Efficacy and safety of NOACs in acute treatment

NOACs may be used for the treatment and prevention of recurrent VTE and, as previously noted, are supported in favour of LMWH / vitamin K antagonists (VKA) for some patients by international guidelines.1,2 They also offer advantages over the drawbacks associated with VKAs,3 and patients receiving NOACs report higher treatment satisfaction compared with those on VKA.4–7

Selected NOACs, apixaban and rivaroxaban, offer an additional advantage, in that no initial treatment with LMWH is required.8,9 Dosing regimens for each NOAC are shown below.8–11

Treatment of VTE Prevention of recurrent VTE
Initial treatment with LMWH Parenteral anticoagulant for at least 5 days
(not to be taken concurrently with dabigatran)
dabigatran 150 mg BD for at least 3 months*
110 mg BD in patients ≥80 years, patients on concomitant verapamil, and those at high risk of bleeding. Refer to the SmPC for other criteria for which a dose reduction should be considered.
Parenteral anticoagulant for at least 5 days
(not to be taken concurrently with edoxaban)
edoxaban 60 mg OD for at least 3 months*
30 mg OD in patients with CrCl 15–50 ml / min or body weight ≤60 kg or with concomitant use of the following P-glycoprotein inhibitors: cyclosporin, dronedarone, erythromycin or ketoconazole.
Single-drug approach rivaroxaban 15 mg BD with food
Day 1–21
rivaroxaban 20 mg OD with food Day 22 onwards for at least 3 months*
Consider reduction to 15 mg OD in patients with CrCl 15–49 ml / min if patient’s assessed bleeding risk outweighs the risk for recurrent DVT and PE.
rivaroxaban 10 mg OD with or without food following completion of at least 6 months treatment for VTE
In patients in whom the risk of recurrent VTE is considered high or who have developed recurrent VTE on 10 mg OD, a dose of 20 mg OD should be considered.
apixaban 10 mg BD
Day 1–7
apixaban 5 mg BD
Day 8 onwards for at least 3 months.*
apixaban 2.5 mg BD
Following completion of 6 months of treatment with apixaban 5 mg BD or another anticoagulant.

Please refer to the individual NOAC SmPCs for full dosing recommendations.
* Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation). The duration of overall therapy should be individualised after careful assessment of the treatment against the risk for bleeding.

Evidence for NOACs in the acute treatment for VTE

Efficacy and safety of NOACs for the treatment and prevention of recurrent VTE have been assessed in randomised controlled trials. Use the tabs below to view the study designs and efficacy and safety outcomes for each NOAC.12–16 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.

In patients with DVT / PE, apixaban is the only factor Xa inhibitor to demonstrate a significant reduction in the rates of both major and major / clinically relevant non-major bleeding vs. enoxaparin / warfarin12,15–17**††

AMPLIFY (apixaban)12 RR
(95% CI)
p-value
Primary efficacy outcome*
Recurrent VTE or VTE-related death
0.84
(0.60-1.18)
<0.001
non-inferiority
Safety outcomes
Major bleeding
0.31
(0.17-0.55)
<0.001
superiority
Major / CRNM bleeding
0.44
(0.36-0.55)
<0.001
00.511.52
Median TTR (INR 2.0-3.0) in patients randomised to warfarin = 61% Favours apixaban Favours enoxaparin / warfarin

* All efficacy analyses included data for patients in the ITT population for whom the outcome status at 6 months was documented.
† All safety analyses included data obtained from patients during study treatment, defined as the time from administration of the first dose until 48 hours after the last dose was administered.
‡ Major bleeding was the primary safety endpoint.

RE-COVER Pooled (dabigatran)14 HR
(95% CI)
p-value
Primary efficacy outcome*
Recurrent symptomatic VTE and VTE-related death
1.09
(0.77-1.54)
0.001
non-inferiority
Safety outcomes
Major bleeding§
0.60
(0.36-0.99)
p-value not available from publication
Major / CRNM bleeding
0.56
(0.45-0.71)
p-value not available from publication
00.511.52
Median TTR (INR 2.0-3.0) in patients randomised to warfarin = 60.6% Favours dabigatran Favours warfarin

* The efficacy analysis was based on the number of randomly assigned patients who received at least one dose of study drug and who had events during the 6 month treatment period, regardless of early discontinuation of study drug.
† The criteria for non-inferiority required that the upper limits of the 95% Cls were below prespecified margins for both the RR (<2.75) and the risk difference (<3.6 percentage points).
‡ The safety analysis of bleeding events was performed on the basis of the number of patients treated with dabigatran or warfarin, rather than the number assigned to the treatment. Events that occurred during the 6 month treatment period or from first to last intake of any study drug plus a 6 day washout period were included.
§ Major bleeding was the primary safety endpoint.

EINSTEIN-DVT (rivaroxaban)15 HR
(95% CI)
p-value
Primary efficacy outcome*
Recurrent VTE
0.68
(0.44-1.04)
<0.001
non-inferiority
Safety outcomes
Major / CRNM bleeding§
0.97
(0.76-1.22)
0.77
Major bleeding
0.65
(0.33-1.30)
0.21
00.511.52
Mean TTR (INR 2.0-3.0) in patients randomised to VKA = 57.7% Favours rivaroxaban Favours enoxaparin / VKA

* The primary efficacy analysis was performed on an ITT basis.
† The non-inferiority margin was 2.0.
‡ The safety analyses included all patients who received the assigned study drug.
§ Major / CRNM bleeding was the primary safety endpoint.

EINSTEIN-PE (rivaroxaban)16 HR
(95% CI)
p-value
Primary efficacy outcome*
Recurrent VTE
1.12
(0.75-1.68)
<0.003
non-inferiority
Safety outcomes
Major / CRNM bleeding§
0.90
(0.76-1.07)
0.23
Major bleeding
0.49
(0.31-0.79)
0.003
00.511.52
Mean TTR (INR 2.0-3.0) in patients randomised to VKA = 62.7% Favours rivaroxaban Favours enoxaparin / VKA

*The primary analysis was performed on an ITT basis.
† The non-inferiority margin was 2.0.
‡ The population for the safety analysis included all patients who received at least one dose of a study drug.
§ Major / CRNM bleeding was the primary safety endpoint.

HOKUSAI-VTE (edoxaban)17 HR
(95% CI)
p-value
Primary efficacy outcome*
Recurrent VTE or VTE-related death
0.89
(0.70-1.13)
<0.0001
non-inferiority
Safety outcomes
First major or CRNM bleeding§
0.81
(0.71-0.94)
0.004
Major bleeding
0.84
(0.59-1.21)
0.35
00.511.52
Overall TTR in patients randomised to warfarin = 63.5% Favours edoxaban Favours warfarin

* All efficacy analyses were performed in the modified ITT population, which included all patients who underwent randomisation and received at least one dose of the study drug.
† Criteria for non-inferiority are not stated in the paper.
‡ Analysis of bleeding outcomes were performed on the safety population, which included patients who received at least one dose of study drug.
§ First major or CRNM bleeding was the primary safety endpoint.

Study drug(dosing) Trial, N Parenteral before NOAC Comparator Treatment length(months) Key inclusion criteria
apixaban(10 mg BD for 7 days, then 5 mg BD) AMPLIFY
5395(double-blind)
No Enoxaparin bridge to warfarin 6 DVT / PE
requiring treatment for at least 6 months
dabigatran(150 mg BD) RE-COVER
2564(double-blind)
Required for at least 5 days Enoxaparin bridge to warfarin 6 DVT of the legs / PE requiring treatment for at least 6 months
dabigatran(150 mg BD) RE-COVER II
2589(double-blind)
Required for at least 5 days Enoxaparin bridge to warfarin 6 DVT of the legs / PE requiring treatment for at least 6 months
rivaroxaban(15 mg BD for 21 days, then 20 mg OD) EINSTEIN-DVT
3449(open-label)
No Enoxaparin bridge to VKA 3, 6 or 12* DVT without PE
rivaroxaban(15 mg BD for 21 days, then 20 mg OD) EINSTEIN-PE
4832(open-label)
No Enoxaparin bridge to VKA 3, 6 or 12* PE with or without DVT
edoxaban(60 mg OD)† HOKUSAI-VTE
8420(double-blind)
Enoxaparin or UFH for at least 5 days Enoxaparin bridge to warfarin 3–12 DVT without PE / PE with or without DVT

* Duration of treatment was determined by the treating physician before randomisation. Most patients received 6 or 12 months of therapy.
† Patients with body weight ≤60 kg or CrCl 30–50 ml/min, or patients receiving concomitant potent P-glycoprotein (P-gp) inhibitors received edoxaban once daily (OD).

Click to learn more about the AMPLIFY clinical trial and the use of apixaban for the treatment of DVT / PE.

** Initial 7 days of apixaban 10 mg BD, followed by apixaban 5 mg BD for up to 6 months.8
†† Based on RCT data from each factor Xa inhibitor. The primary safety endpoint for AMPLIFY was major bleeding.12 In the EINSTEIN-DVT/PE and HOKUSAI-VTE studies, the primary safety endpoint was major / clinically relevant non-major bleeding.15–17

Abbreviations

  • BD = Twice Daily
  • CrCl = Creatinine Clearance
  • DVT = Deep Vein Thrombosis
  • LMWH = Low Molecular Weight Heparin
  • 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

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  8. Apixaban Summary of Product Characteristics.
  9. Rivaroxaban Summary of Product Characteristics.
  10. Dabigatran Summary of Product Characteristics.
  11. Edoxaban Summary of Product Characteristics.
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  16. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–97. https://doi.org/10.1056/NEJMoa1113572; PMID: 22449293.
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December 2019
PP-ELI-GBR-6094