Apixaban (Eliquis®) – On formulary as an alternative to warfarin in patients with atrial fibrillation, and for deep vein thrombosis or pulmonary embolism. Apixaban is contraindicated in patients with mechanical heart valves.

Apixaban crosses the placenta and should not be used in pregnancy. Apixaban should be avoided in nursing mothers, as it is uncertain whether it appears in breast milk.

Apixaban is not recommended in those with CrCl <15 mL/min and in those undergoing dialysis. Apixaban should be avoided in patients with severe hepatic impairment (Child-Pugh class C).

Note: Before initiating therapy, prescribers should ensure that patients have drug coverage or can pay for drugs on discharge.

Guidelines for Management of Patients on Apixaban (Eliquis®)

Conversion to or from parenteral anticoagulants
For patients currently taking apixaban, wait 12 hours after the last dose before administering a parenteral anticoagulant in therapeutic doses.

For patients currently receiving therapeutic doses of a parenteral anticoagulant, start apixaban at the time of discontinuation of a continuous intravenous infusion of heparin or substitute apixaban for the next dose of low-molecular-weight heparin (LMWH) or fondaparinux. In patients receiving prophylactic heparin, LMWH or fondaparinux, apixaban can be started 6 or more hours after the last prophylactic dose.

Conversion to or from warfarin
When converting from apixaban to warfarin, give warfarin for 2 days and then start monitoring the INR daily just before apixaban dosing.  Stop apixaban when the INR is 2.0 or higher.
When converting patients from warfarin to apixaban, discontinue warfarin and start apixaban when the INR is 2.0 or lower.

Conversion to or from dabigatran, rivaroxaban or edoxaban
When converting from apixaban to dabigatran, rivaroxaban or edoxaban, discontinue apixaban and start dabigatran, rivaroxaban (with food) or edoxaban at the time of the next planned dose of apixaban.
When converting patients from dabigatran, rivaroxaban or edoxaban to apixaban, discontinue dabigatran, rivaroxaban or edoxaban and start apixaban at the time of the next planned dose of dabigatran, rivaroxaban or edoxaban.

Administration
Drug interactions – see Table. Apixaban at the 2.5 mg dose should also be avoided in combination with clarithromycin or erythromycin.

Management of Bleeding

There is no specific antidote for apixaban.
In the event of hemorrhagic complications:

• Discontinue treatment with apixaban and other antithrombotic drugs (e.g., ASA).
• Initiate appropriate clinical support, e.g., surgical or local hemostasis, transfusion of red cells, volume replacement with colloid or crystalloid.
• Consider the administration of platelet concentrations if there is thrombocytopenia or the patient is taking long-acting antiplatelet drugs (e.g., clopidogrel).
• Consider evaluating the anticoagulant effect of apixaban by measuring the prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT).  Apixaban has a greater effect on the PT/INR than on the aPTT, but neither test is affected to a great extent by apixaban.
• Determine the creatinine and calculate the creatinine clearance using the Cockcroft
• Gault equation because apixaban is partially excreted via the kidneys.
  Investigate the source of bleeding.

There is experimental evidence that unactivated (Octaplex or Beriplex) or activated prothrombin complex (FEIBA) concentrates or activated factor VII (Novoseven) will reverse the anticoagulant effects of apixaban.  The capacity to attenuate bleeding has only been established clinically in uncontrolled cohort studies. As a first choice in acute major bleeding, PCC 2000 units, infused over 20-30 minutes is suggested. The physician on call for Thrombosis Service MUST approve the order, except in the case of intracranial bleeding or major bleeding with trauma, when prior approval is not required.

In the event of need for emergency surgery or invasive procedure, even in a non-bleeding patient, an infusion of PCC 2000 units over 20-30 minutes is suggested when the following criteria are met:

• Last dose of apixaban within 12 h (longer in case of severe renal impairment),
• AND with surgery/procedure that cannot be postponed at least 8 h,
• AND with surgery/procedure that requires normal hemostasis

The physician on call for the Thrombosis Service MUST approve this order.

Discontinuation before surgery or interventions
For most elective surgeries or interventions, apixaban should be stopped prior to surgery based on a calculated creatinine clearance and the bleeding risk associated with the procedure. If the bleeding risk is moderate, apixaban should be stopped for at least 24 h (i.e., at least 2 doses must be withheld) prior to the procedure.  If the bleeding risk is high, apixaban should be stopped for 48 to 72 h prior to the procedure.

Types of surgery associated with a high risk of bleeding include cardiac surgery, neurosurgery, abdominal surgery, urological surgery or those involving a major organ. Other procedures, such as spinal anesthesia, may also require complete absence of an apixaban effect. Other important determinants of bleeding risk include advancing age, co-morbidities (e.g. major cardiac, respiratory or liver disease) and concomitant use of antiplatelet therapy.

Table. Drug interactions with at least 50% change in the exposure to apixaban. 

The use of apixaban is contraindicated in patients receiving concomitant systemic treatment with strong inhibitors of both CYP 3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole, or posaconazole) and HIV protease inhibitors (e.g., ritonavir).

The concomitant use of apixaban with other strong inducers of both CYP 3A4 and P-gp (e.g., phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may also lead to reduced apixaban plasma concentrations and should generally be avoided.

Reference: Eliquis® product monograph 2018 (PDF).

Reviewed/revised: April 12, 2018

1 vial = 2.5 mL
Dilute in NS or D5W or Ringer’s lactate
Use 1 vial/250 mL diluent bag or 2 vials/500 mL diluent bag (final concentration 1 mg/mL)

Dosing Checklist

• Heparin must be discontinued before administration of Argatroban.
• A baseline aPTT should be obtained before initiating Argatroban therapy. Argatroban is not a good choice in patients with elevated baseline aPTTs and other agents should be considered in this setting.
• The aPTT should be rechecked 2 hours after infusion initiation and the dose should be adjusted by 0.2 – 0.5 µg/kg/min until target steady-state aPTT values of 1.5 to 3.0 times baseline are attained (not to exceed 100 seconds; maximum dose 10 µg/kg/min).
• Monitor the INR daily when converting from Argatroban to warfarin.

Recommended Dosing Regimen for HIT Patients

Standard Starting Infusion Rates for 1 mg/mL final concentration

Conversion to Oral Anticoagulant Therapy

Initiating Oral Anticoagulant (Warfarin) Therapy
When converting to oral vitamin K antagonist therapy, a loading dose of warfarin should not be used; initiate therapy using the expected daily dose of warfarin. Due to risk of warfarin-induced microthrombosis in acute HIT, warfarin therapy should not be started pending substantial resolution of HIT (platelet count >150,000 × 109/L).

Co-Administration of Warfarin and Argatroban at Doses up to 2 µg/kg/min
The concomitant use of Argatroban with warfarin results in prolongation of INR beyond that produced by warfarin alone. INR should be measured daily while Argatroban and warfarin are co-administered. In general, with doses of Argatroban up to 2 µg/kg/min, Argatroban can be discontinued when the INR is > 4.0. After Argatroban is discontinued, repeat the INR measurement in 4 to 6 hours. If the repeat INR is below the desired therapeutic range, resume the infusion Argatroban and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.

Co-Administration of Warfarin and Argatroban at Doses greater than 2 µg/kg/min
For doses greater than 2 µg/kg/min, the relationship between INR on warfarin alone and warfarin plus Argatroban is less predictable. In this case, in order to predict the INR on warfarin alone, temporarily reduce the dose of Argatroban to a dose of 2 µg/kg/min. Repeat the INR on Argatroban and warfarin 4 to 6 hours after Argatroban reduction and follow the process outlined above for dosing Argatroban at up to 2 µg/kg/min.

*If stopping argatroban to measure the true INR while transitioning to warfarin is not an option, Factor Xa levels can be measured and the warfarin dose adjusted to achieve a therapeutic level of less than 25%.

Blood transfusions can confer clinical benefit, but can also carry serious potential risks.  All blood transfusions must be given with informed consent.  Physicians must consider the risks and benefits when they order blood, and explain the trade-offs clearly to their patients.

Information on potential risks of blood and blood products in Canada (BROKEN LINK), as well as the key elements of informed consent.

Provincial information on the evidence based use of blood, including the clinical indications for blood use.

Safe transfusion practice involves giving the right blood product to the right patient in the right way, for the right reason.  Provincial guidance on how to give blood products safely and effectively.

This information was last updated in May 2017, and approved by HRLMP Transfusion Medicine Professional Staff.

Dabigatran (Pradaxa®) – On formulary as an alternative to warfarin in patients with atrial fibrillation. Dabigatran is contraindicated in patients with mechanical heart valves.

Dabigatran crosses the placenta and should not be used in pregnancy. Dabigatran should be avoided in nursing mothers, as it is uncertain whether it appears in breast milk.

Dabigatran is contraindicated in patients with CrCl <30 mL/min.  Dose modification is not needed in patients with hepatic impairment but dabigatran should be used with caution in those with cirrhosis or baseline coagulopathy who are at high risk of bleeding.

Note: Prior to initiating therapy, prescribers should ensure that patients have drug coverage or are able to pay for drug on discharge.

Guidelines for Management of Patients on Dabigatran (Pradax®)

Conversion to or from parenteral anticoagulants
For patients currently taking dabigatran, wait 12 hours (CrCl ?30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of dabigatran before initiating treatment with a parenteral anticoagulant.

For patients currently receiving therapeutic doses of a parenteral anticoagulant, start dabigatran 0 to 2 hours before the time of discontinuation of a continuous intravenous infusion of heparin or substitute dabigatran for the next dose of low-molecular-weight heparin (LMWH) or fondaparinux. In patients receiving prophylactic heparin, LMWH or fondaparinux, daigatran can be started 6 or more hours after the last prophylactic dose.

Conversion to or from warfarin
When converting from dabigatran to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows:

• For CrCl >50 mL/min, start warfarin 3 days before discontinuing dabigatran.
• For CrCl 31-50 mL/min, start warfarin 2 days before discontinuing dabigatran.
• For CrCl 15-30 mL/min, start warfarin 1 day before discontinuing dabigatran.
• For CrCl <15 mL/min, no recommendations can be made – consult with Thrombosis Service.

Because dabigatran can contribute to an elevated INR, the INR will better reflect warfarin’s effect after dabigatran has been stopped for at least 2.0 days.

When converting patients from warfarin therapy to dabigatran, discontinue warfarin and start dabigatran when the international normalized ratio (INR) is below 2.3.

Conversion to or from rivaroxaban, apixaban or edoxaban
When converting from dabigatran to rivaroxaban, apixaban or edoxaban, discontinue dabigatran and start rivaroxaban (with food), apixaban or edoxaban at the time of the next planned dose of dabigatran.

When converting patients from rivaroxaban, apixaban or edoxaban to dabigatran, discontinue rivaroxaban, apixaban or edoxaban and start dabigatran at the time of the next planned dose of rivaroxaban or apixaban.

Administration
Dabigatran is preferably given with food to minimize the risk of dyspeptic side effects. Dabigatran capsules should be swallowed whole. The capsule should not be crushed, chewed or opened before swallowing. Capsules should be stored in their blister package or in the original bottle from the manufacturer to protect them from moisture.

Drug interactions – see Table.

Dabigatran should be taken 2 h before verapamil, quinidine or antacids.

Management of Bleeding
There is an antidote to dabigatran, idarucizumab or Praxbind®. In most situations, however, bleeding can be managed without the antidote.

In the event of hemorrhagic complications:
• Discontinue treatment with dabigatran and other antithrombotic drugs (e.g., ASA)
Initiate appropriate clinical support, e.g. surgical or local hemostasis, transfusion of red cells, volume substitution, inotropic drugs.
• Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs (e.g., clopidogrel) have been used.
• Consider evaluating the anticoagulant effect of dabigatran by measuring the prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT).  Dabigatran has a variable effect on the PT/INR and a non-linear effect on the aPTT. Measurement of aPTT may help guide therapy to the extent that therapeutic levels of dabigatran will cause a prolongation. The thrombin clotting time (TCT) is very sensitive and is always prolonged in the presence of any dabigatran. The dilute TCT (Hemoclot® assay) shows a linear response with dabigatran plasma concentration. This test requires a hematologist’s approval and is not performed as a “stat” assay.
• Determine the creatinine and calculate the creatinine clearance using the Cockcroft Gault equation because dabigatran is mostly excreted via the kidneys.
• Investigate the source of bleeding.
• For life-threatening bleeding, bleeding in a closed space (e.g. intracranial, intraspinal, muscle hematoma with compartment syndrome), or ongoing bleeding despite supportive measures, administer idarucizumab 5 g intravenously.

In the event of need for emergency surgery or invasive procedure, even in a non-bleeding patient, administer idarucizumab 5 g intravenously if the following criteria are met:

• Last dose of dabigatran within 12 h (longer in case of moderate-severe renal impairment),
• AND with surgery/procedure that cannot be postponed at least 8 h,
• AND with  surgery/procedure that requires normal hemostasis

Consult with physician on call for the Thrombosis Service if there is no improvement and always when a second dose of idarucizumab is being considered.
Dabigatran is primarily excreted in the urine; therefore, maintain adequate diuresis. Dabigatran can be dialyzed (protein binding is low) and it may take 6-8 hours to clear dabigatran this way; however, data supporting this approach are limited and dialysis is rarely needed if idarucizumab is administered. The duration of dialysis may be best guided by normalization of aPTT and/or shortening of the 2 U TCT to 60 s.

Discontinuation before surgery
For most elective surgeries or interventions, dabigatran should be stopped prior to surgery based on a calculated creatinine clearance and the bleeding risk associated with the procedure.

1. Data from renal impairment study in healthy volunteers, geometric mean (range).
2. Types of surgery associated with a high risk of bleeding include but are not limited to cardiac surgery, neurosurgery, abdominal surgery, urological surgery or those involving a major organ. Other procedures such as spinal anesthesia may also require complete absence of a dabigatran effect. Other important determinants of bleeding risk include advancing age, co-morbidities (e.g. major cardiac, respiratory or liver disease) and concomitant use of antiplatelet therapy.
3. Dabigatran etexilate is contraindicated for use in these patients. CrCl = creatinine clearance.

Table. Drug interactions with at least 50% change in the exposure to dabigatran

The use of dabigatran is contraindicated in patients receiving concomitant systemic treatment with strong P-gp inbitors, such azole–antimycotics (e.g., ketoconazole or itraconazole), HIV protease inhibitors (e.g., ritonavir), and dronedarone.

The concomitant use of dabigatran with strong P-gp inducers (e.g. rifampin, carbamazepine, phenytoin, phenobarbital or St. John’s Wort) may lead to reduced dabigatran plasma concentations and should be generally avoided.

References
Stangier J, Rathgen K, Stähle H, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate. Clin Pharmacokinet 2010; 49: 259–268.
Pradaxa® product monograph 2020 (PDF)
PraxBind® product monograph 2020 (PDF)

Reviewed/revised: April 12, 2018

Each 0.6 mL ampule of danaparoid contains 750 anti-Xa units.

Loading Dose
2,250 U IV bolus*, followed by 400 U/hour x 4 hours, then 300 U/hour x 4 hours, then use maintenance dose IV, as below.
*Adjust bolus dose for body weight:

Maintenance (IV)
200 U/hour*, with subsequent dose adjustments (bolus adjustments if desired can be given in 50 cc minibags of D5W, NS or Ringer’s Lactate) made using anti-Xa levels (target range 0.5-0.8 anti-Xa U/mL, if available.

Prepare danaparoid for intravenous infusion as follows: add 3 ampules (2250 U) danaparoid to 250 mL D5W or NS or Ringer’s Lactate (ie. 9 anti-Xa U/mL), and infuse at 44 mL/hr (=396 U/hr) x4 hours, then 33 mL/hr (=297 U/hr) x 4 hours, then 22 mL/hr (198 U/mL).

The half-life of anti-Xa activity is approximately 25 hours; when overlapping danaparoid therapy with initiation of warfarin anticoagulation, the physician should consider discontinuing the danaparoid when the INR begins to increase on warfarin.

Maintenance (SC)
After initial IV therapy
2250 U subcutaneously bid*
*Adjust does for body weight

Prophylaxis

Prothrombin Complex Concentrate (PCC) is available through Canadian Blood Services. Two PCCs are currently available, Octaplex and Beriplex; each contains factor II, VII, IX, X, Protein C, Protein S, and small quantities of heparin.

Indications
PCC is indicated for treatment of severe or life-threatening acute bleeding associated with warfarin (Coumadin®) OR for rapid reversal of warfarin for urgent surgical procedures in less than 6 hours.
PCC has also been used for treatment of severe or life-threatening acute bleeding associated with factor Xa inhibitors: apixaban (Eliquis®), rivaroxaban (Xarelto®) or edoxaban (Lixiana®)

Order must be approved by the physician on call for the Thrombosis Service except in cases of intracranial hemorrhage or major bleed with trauma (to expedite product release).

Dosage
Warfarin Reversal

Dosing for target INR ~ 1.5

*    Add 10 IU/kg for target INR < 1.2
*    Also give vitamin K 5-10 mg IV over 30 minutes.
*    Under normal circumstances the dose should not exceed 3000 IU with a maximum infusion speed of 8mL/min.
*    For severe acute bleed with unknown INR, give 2000 IU.

Factor Xa Inhibitor Reversal
Give PCC 2000 IU.

Supplied
Human product supplied as a lyophilized powder with 20 mL diluent for reconstitution.
Each vial is approximately 500 IU
Each vial contains a range of factor activity eg. Factor IX -400-620 IU

Relative Contraindications
Patients with heparin-induced thrombocytopenia (HIT) or suspected HIT (product contains heparin).

Theodore E. Warkentin MD, BSc (Med), FRCPC, FACP
Regional Director, Transfusion Medicine
Hamilton Regional Laboratory Medicine Program
Hematologist, Service of Clinical Hematology

Sam Schulman MD
Professor of Medicine
Thrombosis Service, McMaster Clinic & HHS – General Hospital

Reviewed/revised: April 12, 2018

Rivaroxaban (Xarelto®) – On formulary as an alternative to warfarin in patients with atrial fibrillation, deep vein thrombosis or pulmonary embolism, and for thromboprophylaxis after elective hip or knee arthroplasty. Rivaroxaban is contraindicated in patients with mechanical heart valves.

Rivaroxaban crosses the placenta and should not be used in pregnancy. It has been shown that rivaroxaban appears in breast milk; therefore, this drug should also be avoided in nursing mothers.

There is limited information on rivaroxaban in patients with CrCl <30 mL/min and in those with moderate or severe hepatic impairment (Child-Pugh class B or C). Rivaroxaban should be avoided in such patients.

Note: Prior to initiating therapy, prescribers should ensure that patients have drug coverage or are able to pay for drug on discharge.

Guidelines for Management of Patients on Rivaroxaban (Xarelto®)

Conversion to or from parenteral anticoagulants
For patients currently taking rivaroxaban, wait 24 hours after the last dose before administering a parenteral anticoagulant in therapeutic doses.

For patients currently receiving therapeutic doses of a parenteral anticoagulant, start rivaroxaban at the time of discontinuation of a continuous intravenous infusion of heparin or substitute rivaroxaban for the next dose of low-molecular-weight heparin (LMWH) or fondaparinux. In patients receiving prophylactic heparin, LMWH or fondaparinux, rivaroxaban can be started 6 or more hours after the last prophylactic dose.

Conversion to or from warfarin
When converting from rivaroxaban to warfarin, give warfarin for 2 days and then start monitoring the INR daily, just prior to rivaroxaban dosing.  Stop rivaroxaban when the INR is 2.0 or higher.

When converting patients from warfarin to rivaroxaban, discontinue warfarin and start rivaroxaban when the INR is 2.5 or lower.

Conversion to or from dabigatran, apixaban or edoxaban
When converting from rivaroxaban to dabigatran, apixaban or edoxaban, discontinue rivaroxaban and start dabigatran, apixaban or edoxaban at the time of the next planned dose of rivaroxaban.

When converting patients from dabigatran, apixaban or edoxaban to rivaroxaban, discontinue dabigatran, apixaban or edoxaban and start rivaroxaban at the time of the next planned dose of dabigatran, apixaban or edoxaban.

Administration
When given at doses above 10 mg, rivaroxaban should be given with food for optimal absorption.

Drug interactions – see Table

Management of Bleeding
There is no specific antidote for rivaroxaban.

In the event of hemorrhagic complications:
• Discontinue treatment with rivaroxaban and other antithrombotic drugs (e.g., ASA).
• Initiate appropriate clinical support, e.g., surgical or local hemostasis, transfusion of red cells, volume replacement with colloid or crystalloid.
• Consider administration of platelet concentrates if there is thrombocytopenia or the patient is taking long-acting antiplatelet drugs (e.g., clopidogrel).
• Consider evaluating the anticoagulant effect of rivaroxaban by measuring the prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT).  Rivaroxaban has a greater effect on the PT/INR than on the aPTT.
• Determine the creatinine and calculate the creatinine clearance using the Cockcroft Gault equation because rivaroxaban is partially excreted via the kidneys.
• Investigate the source of bleeding.

There is experimental evidence that unactivated (Octaplex or Beriplex) or activated prothrombin complex (FEIBA) concentrates or activated factor VII (Novoseven) will reverse the anticoagulant effects of rivaroxaban.  The capacity to attenuate bleeding has only been established clinically in uncontrolled cohort studies. As a first choice in acute major bleeding, PCC 2000 units, infused over 20-30 minutes is suggested. The physician on call for Thrombosis Service MUST approve the order, except , however, not required in case of intracranial bleeding or major bleed with trauma, when prior approval is not required.

In the event of need for emergency surgery or invasive procedure associated with a high risk of bleeding, even in a non-bleeding patient, an infusion of PCC 2000 units, over 20-30 minutes is suggested when the following criteria are met:

• Last dose of rivaroxaban within 24 h (longer in case of severe renal impairment),
• AND with surgery/procedure that cannot be postponed for at least 8 h,
• AND with surgery/procedure that requires normal hemostasis

The physician on call for the Thrombosis Service MUST approve this order.

Discontinuation before surgery or interventions
For most elective surgeries or interventions, rivaroxaban should be stopped prior to surgery based on a calculated creatinine clearance and the bleeding risk associated with the procedure. If the bleeding risk is moderate, rivaroxaban should be stopped for at least 24 h prior to the procedure.  If the bleeding risk is high, rivaroxaban should be stopped for 48 to 72 h prior to the procedure.

Types of surgery associated with a high risk of bleeding include cardiac surgery, neurosurgery, abdominal surgery, urological surgery or those involving a major organ. Other procedures, such as spinal anesthesia, may also require complete absence of a rivaroxaban effect. Other important determinants of bleeding risk include advancing age, co-morbidities (e.g. major cardiac, respiratory or liver disease) and concomitant use of antiplatelet therapy.

A normal anti-Xa rivaroxaban level indicates absence of rivaroxaban anticoagulant activity; however, routine checking of rivaroxaban levels prior to surgery is not recommended or required. The anti-Xa rivaroxaban level is a non-stat test and is available only with a hematologist’s approval.

Table. Drug interactions with at least 50% change in the exposure to rivaroxaban.

The use of rivaroxaban is contraindicated in patients receiving concomitant systemic treatment with strong inhibitors of both CYP 3A4 and P-gp such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole or posaconazole) and HIV protease inhibitors (e.g., ritonavir).

The concomitant use of rivaroxaban with other strong inducers of both CYP 3A4 and P-gp (e.g., phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may also lead to reduced rivaroxaban plasma concentrations and should generally be avoided.

Reference: Xarelto® product monograph 2019 (PDF).

Reviewed/revised: April 12, 2018