Recommended dose for initial treatment of acute DVT or PE is 15 mg BD for first 3 weeks followed by 20 mg OD for continued treatment and prevention of recurrent DVT and PE.
† p<0.001 for all comparisons between 10 mg and 20 mg doses of rivaroxaban and aspirin.
‡ Primary safety outcome.

RE-MEDY (dabigatran)3 HR
(95% CI)
p-value
Primary efficacy outcome
VTE / VTE-related death
1.44
(0.78-2.64)
<0.01
non-inferiority
Safety outcomes
Major / CRNM bleeding
0.54
(0.41-0.71)
<0.001
Major bleeding
0.52
(0.27-1.02)
=0.06
00.5123
Median TTR (INR 2.0-3.0) in patients randomised to warfarin = 65.3% Favours dabigatran Favours warfarin
Study drug(dosing) Trial, N Treatment before randomisation Comparator Treatment length(months)
apixaban(2.5 mg or 5 mg BD)* AMPLIFY-EXT
2482(double-blind)
6–12 months of standard therapy or apixaban Placebo 12
dabigatran(150 mg BD) RE-SONATE
1343(double-blind)
6–18 months of approved anticoagulant or dabigatran Placebo 12
dabigatran(150 mg BD) RE-MEDY
2856(double-blind)
3–12 months of approved anticoagulant or dabigatran Warfarin
INR 2.0–3.0
6–36
rivaroxaban(20 mg OD) EINSTEIN-EXT
1196(open-label)
6–12 months of VKA or rivaroxaban Placebo 6 or 12
rivaroxaban(20 mg or 10 mg OD) EINSTEIN CHOICE
3365(double-blind)
6–12 months of anticoagulant therapy(VKA, rivaroxaban, apixaban, dabigatran or edoxaban)† Aspirin
100 mg OD
6–12

* Only the 2.5 mg BD dose of apixaban is licensed for prevention of recurrent DVT / PE.1
† Edoxaban is approved for the treatment and prevention of VTE.6

Click to learn more about the AMPLIFY-EXT clinical trial and the use of apixaban for the prevention of recurrent DVT / PE.

Apixaban is only licensed for prevention of recurrent DVT / PE at a dose of 2.5 mg twice daily.

** In patients for whom there was uncertainty about the benefit / risk of extending anticoagulant therapy.2 Apixaban was compared against placebo in patients who, prior to the study, had been treated for 6 to 12 months with standard anticoagulant therapy or had completed treatment with apixaban or enoxaparin / warfarin as participants in the AMPLIFY trial.1
†† Based on RCT data for each individual NOAC. Edoxaban has not been compared with placebo in these patients.

Abbreviations

  • BD = Twice Daily
  • DVT = Deep Vein Thrombosis
  • INR = International Normalised Ratio
  • NOAC = Non-vitamin K antagonist Oral Anticoagulant
  • OD = Once Daily
  • PE = Pulmonary Embolism
  • RCT = Randomised Controlled Trial
  • VKA = Vitamin K Antagonist
  • VTE = Venous Thromboembolic Events

  1. Apixaban Summary of Product Characteristics.
  2. Agnelli G, Büller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699–708. https://doi.org/10.1056/NEJMoa1207541; PMID: 23216615.
  3. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709–18. https://doi.org/10.1056/NEJMoa1113697; PMID: 23425163.
  4. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–510. https://doi.org/10.1056/NEJMoa1007903; PMID: 21128814.
  5. Weitz JI, Lensing AW, Prins MH, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017;376:1211–22. https://doi.org/10.1056/NEJMoa1700518; PMID: 28316279.
  6. Edoxaban Summary of Product Characteristics.
  7. Rivaroxaban Summary of Product Characteristics.

December 2019
PP-ELI-GBR-6095