Direct Oral AntiCoagulants [DOACs]
Introduction
The Direct Oral AntiCoagulants or DOACs [also known as Novel Oral AntiCoagulants] have a number of advantages over traditional Vitamin K antagonists such as Warfarin. These include:
- Rapid onset of action
- Fixed dosing - in general
- No effect from foodstuffs that contain Vitamin K
- Limited drug interactions
- Shorter time to recovery of normal haemostasis when discontinued compared to Warfarin.
The following tables summarise the DOACs and their effects on a number of tests used in the Haemostasis Lab.
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| Rivaroxaban | Apixaban | Edoxaban | Betrixaban | Dabigatran | |
|---|---|---|---|---|---|
| Mode of action | FXa inhibitor - both free and Prothrombinase-bound FXa | FXa inhibitor - both free and Prothrombinase-bound FXa | FXa inhibitor - both free and Prothrombinase-bound FXa | FXa inhibitor - both free and Prothrombinase-bound FXa | Direct IIa [Thrombin] inhibitor |
| Half-life | 5-9hr 11-13hr - Age >80yr |
8-15hr | 10-14hr | 19-27hr | 12-17hr |
| Tmax | 2.5-4hr | 1-3hr | 1-2hr | 3-4hr | 2hr |
| Binding to plasma proteins | 95% | 87% | 80% | 54% | 35% |
| Elimination | Renal 66% [36% unchanged] Hepatic/Faecal 28% |
Renal 27% Hepatic 2-3% [Faecal 46.7-56%] |
Renal 35% Hepatic/Faecal 46.7-56% |
Renal 11%% Hepatic/GI 82-89% |
Renal 80% Hepatic 20% [Faecal 82-88%] |
| Metabolism | Substrate for P Glycoprotein [P-gp] and therefore drugs that inhibit/induce P-gp can affect drug levels | Substrate for P Glycoprotein [P-gp] and therefore drugs that inhibit/induce P-gp can affect drug levels | Substrate for P Glycoprotein [P-gp] and therefore drugs that inhibit/induce P-gp can affect drug levels | Substrate for P Glycoprotein [P-gp] and therefore drugs that inhibit/induce P-gp can affect drug levels | Substrate for P Glycoprotein [P-gp] and therefore drugs that inhibit/induce P-gp can affect drug levels |
| Quantitative Assay | Anti-FXa assay with Rivaroxaban calibrator | Anti-FXa assay with Apixaban calibrator | Anti-FXa assay with Edoxaban calibrator | Anti-FXa assay with Betrixaban calibrator | Dilute Thrombin Time [dTT] or Ecarin Clotting Time [ECT] |
| Reversal Agents | Andexanet alfa - a modified recombinant Factor Xa molecule that is catalytically inactive but retrains structural similarity to endogenous Factor Xa and can, therefore, bind to FXa inhibitors. it is used for the reversal of Apixaban and Rivaroxaban. | Idarucizumab - a humanized, monoclonal, antibody fragment that reverses the action of Dabigatran | |||
| Comments | 1. Avoid in severe renal impairment [CrCl <15ml/min 2. Moderate liver impairment will increase drug levels. Avoid if ALT >2X upper limit of normal of Child Pugh Score B or C |
2. Moderate liver impairment will increase drug levels. Can be used with caution in liver disease - Child Pugh Score B or C 2. Avoid in severe renal impairment [CrCl <15ml/min |
1. Adjust dose in moderate-severe renal impairment [CrCl 15-50ml/min]. Avoid if CrCl <15ml/min 2. Avoid in patients with significant hepatic impairment and associated coagulation and/ or clinically relevant bleeding. Use with caution in mild-moderate hepatic impairment |
1. Batrixaban is largely excreted unchanged through biliary secretion. 2. Food (both high- and low-fat diets) reduces the mean bioavailability of Betrixaban by 50% to 60%. |
1. Avoid in severe renal impairment [CrCl <30ml/min |
The Effects of DOACs on Tests of Haemostasis
The DOACs can have a number of effects on both screening tests of Haemostasis and more specialised tests. These are summarised below:
1. Screening Tests
| Drug | PT | APTT | Clauss Fibrinogen | Thrombin Time | Reptilase Time | Comments |
|---|---|---|---|---|---|---|
| Rivaroxaban | ↑↑ Not sensitive at low drug concentrations ie trough levels. Results vary with reagents. Mixing studies may demonstrate incomplete correction. |
Normal or slightly ↑ APTT is less sensitive than the PT Mixing studies may demonstrate incomplete correction |
No effect | No effect | No effect | |
| Apixaban | ↑↑ Not sensitive at low drug concentrations ie trough levels Mixing studies may demonstrate incomplete correction |
Normal or slightly ↑ Mixing studies may demonstrate incomplete correction |
No effect | No effect | No effect | |
| Edoxaban | ↑↑ Mixing studies may demonstrate incomplete correction |
↑ Mixing studies may demonstrate incomplete correction |
No effect | No effect | No effect | |
| Betrixaban | ↑↑ Mixing studies may demonstrate incomplete correction |
↑ Mixing studies may demonstrate incomplete correction |
No effect | No effect | No effect | |
| Dabigatran | ↑ Mixing studies may demonstrate incomplete correction |
↑↑ Mixing studies may demonstrate incomplete correction |
May be falsely decreased | ↑↑↑↑ | No effect | A normal Thrombin Time excludes significant Dabigatran levels. The Dilute Thrombin Time [dTT] can be used to assay Dabigatran quantitatively. |
2. Specialised Tests including Factor Assays and Inhibitor Assays
| Drug | ACT | PT-based Factor Assays | APTT-based Factor Assays | Chromogenic FVIII Assay | Inhibitor/Bethesda Assay | Factor XIII Assays |
|---|---|---|---|---|---|---|
| Rivaroxaban | Prolonged and concentration dependent ACT is more sensitive to Dabigatran followed by Edoxaban, Rivaroxaban, Betrixaban and Apixaban. |
May demonstrate a falsely low level | May demonstrate a falsely low level | May demonstrate a falsely low level | May indicate the presence [incorrectly] of an inhibitor | ↓↓
May give rise to falsely low levels using activity assays but no effect on immunological assays |
| Apixaban |
ACT is more sensitive to Dabigatran followed by Edoxaban, Rivaroxaban, Betrixaban and Apixaban. Apixaban shows minimal effect on the ACT |
May demonstrate a falsely low level | May demonstrate a falsely low level | May demonstrate a falsely low level | May indicate the presence [incorrectly] of an inhibitor | No effect |
| Edoxaban | ACT is more sensitive to Dabigatran followed by Edoxaban, Rivaroxaban, Betrixaban and Apixaban. | May demonstrate a falsely low level | May demonstrate a falsely low level | May demonstrate a falsely low level | May indicate the presence [incorrectly] of an inhibitor | No effect |
| Betrixaban | ACT is more sensitive to Dabigatran followed by Edoxaban, Rivaroxaban, Betrixaban and Apixaban. | May demonstrate a falsely low level | May demonstrate a falsely low level | May demonstrate a falsely low level | May indicate the presence [incorrectly] of an inhibitor | No effect |
| Dabigatran | ACT is more sensitive to Dabigatran followed by Edoxaban, Rivaroxaban, Betrixaban and Apixaban. | May demonstrate a falsely low level | May demonstrate a falsely low level | No effect | May indicate the presence [incorrectly] of an inhibitor | ↓↓ May give rise to falsely low levels using activity assays but no effect on immunological assays |
3. Specialised Tests including Thrombophilia Testing
| Drug | Antithrombin Assays | Protein C Assays | Protein S Assays | APTT-based APCr Assays |
Ecarin Clotting Time [ECT] |
Comments |
|---|---|---|---|---|---|---|
| Rivaroxaban | Xa Substrate: ↑ IIa Substrate: No effect |
Chromogenic: Unaffected Clot-based: Elevated levels |
Chromogenic: ↑ Immunological: No effect |
↑ | No effect | Use of a Xa substrate in AT assays may generate false-normal results |
| Apixaban | Xa Substrate: ↑ IIa Substrate: No effect |
Chromogenic: Unaffected Clot-based: Elevated levels |
Chromogenic: ↑ Immunological: No effect |
↑ | No effect | Use of a Xa substrate in AT assays may generate false-normal results |
| Edoxaban | Xa Substrate: ↑ IIa Substrate: No effect |
Chromogenic: Unaffected Clot-based: Elevated levels |
Chromogenic: ↑ Immunological: No effect |
↑ | No effect | Use of a Xa substrate in AT assays may generate false-normal results |
| Betrixaban | Xa Substrate: ↑ IIa Substrate: No effect |
Chromogenic: Unaffected Clot-based: Elevated levels |
Chromogenic: ↑ Immunological: No effect |
↑ | No effect | Use of a Xa substrate in AT assays may generate false-normal results |
| Dabigatran | Xa Substrate: No effect IIa Substrate: ↑ |
Chromogenic: Unaffected Clot-based: Elevated levels |
Chromogenic: ↑↑ Immunological: No effect |
↑↑ | ↑↑ Can be used as a quantitative assay of Dabigatran |
Use of a IIa substrate in AT assays may generate false-normal results |
4. Specialised Tests
| Drug | D-dimer | dRVVT |
|---|---|---|
| Rivaroxaban | No effect | ↑↑↑ Concentration-dependent effect noted May lead to false positive LA detection |
| Apixaban | No effect | ↑↑ Concentration-dependent effect noted May lead to false positive LA detection |
| Edoxaban | No effect | ↑↑ Concentration-dependent effect noted May lead to false positive LA detection |
| Betrixaban | No effect | ↑↑ Concentration-dependent effect noted May lead to false positive LA detection |
| Dabigatran | No effect | ↑ Concentration-dependent effect noted May lead to false positive LA detection |