Direct Oral Anticoagulant Agents guideline HCS-115-01 · c) No antithrombotic therapy for patients aged less than 65 years with no CHADS2 risk factors and free of arterial vascular

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© Alberta Health Services (AHS) PAGE: 1 OF 16

TITLE

DIRECT ORAL ANTICOAGULANT AGENTS

SCOPE

Provincial DOCUMENT #

HCS-115-01

APPROVAL AUTHORITY

Chief Medical Officer INITIAL EFFECTIVE DATE

April 23, 2015

SPONSOR

Medical Director, Anticoagulation Management Services REVISION EFFECTIVE DATE

March 10, 2017

PARENT DOCUMENT TITLE, TYPE AND NUMBER

Not applicable SCHEDULED REVIEW DATE

April 23, 2018

NOTE: The first appearance of terms in bold in the body of this document (except titles) are defined terms – please refer to the Definitions section.

If you have any questions or comments regarding the information in this document, please contact the Policy & Forms Department at [email protected]. The Policy & Forms website is the official source of current approved policies, procedures, directives, standards, protocols and guidelines.

OBJECTIVES

For use by health care practitioners within Alberta Health Services, to support decision making for care of patients requiring anticoagulation for stroke prevention, for atrial fibrillation, and treatment and prevention of venous thrombo-embolism.

To provide guidance pertaining to three new, direct oral anticoagulant agents (DOAC) that are available as an alternative to warfarin and low molecular weight heparin therapy in certain circumstances.

APPLICABILITY

Compliance with this document is required by all Alberta Health Services employees, members of the medical and midwifery staffs, Students, Volunteers, and other persons acting on behalf of Alberta Health Services (including contracted service providers as necessary)

ELEMENTS

Three (3) new direct oral anticoagulant (DOAC) agents have been approved for use in Alberta which may be appropriate for patients with risk of stroke in atrial fibrillation and in some cases for treatment of venous thrombo-embolism (VTE) and VTE prevention after arthroplasty surgery. The three (3) DOACs are: rivaroxaban, apixaban, and dabigatran.

These new agents are significantly different from the prior oral agents in the vitamin K antagonist (VKA) as they act by directly interfering with coagulation at specific points in the cascade by directly inhibiting either factor X, (rivaroxaban or apixaban) or factor two (2) or thrombin (dabigatran). They also have fixed dosing; quicker onset; relatively short half-lives; and less drug interactions and intracerebral hemorrhage risk than VKAs.

mailto:[email protected]


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TITLE EFFECTIVE DATE DOCUMENT #

DIRECT ORAL ANTICOAGULANT AGENTS March 10, 2017 HCS-115-01

These agents do not require routine monitoring of anticoagulation status and do not affect traditionally available coagulation monitoring methods in a consistent effect and dose-based fashion.

There is currently no reversal agent that can be employed that has been proven to completely reverse coagulopathy or control of bleeding or both. All three agents do require some degree of renal clearance, which can vary with acute and chronic kidney disease.

Idarucizumab/Praxbind is an antidote now available for the reversal of dabigatran which is indicated in the setting of severe life threatening bleeding or high risk emergent/urgent procedures in patients with suspected or proven dabigatran related coagulopathy

The degree of renal clearance is least for apixaban and greatest for dabigatran.

1. Patient Selection

1.1 Atrial fibrillation: These new DOAC’s were studied in patients with non-valvular atrial fibrillation (AF) and are not appropriate for patients with rheumatic heart disease or mechanical valves. The 2014 CCS Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation provides the following recommendations for stroke prevention:

a) Oral anticoagulant (OAC) therapy for most patients aged 65 years or older, or CHADS2 score greater than or equal to one (1). When OAC therapy is indicated, most patients should receive dabigatran, rivaroxaban, or apixaban in preference to warfarin for non-valvular AF.

b) Acetylsalicylic Acid (ASA) (81 milligrams [mg]/day) for patients aged less than 65 years with no CHADS2 risk factors besides arterial disease (coronary, aortic, or peripheral).

c) No antithrombotic therapy for patients aged less than 65 years with no CHADS2 risk factors and free of arterial vascular disease (coronary, aortic, peripheral).

1.2 Stroke risk: Those patients with non-valvular AF should be risk stratified based on stroke and bleeding risk using standard measures such as CHADS2/ CHADS2VASc and HASBLED. There is good evidence to support use of these agents for patients with CHADS2 greater than or equal to one (1) for dabigatran and apixaban, and for patients with CHADS2 greater than or equal to two (2) for rivaroxaban. With CHADS2 scores greater than three (3), or with a history of prior stroke, favour the use of higher dosage dabigatran or apixaban.

1.3 Bleeding risk: Those patients with active bleeding should not be on an oral anticoagulant. Once bleeding has been controlled, they can be started on a DOAC, but those with recent or high bleeding risk should be considered for use of apixaban or low dose dabigatran. Those with low risk of bleeding can be started on any of the agents.


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1.4 Renal function: There are significant differences in renal excretion among the agents with apixaban having the lowest renal excretion and dabigatran having the highest level of renal excretion. While any of the agents can be considered with a glomerular filtration rate (GFR) greater than 60 millilitres per minute [mL/min], it is advised that lower dosages of dabigatran be used with GFR less than 50 mL/min, and that apixaban be considered as preferred with a GFR less than 30 mL/min with any degree of renal insufficiency.

Note: The Cockcroft-Gault formula for Creatinine Clearance (CrCl) = (140-age) * (Weight in kilograms [kg] * (0.85 if female) / (72 * Cr) is preferred for estimation of GFR. These agents should only be considered for patients with stable renal function and ongoing monitoring of renal function is required.

1.5 Age: There were significant differences in risk and benefit achieved in patients over the age of 80 among the agents with apixaban and rivaroxaban being favoured over dabigatran in that age group.

1.6 Coronary artery disease: While overall there was no clear difference in risk of coronary artery disease (CAD) associated with use of these agents in patients with AF, there were significant differences in bleeding risk associated with use of these agents in patients being treated for acute coronary syndrome (ACS). This is predominantly associated with use of these agents in addition to antiplatelet agents.

a) While there was a lower risk of bleeding associated with apixaban across all studies, there is still a significant increased risk associated with dual antiplatelet therapy in addition to OAC. There was very little evidence of benefit from an ACS standpoint, so at this point, in patients who require OAC for AF with recent ACS, the preference would be to provide dual antiplatelet alone for those with CHADS2 score less than or equal to one (1) and consider use of VKA's in those with CHADS2 score greater than one (1) while they require dual antiplatelet therapy. Studies are still being completed, which might suggest ability to use single antiplatelet and DOAC, which are not yet reported but would favour use of direct factor Xa inhibitors (Xa inhibitors) rivaroxaban or apixaban over thrombin inhibitors such as dabigatran.

1.7 Presence of arterial clot or recent stroke: The DOACs were not used in setting of recent stroke (less than six (6) months) or with acute arterial clot/embolism. The initial management of venous thromboembolism (VTE) was also handled differently with these agents, with some using low molecular weight heparin/ unfractionated heparin (LMWH/UFH) to DOAC or higher dosage DOAC initially. This would suggest that in setting of recent arterial clot/embolism/stroke that stroke neurologist or hematologist be consulted regarding a preferred agent and timing of anticoagulation. There have been reports of occurrence or increase in cardiac or venous clotting in setting of low dose dabigatran and rivaroxaban.


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1.8 Medication interactions: While there are not as many medication interactions with the DOAC's there are specific situations in which they should be avoided where certain medications need to be continued including: rifampin, phenytoin, carbamazepine, clarithromycin, fluconazole, and other azoles and protease inhibitors. Refer to Table # 5, this document.

2. Venous Thrombo-embolism

2.1 All of the new DOAC’s have been studied for treatment and prevention of VTE and found to be non-inferior to VKA’s based on rates of recurrence of VTE and bleeding risk. They have been studied for deep vein thrombosis (DVT) and pulmonary embolism (PE). Health Canada has approved all three agents for treatment and secondary prevention of VTE.

2.2 Initial DOAC dosing: Rivaroxaban and apixaban have initial higher twice-daily dosing for VTE while dabigatran used an initial five (5) to 10 days of LMWH or UFH.

2.3 Thrombophilia and cancer: Too few patients with active cancer were included in clinical trials with DOACs to date to enable any meaningful efficacy/safety conclusions. While these studies did include some patents with thrombophilia and some patients with active cancer, these higher risk patients should not be considered for initial management with the DOAC's without reviewing with oncology or hematology.

2.4 Massive VTE: For patients with massive DVT or PE, who would have been excluded from the prior studies of DOAC’s, it would be preferred to use standard therapies with LMWH/UFH if considering for thrombolysis or thrombectomy. Low molecular weight heparin may be preferred for an initial three (3) months for those with proximal ileofemoral DVT or sub massive PE, and those with active cancer, where there is evidence for specific benefit for these patients with LMWH.

2.5 Longer term therapy/secondary prevention: There have been extension studies completed with all three of the DOAC's suggesting that there is significant benefit with six (6) to 12 months in prevention of recurrent VTE after an initial six (6) months with standard therapy. Bleeding risk was significantly higher than placebo with use of dabigatran and rivaroxaban, and equivalent or less than placebo with usual dosage and low dosage apixaban, respectively.

2.6 Obesity: There are concerns about the use of DOACS in patients with weight greater than 120kg for management of acute clot as there have not been sufficient studies to ensure that standard doses are adequate. It is recommended that alternative agents be used in these cases until further evidence is available.


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3. Venous Thrombo-embolism Prevention

3.1 All three (3) DOAC’s have been studied for prevention of VTE after elective hip and knee arthroplasty, and have been found to be at least as effective as standard once-daily intermediate dose LMWH.

a) Currently rivaroxaban and apixaban have been approved by ABC for 14 – 35 days after knee and hip replacement.

b) Dabigatran was not approved by CDR or ABC for this purpose because they did not reach the non-inferiority criteria in one study, which compared them to nonstandard bid enoxaparin after hip replacement.

c) There have been some concerns about bleeding risk after hip and knee replacement in patients receiving rivaroxaban within four to six (4 – 6) hours of surgery. This has led to some centres using LMWH initially, after surgery, and then switching to DOAC at 24 – 48 hours or at discharge. Otherwise the DOAC’s should be given at the initial lower dosage at eight (8) to 12 hours post-op and then daily.

4. Monitoring

4.1 Monitoring of medication effect is not routinely required. For most indications, standard prothrombin time/international normalized ratio/partial thromboplastin time (PT/INR/PTT) monitoring will identify whether significant residual medication effect remains from a qualitative perspective.

4.2 For dabigatran, values of PTT greater than two (2) times normal are associated with increased risk of bleeding and levels higher than therapeutic range.

4.3 International normalized ratio and PTT values will differ significantly in individual patients, and with different INR and PTT reagents, and absolute values do not correlate with anticoagulant effect.

4.4 For patients who require high risk bleeding procedures, a normal INR/PTT may not be sufficient to exclude significant residual effect of DOAC.

4.5 For dabigatran, a normal thrombin time can be used to exclude any significant residual anticoagulant effect. Thrombin time testing is now available in all urban and regional stroke centres in Alberta.

4.6 For Xa inhibitors, a heparin calibrated anti-Xa level less than 0.1 will exclude any significant residual effect of rivaroxaban anticoagulant.

4.7 For rivaroxaban or apixaban, anti-xa testing is currently only available in urban and some regional centres.


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5. Recommended Dosages

Table 1: Dosage

Indication DOAC1 DOAC2 DOAC3 Additional info

AF Dabigatran 110 mg po bid 150 mg po bid

Rivaroxaban 15 mg po daily 20 mg po daily

Apixaban 2.5 mg bid 5 mg po bid

Cr Cl 30 – 50 mL/min Cr Cl greater than 50 mL/min

VTE (LMWH x 7 days then Dabigatran 150 mg po bid)

Rivaroxaban 15 mg po bid x 3 weeks then 20 mg po daily

Apixaban 10 mg po bid x 7 days than 5 mg po bid)

VTE prophylaxis

Rivaroxaban 10 mg daily x 14 – 35 days

Apixaban 2.5 mg po bid x 14 – 35 days

5.1 Patients may be placed on these agents in the community and come into the Alberta Health Services setting in a variety of ways including:

a) Emergently with bleeding –

(i) Management of bleeding should be based on timing of last DOAC dosage, severity of bleeding and results of initial lab testing. This information should also be used to determine type and dosage of procoagulant agents.

(ii) Transfusion medicine or hematology should be consulted when considering additional agents or doses of procoagulants.


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Table 1a: Management of patients with bleeding on dabigatran

Patients on Dabigatran (Pradaxa) with Bleeding

Minor Bleeding Moderate Bleeding Major Bleeding

Testing CBC,

INR/PTT;

Creatinine

CBC, INR/PTT;

Creatinine;

Fibrinogen;

Type and Screen;

Thrombin Time

CBC, INR/PTT;

Creatinine;

Fibrinogen;

Cross-match;

Thrombin Time

Supportive Therapy Local therapy

Local therapy/site control;

Transfusion;

Surgery/Intervention

Local therapy;

Transfusion;

Surgery/Intervention;

Consider platelet transfusion if antiplatelet agents are in use

Medication Dosing

Hold Dabigatran;

Hold antiplatelet agents

Hold Dabigatran;


Reversal/Removal None None

Consider charcoal** less than 2-4 hours post-dose;

Consider dialysis

Consider Idarucizumab (5g IV) with severe life threatening major bleeding

Procoagulant Agents None Tranexamic acid (10 mg/kg or

1000 mg IV every eight hours or 25 mg/kg PO)*

If no Idarucizumab, consider Factor VIII Inhibitor Bypass Activity (FEIBA) 25 to 50 units/kg or Prothrombin Complex Concentrate (PCC) 25 to 50 units/kg to maximum single dosage of 3000 units, with option to call for additional product if needed. Tranexamic acid may also be considered in this category.

Table 1b: Management of patients with bleeding on rivaroxaban/apixaban

Patients on Rivaroxaban (Xarelto) or Apixaban (Eliquis) with Bleeding

Minor Bleeding Moderate Bleeding Major Bleeding

Testing CBC, INR/PTT

CBC, INR/PTT;

Fibrinogen;

T & S;

Anti Xa level

Supportive Therapy Local therapy

Local therapy/site control;

Transfusion;

Surgery/Intervention

Local Therapy;

Transfusion;

Surgery/intervention;

Consider platelet transfusion if recent antiplatelet agents

Medication Dosing

Hold Rivaroxaban/ Apixaban;


Hold Rivaroxaban/Apixaban;



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Reversal None Consider charcoal ** (no evidence for

effectiveness);

Not dialyzable

Procoagulant agents None Tranexamic acid (10 mg/kg IV or 25 mg/kg PO)*

Consider PCC 25 – 50 unit/kg or fixed dosage of PCC 3000 units or FEIBA 25 – 50unit/kg;

Tranexamic acid (10 mg/kg IV) *

Note: * Upper urinary tract bleeding is a relative contraindication for Tranexamic acid, which can cause “clot colic”;

**Major upper GI bleeding is a relative contraindication for activated charcoal.

b) In need of emergent/urgent procedure –

(i) For patients admitted with a need for emergent surgery, there is no potential for reversal prior to proceeding, nor is there time to get results of coagulation testing.

(ii) It is reasonable to proceed with a plan to transfuse as necessary and inform the need for other products as time permits. This would include drawing blood for: Complete blood count (CBC), INR, PTT, fibrinogen, thrombin time, anti-Xa activity, type and screen, creatinine.

(iii) Should testing determine evidence of residual effect of drug present and need for higher bleeding risk surgery then a dose of tranexamic acid (10 mg/kg IV) may be considered prior or during procedure.

(iv) Consider idaruCIZUmab if recent dabigatran in setting of:

intracranial hemorrhage

retroperitoneal intra-spinal, intra-ocular, or intra-articular bleed

unstable gastrointestinal bleed not responding to initial resuscitation

emergent intervention (intra-abdominal sepsis ruptured viscus, ruptured abdominal aortic aneurysm, acute dissection

(v) For patients admitted with a need for urgent surgery, it is reasonable to assess the level of effect of the oral anticoagulant agent and, depending on level of risk of bleeding, either waiting until the effect is minimal or below detection prior to proceeding.

(vi) No evidence that providing reversal/hemostasis agents in this setting is safe or necessary. Should thrombin time testing determine evidence of residual effect of dabigatran present and need for higher bleeding risk surgery, then a dose of


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idaruCIZUmab and/or tranexamic acid may be considered prior or during procedure.

(vii) Determining timing of expected reversal of effect – in general, the expected timing of reversal will primarily be affected by time from the last dosage of oral anticoagulant and renal function.

(viii) Dabigatran's effect will be influenced more by renal dysfunction than that of rivaroxaban or apixaban.

Table 2: Peri-procedural management of direct anticoagulant agents

Testing Required Procedure with low

Bleeding Risk Procedure with Higher Bleeding

Risk

Initial Testing CBC, INR/PT;

Type and screen;

Creatinine

INR, PTT normal OK to proceed

Thrombin time (Dabigatran) or anti Anti-Xa level (Rivaroxaban/Apixaban)

Subsequent Testing Thrombin time

or Anti-Xa level Not needed unless

current bleeding issues OK to proceed once thrombin

time or Anti-Xa level normal

Example of Procedure

Colonoscopy;

Cardiac Cath;

Uncomplicated laparoscopic procedure

Hip #;

Cardiac surgery;

Neurosurgery;

Major abdominal surgery;

Neuraxial blockade

2014 CCS Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation (for a complete listing and categorization of surgical bleeding risk please review the 2014 CCS guidelines for the management of Atrial Fibrillation Table 1).

6. Approach to the Acute Stroke Patient Taking New Oral Anticoagulants in Alberta

6.1 Background: Reliable quantitative measures of anticoagulant activity in patients taking DOACS are not yet readily available. An assessment of the degree of anticoagulant activity is fundamental to acute stroke patient assessment and treatment selection. Ideally, a quantitative hemoclot assay should be done, but this test is not currently available at any sites in Alberta. Furthermore, delays in obtaining the result of this infrequent test will likely limit its use in acute stroke patient care. Similarly, anti-Xa activity assays calibrated specifically for measurement of each medication would be ideal for definitively assessing anticoagulant activity in patients taking rivaroxaban or apixaban. Currently, these tests are not available at any sites in Alberta, particularly secondary care stroke centres and tele stroke centres.

6.2 The following is a suggested approach to DOAC treated patients presenting with acute stroke in Alberta:

a) Dabigatran –

(i) In cases of ischemic stroke, assess aPTT and, where possible, a TT. A thrombolysis decision can be made using the aPTT alone. If


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the aPTT is within the normal reference range at the treatment centre, it is reasonable to treat with intravenous (IV) tissue plasminogen activator (tPA). When a rapid TT is available, it should also be used to guide systemic thrombolysis decisions.

(ii) In cases of acute intracranial bleeding, an aPTT and TT should be measured. When available, patients should be treated with 100 unit/kg of FEIBA, without waiting for the results of the aPTT or TT. When FEIBA is unavailable, patients should be treated with 50 unit/kg (high dose) of PCC, without waiting for test results. This empiric therapy is aimed at preventing hematoma expansion. A post-treatment aPTT and TT should be drawn immediately following therapy.

b) Rivaroxaban/apixaban/edoxaban –

(i) In cases of ischemic stroke, the PTT or PT/INR should be assessed. In cases where the PTT or INR is prolonged, tPA should be considered contraindicated. Although normal PTT and PT may reflect a lack of anticoagulant activity, the relationship is qualitative and unreliable. Therefore, tPA use in this setting must be considered very high risk and should be avoided. The introduction of anti-Xa activity assays across the province (calibrated to low molecular weight heparin) in the coming years may permit the safe use of tPA in these patients with undetectable "heparin levels" being the safest way to ensure medication clearance. In the interim, it is suggested that patients taking these agents be diverted to centres with endovascular treatment capabilities.

(ii) In cases of intracranial bleeding, the PTT and PT/INR should be assessed. When available, patients should be treated with 50 unit/kg (high dose) of PCC, without waiting for the results of testing. This empiric therapy is aimed at preventing hematoma expansion. A post-treatment PTT and PT/INR should be drawn immediately following therapy, though it should be noted that there is no evidence that correction indicates a real therapeutic benefit.

7. Patients Presenting for Elective Procedures

7.1 For patients who are presenting electively, ensuring that the oral anticoagulant has been held appropriately will depend on the type of procedure, bleeding risk and renal function.

7.2 Patients should be seen in pre-operative assessment clinic to ensure that this is determined.

7.3 Anesthesia should be involved and informed of the presence of oral anticoagulant agents in order to plan for type of anesthesia to be used.


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7.4 For surgeries that require full reversal of anticoagulant effect, testing of INR/PTT the morning of surgery may not suffice (high bleeding risk procedures including neuraxial blockade, neurosurgery or major thoracic or abdominal surgeries) and completion of urgent thrombin time or anti-Xa activity levels may be requested. (Thrombin time and anti-Xa levels subject to availability outside of regional or urban centres.)

7.5 For those procedures with standard risk of bleeding, demonstrating a normal INR/PTT on am of surgery should suffice. (Standard protocols based on time since last dosage and renal functions were used during RCT's with good results and are being studied currently).

Table 3: Preoperative interruption of new oral anticoagulants: an empiric formulation

Medication (Half-Life)

Renal Function

Aim for No or Minimal Residual Anticoagulant Effect at Surgery

(4 - 5 Medication Half-Lives Separate Last Dose and

Surgery)

Aim for Mild - Moderate Residual Anticoagulant Effect at Surgery

(2 - 3 Medication Half-Lives Separate Last Dose and Surgery)

Dabigatran: t ½ = 14 hrs

t½ = 15 - 18 hrs

Normal or Mild Impairment (CrCl greater than 50 mL/min)

Moderate Impairment (CrCl 30 - 50 mL/min)

Last dose: Day 3 before surgery (skip 4 doses)

Last dose: Day 4 to Day 5 before surgery (skip 6 - 8 doses)



Rivaroxaban: t½ = 9 hrs

Normal to Moderate Renal Impairment

(CrCl greater than 30 mL/min)


Last dose: Day 2 before surgery (skip 1 dose)

Apixaban: t½ = 9 hrs

Normal to Moderate Impairment

(CrCl greater than 30 mL/min)



Note: For high VTE risk surgery consider administering a reduced dose of Dabigatran (e.g., 110 – 150 mg once daily) on evening after surgery and on the first postoperative day CrCl, creatinine clearance. Cockcroft-Gault formula for Creatinine Clearance (CrCl) = (140-age) * (Wt in kg) * (0.85 if female) / (72 * Cr) is preferred for estimation of GFR.


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Table 4: Timing of interruption of dabigatran or rivaroxaban before surgery or invasive procedures

Calculated creatinine clearance, mL/min

Half-life, hours

Timing of Last Dose Before Surgery

Standard Risk of Bleeding * High Risk of Bleeding **

Dabigatran

greater than 80 13 (11 - 22) 24 h 2 d

greater than 50 less than or equal to 80

15 (12 - 34) 24 h 2 d

greater than 30 less than or equal to 50

18 (13 - 23) 2 d 4 d

less than or equal to 30 27 (22 - 35) 4 d 6 d

Rivaroxaban

greater than 30 12 (11 - 13) 24 h 2 d

less than 30 unknown 2 d 4 d

* Examples are cardiac catheterization, ablation therapy, colonoscopy without removal of large polyps, and uncomplicated laparoscopic procedures, such as cholecystectomy.

** Examples are major cardiac surgery, insertion of pacemakers or defibrillators (resulting from the risk for pocket hematoma), neurosurgery, large hernia surgery, and major cancer/urologic/vascular surgery.

Schulman et al, Blood; 2012;119(13):3016-23

Table 5: Postoperative Resumption of New Oral Anticoagulants: A Suggested Management Approach

Medication Low Bleeding Risk Surgery High Bleeding Risk Surgery

Dabigatran Resume on day after surgery (24 h

postoperative), 150 mg bid Resume 2 - 3 days after surgery

(48 - 72 h postoperative), 150 mg bid*

Rivaroxaban Resume on day after surgery (24 h postoperative), 20 mg once daily

Resume 2 - 3 days after surgery (48 - 72 h postoperative), 20 mg once daily**

Apixaban Resume on day after surgery (24 h

postoperative), 5 mg bid Resume 2 - 3 days after surgery

(48 - 72 h postoperative), 5 mg bid**

* For patients at high risk for thromboembolism, consider administering a reduced dose of Dabigatran (e.g., 110 - 150 mg once a day) on the evening after surgery and on the following day (first postoperative day) after surgery.

** Consider a reduced dose (e.g., Rivaroxaban 10 mg once a day or Apixaban 2.5 mg twice a day) in patients at high risk for thromboembolism.

Schulman et al, Blood; 2012;119(13):3016-23


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8. Patients presenting to hospital with other health issues

8.1 Patients on new direct oral anticoagulants will present to hospital with other acute medical issues and it is important that clinicians be aware of these agents and the impact of renal failure as well as indications and contraindications to use of these agents.

8.2 In the setting of acute renal failure, it is important to consider the need to hold/discontinue the new direct oral anticoagulant.

8.3 Patients may require other agents such as warfarin.

8.4 In the setting of acute illness with inability to eat, bridging with heparin/low molecular weight heparin may be required until the gut is working. Should a patient present with an acute coronary syndrome, use of antiplatelet therapies in addition to the anticoagulant will be required.

8.5 This will likely result in a temporary switch to a parenteral anticoagulant at standard acute coronary syndrome doses.

8.6 Some agents have been found to cause significant medication interactions with new direct oral agents (Table 5) (Shulman et al, Blood 2012).

9. Contraindications/Cautions

Table 6: Contraindications/Cautions

Dabigatran Rivaroxaban Apixaban

Contraindicated

Dronedarone Ketoconazole Rifampin

Both CYP3A4 and P-glycoprotein (P-gp) inhibitors Itraconazole Ketoconazole Posaconazole Ritonavir Voriconazole

Both CYP3A4 and P-glycoprotein (P-gp) inhibitors Itraconazole Ketoconazole Posaconazole Ritonavir Voriconazole

Caution

Amiodarone Carbamazepine Cyclosporine Quinidine Ritonavir Saint John’s Wort Saquinavir Tacrolimus Verapamil

Carbamazepine Phenobarbitone Phenytoin Rifampin Saint John’s Wort

Carbamazepine Phenobarbital Phenytoin Rifampin Saint John’s Wort


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DEFINITIONS

None

REFERENCES

Appendix A: References

Non Alberta Health Services Documents: o Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation

(2014 CCS Focused Update)

VERSION HISTORY

Date Action Taken

March 10, 2017 Revised

May 05, 2017 Non-substantive change


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APPENDIX A

References 1. Jeff S. Healey, MD, MSc; John Eikelboom, MD; James Douketis, MD; Lars Wallentin,

MD, PhD; Jonas Oldgren, MD, PhD; Sean Yang, MSc; Ellison Themeles, BA; Hein Heidbuchel, MD; Alvaro Avezum, MD; Paul Reilly, PhD; Stuart J. Connolly, MD; Salim Yusuf, MD, DPhil; Michael Ezekowitz, MB, ChB, DPhil; on behalf of the RE-LY Investigators Periprocedural Bleeding and Thromboembolic Events With Dabigatran Compared With Warfarin: Results From the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized Trial. Circulation. 2012;126:343-348

2. Sam Schulman and Mark A. Crowther; How I anticoagulate in 2012, new and old anticoagulant agents, and when and how to switch: Blood First Edition Paper, Blood; 2012;119(13):3016-23.

3. Van Ryn J, et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb and

Haemost 2010; 103(6):1116-27Crowther MA, Warkentin TE. Managing bleeding in

anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost 2009; 7 (Suppl 1):107-10

4. Levy JH. Novel oral anticoagulants: implications in the perioperative setting.

Anesthesiology 2010; 113(3):726-45 5. Van Ryn J et al. Successful reversal of Dabigatran-induced bleeding by coagulation

factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of

anticoagulation. Blood (ASH Annual Meeting Abstracts), Nov 2011; 118: 2316 6. Elise S. Eerenberg, MD; Pieter W. Kamphuisen, MD; Meertien K. Sijpkens, BSc; Joost

C. Meijers, PhD; Harry R. Buller, MD; Marcel Levi, MD. Reversal of Rivaroxaban and Dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573-9

7. Weltermann, M. Brodmann, H. Domanovits, B. Eber, M. Gottsauner-Wolf, W. M.

Halbmayer,J. M. Hiesmayr, P. A. Kyrle, F. Längle, F. X. Roithinger, H. Watzke, R.

Windhager, C. Wolf, R. Zweiker Dabigatran in patients with atrial fibrillation: perioperative and periinterventional management. Wien Klin Wochenschr (2012) 124:340–347

8. Joanne van Ryn; Joachim Stangier; Sebastian Haertter; Karl-Heinz Liesenfeld; Wolfgang Wienen; Martin Feuring; Andreas Clemens. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116–1127

9. Birgitta Salmela, M.D., Ph.D. Lotta Joutsi-Korhonen, M.D., Ph.D. Elina Armstrong, M.D., Ph.D. Riitta Lassila, M.D., Ph.D. Active Online Assessment of Patients Using New Oral Anticoagulants: Bleeding Risk, Compliance, and Coagulation Analysis, Semin Thromb Hemost 2012;38:23–30.

10. Douketis JD. Pharmacologic properties of the new oral anticoagulants: a clinician-oriented review with a focus on perioperative management. Curr Pharm Des 2010; 16(31):3436–3441.

11. Jeffrey I. Weitz, MD; Daniel J. Quinlan, MBBS; John W. Eikelboom, MBBS. Periprocedural management and approach to bleeding in patients taking Dabigatran. Circulation. 2012; 126:2428-2432.

12. Gage BF,Waterman AD, ShannonW, Boechler M, RichMW, Radford MJ. Validation of


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clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285(22):2864-70.

13. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010 Feb;137(2):263-72.

14. European Heart Journal (2012) 33, 2719-2747 Camm AJ et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation.

15. Skanes AC, Healey JAC, Dorian P, Gillis AM, McMurtry MS, Mitchell LB, Verma A Nattel S, Focused 2012 Update of the Canadian Cardiovascular Society Atrial Fibrillation Guidelines: Recommendations for Stroke Prevention and Rate/Rhythm control.Canadian Journal of Cardiology – March 2012 (vol 28 issue 2): 125-136.

16. Wells G, et al. Safety, Effectiveness, and Cost-effectiveness of New Oral Anticoagulants Compared with Warfarin in Preventing Stroke and Other Cardiovascular Events in Patients with Atrial Fibrillation, Therapeutic Review Report, Canadian Agency for Drug and Technologies in Health (CADTH), 2012; 1-73.

17. Atul Verma MD, et al. 2014 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation, Society Guidelines, Canadian Journal of Cardiology 30 (2014) 1114 – 1130.