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DOAC Reversal

Nov 29, 2024

This is a review from the International Society on Thrombosis and Haemostasis, of the data supporting their use of specific and non-specific reversal agents.

The Paper
Levy J H et al. Reversal of direct oral anticoagulants:guidance from the SSC of the ISTH. J Thromb Haemost. 2024;22:2889-2899

The most common side effect of direct oral anticoagulants (DOACs) is bleeding. Although the risk of bleeding with these agents is less than with Vitamin K antagonists, intracranial haemorrhage is still a potential serious side effect.

Specific DOAC Reversal Agents

Idarucizumab

Reversal agent for Dabigatran.
Monoclonal antibody Fab fragment
Half-life without renal impairment of 45 minutes
RE-VERSE AD Study looked at the efficacy in patients with life-threatening bleeding or requiring urgent surgery.
- Dose was 5 g IV bolus of idarucizumab followed by infusion over 30 minutes.
- N=503
  - 301 had life-threatening bleeding.
    - Median time to haemostasis in life threatening bleeding ...

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This is a review from the International Society on Thrombosis and Haemostasis, of the data supporting their use of specific and non-specific reversal agents.

The Paper
Levy J H et al. Reversal of direct oral anticoagulants:guidance from the SSC of the ISTH. J Thromb Haemost. 2024;22:2889-2899

Specific DOAC Reversal Agents

Idarucizumab

Reversal agent for Dabigatran.
Monoclonal antibody Fab fragment
Half-life without renal impairment of 45 minutes
RE-VERSE AD Study looked at the efficacy in patients with life-threatening bleeding or requiring urgent surgery.
- Dose was 5 g IV bolus of idarucizumab followed by infusion over 30 minutes.
- N=503
  - 301 had life-threatening bleeding.
    - Median time to haemostasis in life threatening bleeding was 2.5 hours.
  - 202 required urgent surgery
    - Haemostasis was considered normal in 93% of patients
- Duration of reversal was 24 hours.
- 30-day risk of thromboembolic complications following reversal was 4.8%, mostly in patients where anticoagulation had not been restarted.

Andexanet Alfa

Reversal agent for patients treated with FXaI agents such as Rivaroxaban or Apixaban
ANNEXA-A and ANNEXA-R trials,
- An IV bolus followed by an infusion significantly reduced anti-FXa activity for up to 4 hours in healthy volunteers.
The ANNEXA-4 study looked at major bleeding in patients on rivaroxaban, apixaban, edoxaban, or enoxaparin.
- Outcomes were the percentage change in anti-FXa activity and the percentage of patients with excellent or good hemostatic efficacy 12 hours after the infusion.
- N = 479
- Following treatment, the median anti-FXa activity decreased by 93%, and 80%
The ANNEXA-I trial(5), looked at patients with ICH presenting within 6 hours of symptom onset and 15 hours after the last dose of apixaban, edoxaban, or rivaroxaban.
- The primary endpoint was hemostasis at 12 hours, which was defined as:
  - ≤35% haematoma volume expansion at 12 hours
  - National institutes of Health Stroke Scale score increase of <7 at 12 hours, and
  - no rescue therapy, (surgical or prothrombin complex), administered between 3 and 12 hours after randomization.
- A higher proportion of patients receiving andexanet had excellent or good hemostatic efficacy (67% vs 53.1%)
- 30 days, mortality (27.8% vs 25.5%) survivors with favorable functional status (modified Rankin scale score, ≤3; 28.0% vs 30.9%) were not statistically different in andexanet versus usual care groups.
- Thromboembolic events were significantly more frequent in the andexanet group (10.3% vs 5.6%) especially ischemic stroke (6.5% vs 1.5%);
- This study had significant issues related to open label design and potential bias. Also the results were not clinically based.

Non-Specific Reversal Agents

PCC

Concentrates purified from plasma that contain factors II (pro- thrombin),IX, X, and VII.
3 factor PCCs have no FVII.
4 factor PCCs contain all 4 the vitamin K–dependent (II, VII, IX, X) plus small amounts of protein C and S.
- 4F-PCCs act by increasing thrombin generation, and are used for DOPAC reversal.
- They can be given as a weight-based dose (25-50 IU/kg) or as a fixed dose (a single dose of 2000 IU).

Activated PCC

Contains FVIIa and FX, FIX, and FII in their zymogen state.
A retrospective study on the use of activated PCC on DOAC patients requiring surgery reported a haemostasis of 56%

Recombinant FVIIa

There is no evidence to support its use for DOAC related bleeding.

Use and Non-Use of Antidotes and Other Therapies

How do these Agents Compare?

Andexanet vs PCC

ANNEXA-I showed better haemostatic effect with Andexanet vs usual care.

Observational studies have suggest comparable effectiveness, with Andexanet resulting in greater numbers of thromboembolic complications.
Other studies including retrospective and observational studies;
- Lower in-hospital mortality in patients receiving andexanet.
- Lower 30-day mortality in patients teated with andexanet

4F PCC

In patients with DOAC-associated ICH:
- It was not associated with better neurological recovery and in some studies was associated with higher 90 day mortality.

Laboratory Testing

Laboratory testing should not delay treatment in life-threatening bleeding.
Normal thrombin time rules out the presence of dabigatran
Normal activated partial thromboplastin time rules out the presence of asundexian or milvexian.
Dabigatran levels can be obtained by the diluted thrombin time or the ecarin clot time using dabigatran calibrators is the preferred assay.
Levels of apixaban, rivaroxaban, or edoxaban are obtained by chromogenic anti-FXa assays.

References

Pollack Jr CV, et al. Kam CW, Weitz JI. Idarucizumab for dabigatran reversal. NEJM. 2015;373:511–20.
Siegal DM, et al. Andexanet Alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413–24.

Siegal D, et al. Safety, pharmacokinetics, and reversal of apixaban anticoagulation with andexanet alfa. Blood Adv. 2017;1:1827–38.
Connolly SJ, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380:1326–35.
Chiasakul T, Crowther M, Cuker A. Four-factor prothrombin com- plex concentrate for the treatment of oral factor Xa inhibitor- associated bleeding: a meta-analysis of fixed versus variable dosing. Res Pract Thromb Haemost. 2023;7:100107. https://doi.org/ 10.1016/j.rpth.2023.100107
Shaw JR, Carrier M, Dowlatshahi D, Chakraborty S, Tokessy M, Buyukdere H, Castellucci LA. Activated prothrombin complex con- centrates for direct oral anticoagulant-associated bleeding or urgent surgery: hemostatic and thrombotic outcomes. Thromb Res. 2020;195:21–8.
Gomez-Outes A, et al. Meta-analysisof reversal agents for severe bleeding associated with direct oral an- ticoagulants. J Am Coll Cardiol. 2021;77:2987–3001.
Chaudhary R, et al. Evaluation of direct oral anticoagulant reversal agents in intracranial hemorrhage: a systematic review and meta-analysis. JAMA Netw Open. 2022;5:e2240145