NOACS (DOACS)

ICU EDUCATION

APRIL 2017

Karlee Johnston – ICU Pharmacist Canberra Hospital

What

� Direct oral anticoagulants

� Factor Xa inhibitors � Apixaban

� Rivaroxaban

� Direct thrombin inhibitor� Dabigatran

Dabigatran (Pradaxa®)

Dabigatran

o Reversibly inhibit thrombino Preventing conversion of fibrinogen to fibrin

o Thrombin-induced platelet aggregation is also inhibited

o Indications:o Prevention of VTE after elective total hip or knee replacement

o Treatment of acute VTE (not commonly used)

o Prevention of subsequent VTE

o Non-valvular AF & high risk of stroke or systemic embolism

Dabigatran dosing

Indication DoseAF & prevention of subsequent VTE 150mg BD

110mg BD (CrCl 30-50mL/min; >75yrs or greater risk of bleeding)

Acute VTE IV therapy for 5 days before starting dabigatran150mg BD110mg BD (CrCl 30-50mL/min; >75yrs or greater risk of bleeding)

Prevention of VTE after hip/knee replacement (for 10/7 days post TKR; 28-35/7 post THR

110mg 1-4 hours post-op220mg DAILY150mg DAILY (CrCl 30-50ml/min)

Dabigatran

o Monitoring:o Renal function

o Dose reduction 30-50mL/mino CI < 30mL/min

o Other considerations:o age (>75 years recommend reduced dosing)o bleeding risko Surgeryo Drug interactions

o Substrate P-Glycoprotein o Inhibitors: amiodarone, verapamilo Inducers: rifampicin, phenytoin

Apixaban (Eliquis®)

Apixaban

o Selectively inhibits factor Xa, blocking thrombin production, conversion of fibrinogen to fibrin, and thrombus development

Indications:• Prevention of VTE following elective hip/knee replacement

• Treatment of acute VTE and prevention of subsequent VTE

• Non valvular AF and high risk of stroke or systemic emboli

o Use contraindicated in patients with CrCl <25mL/min

Dosage

* Risk factors: Weight <60 kg, age >80 years, serum creatinine >133 micromol/L

Indication DoseAF 5mg BD

* If 2 risk factors use 2.5mg BDPrevention of VTE (after 6/12 Tx) 2.5mg BDAcute VTE 10mg BD x 7/7 then 5mg BDPrevention of VTE after hip/knee replacement (for 10/7 days post TKR; 28-35/7 post THR

2.5mg BD 12-34/24 post-op

Rivaroxaban (Xarelto®)

Rivaroxaban

o Selectively inhibits factor Xa, blocking thrombin production, conversion of fibrinogen to fibrin, and thrombus development

Indications:• Prevention of VTE following elective hip/knee replacement• Treatment of acute VTE and prevention of subsequent VTE• Non valvular AF and high risk of stroke or systemic emboli

• Contraindicated CrCl <30mL/min

Dosing

o Renal:• CrCl <15 mL/min contraindicated

• CrCl 15-30 mL/min contraindicated for AF & tx/prevention VTE; caution for VTE prevention after surgery

Indication DoseAF 20mg Daily

15mg Daily (CrCl 30-49mL/min)Acute VTE and prevention of subsequent VTE

15mg BD for 21/7 then 20mg Daily

Prevention of VTE after hip/knee replacement (for 14/7 days post TKR; 35/7 post THR

10mg Daily 6-10/24 post-op

Edoxaban

Edoxaban

o Not approved for use in Australiao Selectively inhibits factor Xa, blocking thrombin

production, conversion of fibrinogen to fibrin, and thrombus development

o Clinical trials underway in Australia (including in malignancy)

Monitoring for factor XaInhibitors� Routine laboratory monitoring not required as there is currently no method to

guide dose adjustments� Regular renal function monitoring is required, especially for the elderlyo Age (>65 years shown to have higher blood concentrations)o Weighto Drug interactionso Gender (higher exposure in women – no dose adjustment required) o Signs of bleeding – bruising, spontaneous bleeding (e.g. epistaxis), black/tarry

stools, coffee ground vomito Anti-FXa, INR, aPTT – not a measure of anticoagulant effect but can be used to

test adherenceo Rivaroxaban & INR – given with warfarin affect INR more than additively; INR

will be misleadingly high (e.g. up to 12).

Coagulation studies

Test Dabigatran Apixaban Rivaroxaban

PT/INR Can be increased but a normal value does not exclude an anticoagulant effect.

Can be increased but a normal value does not exclude an anticoagulant effect.

Can alter INR up to 12! Does not indicate coagulation status and should not be used

aPTT Can be increased but a normal value does not exclude an anticoagulant effect.

Dilute TT (Hemoclot) or ECT (Ecarin clotting time)

<30-50 ng/ml = likely no significant anticoagulant effect

NA NA

Thrombin time Normal = no dabigatran effectIncreased = some dabigatran effect. Not as sensitive as dilute TT.

NA NA

Calibrated anti-Xa NA <30-50 ng/ml = likely no significant anticoagulant effect.

<30-50 ng/ml = likely no significant anticoagulant effect.

Interactions – Direct factor Xa inhibitors

o Metabolised by CYP3A4 & substrate of P-glycoproteino Therefore interacts with strong inhibitors/inducers of P-gp and

CYP3A4o CYP3A4 inhibitors – increased risk of bleeding; exacerbated in

renal impairmento CYP3A4 inducers – concentration & efficacy may be

reducedo Manufacturer contraindicates combination with strong

inhibitors of both CYP3A4 and P-gp, eg ritonavir. o For treatment of VTE, the manufacturer does not recommend

combination with strong inducers of both CYP3A4 and P-gp(e.g. St John’s wort, rifampicin) and advises use with caution for other indications.

Com

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Phar

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Drug Absorption Tmax(hrs)

Dosing interval

Elimination route and metabolism

t1/2 (hrs)

% protein bound

Dialysed Interactions

Warfarin 4 Daily CYP450 enzymes

20-60 99 No -Drugs affecting the clotting process & platelets- Substrates of CYP2C9, CYP1A2, CYP2C19 & CYP3A4/5

Dabigatran Stomach 2 BD or daily

Faecal 20%; renal 80-85%

14-17 35 Yes Strong P-gp inducers and inhibitors

Apixaban Stomach 2-4 BD or daily

Faecal 65%; renal 33-36%

7-13 90 No Strong P-gp inducers and inhibitors & CYP3A4

Rivaroxaban Distal small bowel and ascending colon

3-4 BD or daily

Faecal 75%; renal 25-27%

8-15 87 No Strong P-gp inducers and inhibitors & CYP3A4

Edoxaban Rapidly afterPO admin

1-2 Daily Renal 35% 8-10 40-59 ? Strong G-gp inhibitors

BLEEDING

1.

� Do what you would normally do to stop bleeding� Manage the source!

� Reversing an agent won’t stop the bleeding

Dabigatran

� Management of bleeding/over-anticoagulation:� Minor bleeding: skip or delay the next dose � Major bleeding

� Cease dabigatran � Administer oral activated charcoal if within 2 hours of dose � Consider dialysis – low protein binding

� Removes ~60% over 2-3 hours� Difficult in an emergency situation

� Maintain adequate hydration – approximately 80% renal excretion � Risk of death

� Reversal agent: idarucizumab� Activated prothrombin complex concentrates (prothrombin X)– limited

evidence (50units/kg)� Recombinant factor VIIa - limited evidence and risk of thrombosis – not

recommended

Idarucizumab

� Binds to dabigatran and its metabolites neutralising its anticoagulant activity � Idarucizumabs affinity for dabigatran is 350 times greater than

that of dabigatran to thrombin � RE-VERSE AD Study (Reversal Effects of Idarucizumab on

Active Dabigatran) 2015� Interim analysis of 90 patients in a prospective cohort study

with serious bleeding or required an urgent procedure � Idarucizumab normalized the test results in 88 to 98% of

patients� Effective within minutes� Median time to the cessation of bleeding was 11.4 hours

Idarucizumab Dosing

� Praxbind: available as 5g (2 x 2.5g/50mL vials)� 5g IV administered as 2 separate 2.5g doses no more than 15 minutes

apart� May consider administration of an additional 5g dose if still bleeding

or clinically indicated but limited data to support its use � Administer undiluted as an IV bolus or infusion no longer than 5-10min� Use with 1hour of removing solution from vial � High cost! $

Idarucizumab Points

� Formulary restriction:• “available from transfusion laboratory for use in patients

requiring urgent dabigatran reversal on the recommendation of haematologist only according to SAS requirements”

� Compassionate stock from the company held in pharmacy but obtained from the blood bank

� Ongoing trial and SAS forms required� Recommended monitoring schedule:

� baseline APTT, repeat 2 hours post exposure and every 12 hours until APTT returns to normal

� APTT helps determine dabigatran effect but not extent of haemostatic impairment

Factor Xa Inhibitors

� Management of bleeding/over anticoagulation:1,3

� No antidotes available, use supportive measures� Consider activated charcoal if dose within last few hours (2

hours)� Blood and platelet transfusions� Fresh frozen plasma and/or cryoprecipitate � Prothrombin complex concentrates � Recombinant activated factor VII – not recommended

� Rivaroxaban and apixiban� Rivaroxaban half life 5-9hours, apixaban 12hours � Highly plasma protein bound (not dialysable)12,14

New kid on the block...Andexanet Alfa

� Reversal agent for:� Direct factor Xa inhibitors (apixaban, fondaparinux and rivaroxaban)� LMWH (dalteparin, enoxaparin, nadroparin and danaparoid)

� Modified factor Xa molecule – still undergoing trials � Factor Xa inhibitors bind to the molecule and are neutralized

� Dose based on Xa inhibitor and time since last dose � Administered as an IV infusion � Works within 5 minutes � Duration of action 2 hours – subsequent infusions may be required � Rebound when infusion completed

� Ongoing trial ANNEXA-4

Recombinant Factor VIIa

� Also known as Eptacog alfa or NovoSeven� Routine use not recommended � Must be approved by haematologist and 1 other specialist � 90mcg/kg/dose every 2-3hours until haemostasis achieved � Administer as slow IV bolus � Available as 1mg vials costing $1300

� Ie, for a 60kg patient dose is 5.4mg� Rounding down, 1 5mg dose = $6500� Found as stock

Pre-op management

From anticoagulant to NOAC