Bleeding perioperative discontinuation, bridging, and reversal of anticoagulation and antiplatelet therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

In case of bleeding among patients on vitamin K antagonists, oral or intravenous vitamin K and fresh frozen plasma have been used for anticoagulation reversal at the expense of several limitations including time for vitamin K and the need for cross matching and risk of volume overload for fresh frozen plasma. Prothrombin complex concentrate (PCC) should be considered among patients on vitamin K anatagonist who develop severe bleeding.ref name="pmid23935012">Quinlan DJ, Eikelboom JW, Weitz JI (2013). "Four-factor prothrombin complex concentrate for urgent reversal of vitamin K antagonists in patients with major bleeding". Circulation. 128 (11): 1179–81. doi:10.1161/CIRCULATIONAHA.113.005107. PMID 23935012.CS1 maint: Multiple names: authors list (link) </ref> As for new oral anticoagulation therapy agents, there are so far no available antidotes and the management for severe bleeding among patients on these medications is problematic. The evidence for the use of PCC in case of severe bleeding among patients on oral anticoagulation therapy is not robust.

Reversal of Vitamin K Antagonist

• Oral or intravenous vitamin K and fresh frozen plasma were the two available agents for the reversal of vitamin K antagonist, until evidence from randomized clinical trials supported the use of prothrombin complex concentrate (PCC).
• There are significant limitations for vitamin K and fresh frozen plasma use. First of all, the reversal of vitamin K antagonist with vitamin K is a time dependent process because it relies on the vitamin K dependent synthesis of the coagulation factors 2, 7, 9 and 10. As for the treatment with fresh frozen plasma, it is also time dependent due to the need of cross matching before administration in addition to being associated with a risk of fluid overload particularly among patients with heart or kidney diseases.
• The need for a rapid reversal for vitamin K antagonist has fueled interest in prothrombin complex concentrate (PCC), which can be either activated or inactivated. The inactivate type exists in two forms:
  • 3 factor PCC which contains factor 2, factor 9, and factor 10 in addition to protein C and protein S
  • 4 factor PCC which contains factor 2, factor 7, factor 9, and factor 10 in addition to protein C and protein S
• According to the 2011 British guidelines on oral anticoagulation with warfarin, the administration of 4 Factor PCC and IV vitamin K is recommended to reverse warfarin among subjects with major bleed, emergency surgery and high suspicion of intracebral hematoma following head trauma.

• The 2012 American College of Chest Physicians Evidence-Based Clinical Practice Guideline recommends the administration of Factor 4 PCC in cases of major bleeding among patients on vitamin K anatagonist, and it advises for the concomitant administration of vitamin K along with it.

• The 2013 updated European guideline recommends the use of PCC among trauma patients after assessing the urgency of reversal of vitamin K antagonist versus the accompanied risk of increased risk of PCC associated thrombosis.

• A Randomized phase IIIb study on the use of PCC versus plasma for urgent vitamin K antagonist reversal among patients with acute major bleeding revealed that the administration of PCC was not inferior to plasma in decreasing the INR and increasing factor concentrations.

Reversal of New Oral Anticoagulation Therapy

New oral anticoagulation (NOA) therapy agents are characterized by a short half life and a better bleeding profile than vitamin K anatagonist. However, there are no antidotes for NOA and the management for severe bleeding among patients on these medications is problematic.

Direct Thrombin Inhibitors

In case of non life threatening bleeding associated with direct thrombin inhibitors, the management should be targeted on the following:

• Identification of the dose and time of the last administration of the medication
• Maintenance of diuresis
• Supportive measures if needed, such as administration of colloids, red blood cells, platelets, fresh frozen plasma, tranexamic acid, desmopressin, and dialysis

In case of life threatening bleeding, the management should include the similar previously noted measures. The administration of PCC or activated PCC should be considered in severe bleeding when urgent rapid reversal of anticoagulation is needed; however, there is not enough evidence to support its use.

Factor Xa Inhibitors

In case of non life threatening bleeding associated with factor Xa inhibitors, the management should be targeted on the following:

• Identification of the dose and time of the last administration of the medication
• Supportive measures if needed, such as administration of colloids, red blood cells, platelets, fresh frozen plasma, tranexamic acid, and desmopressin

In case of life threatening bleeding, the management should include the similar previously noted measures. The administration of PCC or activated PCC should be considered in severe bleeding when urgent rapid reversal of anticoagulation is needed; however, there is not enough evidence to support its use.

2013 ESA Guidelines for the Management of Severe Perioperative Bleeding (DO NOT EDIT)

Antiplatelet Agents

Class 1

"1. We recommend that aspirin therapy should continue perioperatively in most surgical settings, especially cardiac surgery. (Level of Evidence: C)"

"2. Where aspirin withdrawal is considered, we recommend a time interval of 5 days. (Level of Evidence: C)"

"3. Clopidogrel increases perioperative bleeding. In cases of increased bleeding risk, we recommend that it should be withdrawn for no more than 5 days. (Level of Evidence: C)"

"4. Prasugrel increases perioperative bleeding. In cases of increased bleeding risk, we recommend that it should be withdrawn for no more than 7 days. (Level of Evidence: C)"

"5. We recommend that antiplatelet agent therapy should resume as soon as possible postoperatively to prevent platelet activation. (Level of Evidence: C)"

"6. We recommend postponement of elective surgery following coronary stenting (at least 6 to 12 weeks for bare metal stent and one year for drug-eluting stents). (Level of Evidence: C)"

"7. We recommend that a multidisciplinary team meeting should decide on the perioperative use of antiplatelet agents in urgent and semi-urgent surgery. (Level of Evidence: C)"

Class 2

"1. For intra- or postoperative bleeding clearly related to aspirin, we suggest that platelet transfusion be considered (dose: 0.7 × 1011 [i.e. two standard concentrates] per 7 kg body weight in adults). (Level of Evidence: C)"

"2. We suggest that the first postoperative dose of clopidogrel or prasugrel should be given no later than 24 h after skin closure. We also suggest that this first dose should not be a loading dose. (Level of Evidence: C)"

"3. We suggest that urgent or semi-urgent surgery should be performed under aspirin/clopidogrel or aspirin/prasugrel combination therapy if possible, or at least under aspirin alone. (Level of Evidence: C)"

"4. We suggest that platelet transfusion should be considered (dose: 0.7 × 1011 [i.e. two standard concentrates] per 7 kg body weight in adults) in cases of intra- or postoperative bleeding clearly related to clopidogrel or prasugrel. (Level of Evidence: C)"

"5. According to pharmacological characteristics, we suggest that the management of ticagrelor may be comparable to clopidogrel (i.e. withdrawal interval of 5 days). (Level of Evidence: C)"

"6. Platelet transfusion may be ineffective for treating bleeding clearly related to ticagrelor when given 12 h before. (Level of Evidence: C)"

Heparin

Class 1

"1. We recommend that severe bleeding associated with intravenous unfractionated heparin (UFH) should be treated with intravenous protamine at a dose of 1 mg per 100 IU UFH given in the preceding 2–3 h. (Level of Evidence: A)"

Class 2

"1. We suggest that severe bleeding associated with subcutaneous UFH unresponsive to intravenous protamine at a dose of 1 mg per 100 IU UFH could be treated by continuous administration of intravenous protamine, with dose guided by aPTT. (Level of Evidence: C)"

"2. We suggest that severe bleeding related to subcutaneous low molecular weight heparin (LMWH) should be treated with intravenous protamine at a dose of 1 mg per 100 anti-Xa units of LMWH administered. (Level of Evidence: C)"

"3. We suggest that severe bleeding associated with subcutaneous LMWH and unresponsive to initial administration of protamine could be treated with a second dose of protamine (0.5 mg per 100 anti-FXa units of LMWH administered). (Level of Evidence: C)"

Fondaparinux

Class 2

"1. We suggest that the administration of rFVIIa could be considered to treat severe bleeding associated with subcutaneous administration of fondaparinux (off-label treatment). (Level of Evidence: C)"

Vitamin K Antagonists

Class 1

"1. We recommend that vitamin K antagonists (VKAs) should not be interrupted for skin surgery, dental and other oral procedures, gastric and colonic endoscopies (even if biopsy is scheduled, but not polypectomy), nor for most ophthalmic surgery (mainly anterior chamber, e.g. cataract), although vitreoretinal surgery is sometimes performed in VKA treated patients. (Level of Evidence: C)"

"2. We recommend that for low-risk patients (e.g. atrial fibrillation patients with CHADS2 score ≤2, patients treated for > 3 months for a non-recurrent VTE) undergoing procedures requiring INR <1.5, VKA should be stopped 5 days before surgery. No bridging therapy is needed. Measure INR on the day before surgery and give 5 mg oral vitamin K if INR exceeds 1.5. (Level of Evidence: C)"

"3. We recommend bridging therapy for high-risk patients (e.g. atrial fibrillation patients with a CHADS2 score > 2, patients with recurrent VTE treated for <3 months, patients with a mechanical valve). Day 5: last VKA dose; Day 4: no heparin; Days 3 and 2: therapeutic subcutaneous LMWH twice daily or subcutaneous UFH twice or thrice daily; Day 1: hospitalisation and INR measurement; Day 0: surgery. (Level of Evidence: C)"

"4. We recommend that for groups 1 and 2 above, VKAs should be restarted during the evening after the procedure. Subcutaneous LMWH should be given postoperatively until the target INR is observed in two measurements. (Level of Evidence: C)"

"5. We recommend that for group 3 above, heparin (UFH or LMWH) should be resumed 6–48 h after the procedure. VKA can restart when surgical hemostasis is achieved. (Level of Evidence: C)"

"6. We recommend that, in VKA treated patients undergoing an emergency procedure or developing a bleeding complication, PCC (25 IU FIX/kg) should be given. (Level of Evidence: B)"

"7. We recommend to assess creatinine clearance in patients receiving NOAs and being scheduled for surgery. (Level of Evidence: B)"

New Oral Anticoagulants

Class 1

"1. We recommend that for low-risk patients (e.g. atrial fibrillation patients with CHADS2 score 2, patients treated for >3 months for a non-recurrent VTE) undergoing procedures requiring normal coagulation (normal diluted thrombin time or normal specific anti-FXa level), NOAs can be stopped 5 days before surgery. No bridging is needed. (Level of Evidence: C)"

Class 2

"1. We suggest that new oral anticoagulant agents (NOAs) should not be interrupted for skin surgery, dental and other oral procedures, gastric and colonic endoscopies (even if biopsy is scheduled, but not polypectomy), nor for most ophthalmic surgery, (mainly anterior chamber, e.g. cataract), although vitreoretinal surgery is sometimes performed in NOA treated patients. (Level of Evidence: C)"

"2. In patients treated with rivaroxaban, apixaban, edoxaban and in patients treated with dabigatran in which creatinine clearance is higher than 50 ml/min, we suggest bridging therapy for high-risk patients (e.g. atrial fibrillation patients with a CHADS2 score >2, patients with recurrent VTE treated for <3 months). Day 5: last NOA dose; Day 4: no heparin; Day 3: therapeutic dose of LMWH or UFH; Day 2: subcutaneous LMWH or UFH; Day 1: last injection of subcutaneous LMWH (in the morning, i.e. 24 h before the procedure) or subcutaneous UFH twice daily (i.e. last dose 12 h before the procedure), hospitalisation and measurement of diluted thrombin time or specific anti-FXa; Day 0: surgery. (Level of Evidence: C)"

"3. In patients treated with dabigatran with a creatinine clearance between 30 and 50 ml/min, we suggest to stop NOAs 5 days before surgery with no bridging. (Level of Evidence: C)"

"4. We suggest that for groups 2 and 3, heparin (UFH or LMWH) should be restarted 6–72 h after the procedure, taking the bleeding risk into account. NOAs may be resumed when surgical bleeding risk is under control. (Level of Evidence: C)"

Comorbidities Involving Hemostatic Derangement

Class 1

"1. We do not recommend discontinuation of Gingko biloba extracts. (Level of Evidence: B)"

Class 2

"1. We suggest that patients with hemostatic derangements associated with systemic, metabolic and endocrine diseases should be managed perioperatively in collaboration with a hematologist. (Level of Evidence: C)"

"2. We suggest that selective serotonin reuptake inhibitor (SSRI) treatment should not be routinely discontinued perioperatively. (Level of Evidence: B)"

"3. We suggest individualised perioperative discontinuation of antiepileptic agents, such as valproic acid, which may increase bleeding. (Level of Evidence: C)"

Sources

• 2013 ESA Guidelines for the Management of Severe Perioperative Bleeding