Background
INDICATIONS FOR DOACs
Dabigatran | Rivaroxaban | Apixaban | Edoxaban | |
---|---|---|---|---|
Target | Factor lla | Factor Xa | Factor Xa | Factor Xa |
Prodrug | Yes | No | No | No |
Tmax (h) | 1.0–3.0 | 2.0–4.0 | 3.0–4.0 | 1.0–2.0 |
Half-life (h) | 12-17 h | 5–9: healthy individuals 11–13: elderly | 8–15: healthy individuals | 10–14 |
Bioavailability | 3–7% pH sensitive | For 2.5 mg and 10 mg: 80–100% (fasting or fed) For 15-20 mg: 66%: (fasting) almost 100% (fed) | ± 50% | 62% |
Metabolism | Conjugation | CYP-dependent and independent mechanism | CYP-dependent mechanism (25%) | CYP-dependent (<5%) and independent mechanism (<10%) |
Active metabolites | Yes - acylglucuronides | No | No | Yes (<15%) |
Elimination of absorbed dose | 80% renal | 33% unchanged via the kidney | 27% renal | 50% renal |
20% bile (glucuronide conjugation) | 66% metabolized in the liver into inactive metabolites then eliminated via the kidney or the colon in an approximate 50% ratio | 73% through the liver, the residue is excreted by the hepatobiliary route | 50% metabolism and biliary/intestinal excretion | |
CYP substrate | No | CYP3A4, CYP2J2 | CYP3A4 | CYP3A4 (<5%) |
P-gp substrate | DE: Yes | Yes | Yes | Yes |
BRCP substrate | No | Yes | Yes | No |
PERIOPERATIVE MANAGEMENT OF DOACs
THE PERIOPERATIVE CHECKLIST | |
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➢ The thrombo-embolic risk of the patient | |
➢ The bleeding risk of the patient | |
➢ Timing of stopping DOAC before an invasive procedure: • The bleeding risk of the invasive procedure • The elimination half-life of the DOAC used depending on the patient’s ° renal function, liver function, and co-medication | |
➢ Specific considerations for some invasive procedures: ° Neuraxial anesthesia ° Atrial fibrillation ablation | |
➢ When should bridging therapy with heparin be suggested? | |
➢ Resuming a DOAC after an invasive procedure or surgery |
The thrombo-embolic risk of the patient
CHADS2 or CHA2DS2-VASc score
Timing of last thrombo-embolic event
Other risk factors
The bleeding risk of the patient
Time of stopping DOACs before an invasive procedure
The bleeding risk of invasive procedures
Minimal risk of bleeding or feasible with on-therapy levels of direct oral anticoagulantsa
| Low to moderate risk of bleeding | High risk of bleeding |
---|---|---|
Tooth extraction: 1 to 3 teeth Periodontology Simple endoscopy without biopsy Superficial surgery (e.g. abscess incision or minor dermatologic procedures (small superficial excision) Cataract procedure Double J stent insertion | Endoscopy with simple biopsy Prostate or bladder biopsy Coronary angiography Simple abdominal hernia repair Anal surgery Gynecologic surgery: simple total laparoscopic hysterectomy Orthopedic surgery: hand surgery, arthroscopy Pace-maker or cardioverter-defibrillator implantationb
| Neuraxial anesthesia Intracranial surgery Thoracic surgery Cardiac surgery Complex abdominal or gynecological cancer surgery Major orthopedic surgery Ear/Nose/Throat complex cancer surgery or specific surgery requiring good hemostasis (e.g. cochlear implant or thyroid surgery) Liver and kidney biopsy Transurethral prostate or bladder resection Extracorporeal shockwave lithotripsy Infected pace maker lead extraction (increased risk of cardiac tamponade) Robotic surgery |
The elimination half-life of the DOAC
DOAC | Dabigatran | Rivaroxaban - Apixaban | Edoxaban | |||||
---|---|---|---|---|---|---|---|---|
Bleeding risk of invasive procedure | LOW Bleeding risk | HIGH Bleeding risk | LOW Bleeding risk | HIGH Bleeding risk | LOW Bleeding risk | HIGH Bleeding risk | ||
GIHP (Groupe d’Intérêt en Hémostase Péri-opératoire) | Preoperative interruption
No bridging (except patients with high risk of TE)
| CrCl ≥50 ml/min | Last dose ≥ 24 h before surgery | Last dose 4 days before surgery | Last dose ≥ 24 h before surgery | Last dose 3 days before surgery | Last dose ≥ 24 h before surgery | Last dose 3 days before surgery |
CrCl >30 ml/min | Last dose 5 days before surgery | |||||||
For very high risk procedure (neuraxial anaesthesia) | Last dose 5 days before surgery | |||||||
Resumption after invasive procedure or surgery | LOW Bleeding Risk: Resume minimum 6 h after invasive procedure or surgery HIGH Bleeding Risk: Prophylactic dose of LMWH, UFH or fondaparinux minimum 6 h after invasive procedure or surgery if venous thromboprophylaxis is indicated Therapeutic dose of DOACs when hemostasis is controlled (24-72 h) For neuraxial anesthesia with indwelling catheter: Resumption with LMWH or UFH until indwelling catheter is out | |||||||
Heidbuchel et al. | Preoperative interruption
No bridging
| CrCl ≥80 ml/min | ≥ 24 h | ≥ 48 h | ≥ 24 h | ≥ 48 h | ≥ 24 h | ≥ 48 h |
CrCl 50–80 ml/min | ≥ 36 h | ≥ 72 h | ≥ 24 h | ≥ 48 h | ≥ 24 h | ≥ 48 h | ||
CrCl 30–50 ml/min | ≥ 48 h | ≥ 96 h | ≥ 24 h | ≥ 48 h | ≥ 24 h | ≥ 48 h | ||
CrCl 15–30 ml/min | Not indicated | Not indicated | ≥ 36 h | ≥ 48 h | ≥ 36 h | ≥ 48 h | ||
CrCl <15 ml/min | No official indication for use | |||||||
Resumption after invasive procedure or surgery | LOW Bleeding Risk: • DOACs 6-8 h HIGH Bleeding Risk: • Low TE risk ➔ resume DOACs 48-72 h after procedure • High TE risk ➔ prophylactic or intermediate dose of LMWH 6-8 h after procedure, resume DOACs when hemostasis is controlled (48-72 h) | |||||||
Spyropoulos et al. | Preoperative interruption
No bridging
| CrCl >50 mL/min | Last dose 2 days before surgery | Last dose 3 days before surgery | Last dose 2 days before surgery | Last dose 3 days before surgery | Last dose 2 days before surgery | Last dose 3 days before surgery |
CrCl 30–50 mL/min | Last dose 3 days before surgery | Last dose 4–5 days before surgery | Last dose 2 days before surgery | Last dose 3 days before surgery | ||||
CrCl 15–29 mL/min | Depends on patient and procedural factors | Depends on patient and procedural factors | ||||||
Resumption after invasive procedure or surgery | LOW Bleeding Risk: • DOACs 24 h HIGH Bleeding Risk: • Low TE risk ➔ resume DOACs 48-72 h after procedure • High TE risk ➔ consider a reduced dose of dabigatran (75 mg twice daily), rivaroxaban (10 mg once daily) or apixaban (2,5 mg twice daily) on the evening after surgery and on the following day (first postoperative day) after surgery. |
Specific consideration for some invasive procedures
Neuraxial anesthesia
Atrial fibrillation ablation
When should bridging therapy with heparin be suggested?
Resuming a DOAC after an invasive procedure or surgery
Doac laboratory testing
Other options to rapidly screen for the presence of DOACs
Point of care monitoring and other global assays
Management of emergencies
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reduction of intestinal absorption: activated charcoal should be considered in the first hours after ingestion [106].
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increase in DOAC clearance: ensure adequate diuresis, especially for patients taking dabigatran. Only patients on supratherapeutic level of dabigatran may be candidates for renal replacement therapy (RRT) when an invasive procedure needs to be rapidly planned. However, within 4 h after RRT, a rebound of dabigatran plasma concentration can occur with a potential risk of bleeding [104].
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administration of coagulation factors: Prothrombin complex concentrates (PCCs) contain lyophilized human plasma-derived vitamin-K dependent coagulation factors (clotting factors II, VII, IX and X) and are standardised according to their factor IX content. They may also contain anticoagulation proteins such as protein C, protein S, protein Z, antithrombin and heparin. They are categorized as 4-factor PCC if their content of FVII is high and as 3-factor PCC if it is low. Furthermore, aPCCs (FEIBA®) are available which contain non-activated factors II, IX and X, and activated factor VII [104]. Prophylactic administration of PCCs is not recommended. The mechanisms of action of PCCs and aPCCs are similar as both increase thrombin generation and animal studies have not shown any significant differences in the reduction of bleeding. Therefore, it is not useful to switch from one to the other when trying to manage bleeding in a patient on dabigatran [45, 103]. In the pre-clinical setting, PCC or aPCC showed an improvement in coagulation parameters, blood loss and mortality. Dose recommendations are difficult to make with the lack of high-level evidence with PCCs and aPCCs for dabigatran reversal, but it appears necessary to use the minimum effective dose because of the theoretical thromboembolic risk (starting with an initial dose of 25 U/kg). Suggested doses for 4-Factor PCCs and aPCC are 50 U/kg and 80 U/kg respectively.