Novel Oral Anticoagulants (NOAC)

• No INR monitoring is required. 
• Care must be shown if there is renal dysfunction (especially dabigatran – 80% renally cleared). 
• 3 currently approved in Australia

-­ Direct thrombin inhibitors: Dabigatran

-­ Factor Xa inhibitors: Rivaroxaban, Apixaban

Indications:

 

NOAC dosing and PBS listings for prevention of stroke and SE in patients with NVAF

Recommendation	Apixaban1,4	Dabigatran2,5	Rivaroxaban3,6
Dosing	5 mg twice daily	150 mg twice daily	20 mg once daily
Dose adjustments	2.5 mg twice daily for patients with ≥ 2 of:age ≥ 80 years body weight ≤ 60 kg serum creatinine ≥ 133 µmol/L	110 mg twice daily in patients with any of:age ≥ 75 years CrCl 30–50 mL/min high risk of major bleeding	15 mg once daily in patients with CrCl 30–49 mL/min 15 mg once daily in patients with CrCl 15-29 mL/min  (Use with caution)
PBS listed	Yes	Yes	Ye

 

NOAC dosing and PBS listings for treatment or prevention of DVT and PE

Recommendation	Apixaban1,4	Dabigatran2,5	Rivaroxaban3,6
Dosing	Treatment: 10 mg twice daily for 7 days, then 5 mg twice daily Prevention: 2.5 mg twice daily, after ≥ 6 months of DVT/PE treatment	150 mg twice daily, following treatment with a parenteral anticoagulant for ≥ 5 days	Treatment: 15 mg twice daily for 21 days Prevention: 20 mg once daily, after 21 days of DVT/PE treatment. Consider 10 mg once daily after 6-12 months of DVT/PE treatment based on individual assessment of risk of recurrence vs bleeding risk
Dose adjustments	Not stated in PI	110 mg twice daily in patients with any of:age ≥ 75 years CrCl 30–50 mL/min high risk of major bleeding	Not stated in PI
PBS listed	Yes	No	Yes

Rivaroxaban dosing and PBS listing for prevention of major cardiovascular events in CAD and/or PAD

Rivaroxaban is PBS listed for the prevention of major cardiovascular events (composite of stroke, myocardial infarction and cardiovascular death) in patients with CAD and/or PAD when used in combination with aspirin but no other anti-platelet therapy

 

Recommendation	Rivaroxaban3,8
Dosing	Rivaroxaban 2.5 mg twice daily in combination with 100 mg aspirin daily
Dose adjustments	Not stated in PI
PBS listed	Yes

 

Choosing between warfarin and NOACs

• All of the NOACs have some degree of renal excretion so for those with severe renal impairment or labile renal function, warfarin should remain the anticoagulant of choice
• Many patients find INR monitoring burdensome and request change to NOACs
• Must remember that they are currently non-­reversible, although dabigatran can be dialysed off
• -For patients on warfarin with whose INR levels are easily maintained the benefit of a change is limited
• For those with labile INRs;; home monitoring or a change to the NOACS should be considered
• Warfarin remains standard of care for those with valvular AF or prostheticvalves
• Rivaroxaban is OD in comparison to BD for the other  NOACs
• Most important drug interaction are with verapamil and amiodarone (increased levels of NOACs). Effect is minimised by taking NOACs 2-­3 hours before ingestion of other medication.

Advantages compared to warfarin

• Fixed doses and no need for frequent blood tests as pharmacokinetics are more predictable however renal function should be monitored particularly in those with chronic kidney disease or those who are elderly.
• Onset of action within 2-3 hours (apixaban and rivaroxaban does not require bridging with heparin or LMWH).
• Less likely to interact with foods, other drugs or illnesses.
• Possibly lower incidence of life-threatening bleeding.

Disadvantages compared to warfarin

• Less experience with reversal of dabigatran; at the time of writing, no specific reversal agent for rivaroxaban and apixaban available.
• Not suitable for prosthetic heart valves or in those with moderate-to-severe renal failure.
• Authority prescription required.
• Possible increase in incidence of GI bleeding.

 

Contraindications listed in the NOAC product information sheets

Contraindication	Apixaban	Dabigatran	Rivaroxaban
Renal	CrCl < 25 mL/min	CrCl < 30 mL/min	Undergoing dialysisCrCl < 30 mL/min (15 mg and 20 mg tablets)CrCl < 15 mL/min (10 mg tablets)
Hepatic	Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including severe hepatic impairment (Child-Pugh C)	Hepatic impairment or liver disease expected to have any impact on survival Manufacturer also contraindicates use if liver enzymes > 2 x ULN	Significant hepatic disease (including Child-Pugh B and C), which is associated with coagulopathy leading to a clinically relevant bleeding risk
Bleed-related	Spontaneous or pharmacological impairment of haemostasis Clinically significant active bleeding Lesion or condition at significant risk of major bleeding	Haemorrhagic manifestations, bleeding diathesis, or spontaneous or pharmacological impairment of haemostasis Lesion or condition, if considered a significant risk factor for major bleeding History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding GI haemorrhage within the past year unless the cause has been permanently eliminated Conditions associated with increased risk of bleeding	Clinically significant active bleeding Lesions at increased risk of clinically significant spontaneous impairment of haemostasis
Concomitant medicines	Strong inhibitors of both CYP3A4 and P-gp (eg, ketoconazole, ritonavir) Other anticoagulants	Systemic ketoconazole, ciclosporin, itraconazole Other anticoagulants	Strong inhibitors of both CYP3A4 and P-gp (eg, azole antifungals, ritonavir) Other anticoagulants not recommended (precaution)

Risk factors for developing stroke

Risk factors for developing stroke or SE (ischaemic) specified by the PBS are listed below. They are the same for apixaban, dabigatran and rivaroxaban

• Prior stroke (ischaemic or unknown type), transient ischaemic attack or non-central nervous system SE
• Age ≥ 75 years
• Hypertension
• Diabetes mellitus
• Heart failure and/or left ventricular ejection fraction ≤ 35%

 

Reversal of NOACs

• NOAC Guidelines: Management of NOAC associated bleeding (CEC, July 2017).
• Tran, H. et al. (2014) New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural / bleeding management, Internal Medicine Journal, vol. 44, pp. 525-36.

General principles for reversal

• Organise urgent FBC, group and hold, creatinine.
• Send coagulation profile, including relevant levels (dabigatran level, aPTT, TT, prothrombin time and/or anti-Xa level).
• Withhold further doses of anticoagulant.
• For ingestion within 2 hours: activated charcoal.
• Early haematology consultation.
• Recombinant factor VIIa (NovoSeven® RT) is no longer recommended but other pro-haemostatic agents may be considered in consultation with haematology for life-threatening bleeding (significant risk of thrombotic complications).

Dabigatran reversal

• Consider idarucizumab (Praxbind) – study dose: 5 g IV as a single dose (Pollack, 2015).

Give as 2 consecutive IV infusions of 2.5 g over 5–10 minutes each OR as 2 consecutive 2.5 g bolus injections

• Consider dialysis in patients treated with dabigatran who have life-threatening bleeding and:
  • Renal impairment, or
  • aPTT >80 seconds or a dabigatran level >500 mg/mL.
• Idarucizumab: Reversing the effects of Dabigatran (CEC Factsheet, August 2016).

Rivaroxaban / Apixaban reversal

• For life-threatening bleeding or emergency surgery, consider the use of prothrombin complex concentrate (Prothrombinex®-VF) in consultation with haematology (risk of thrombotic complications). It has been shown to normalise prothrombin time in a trial of 12 healthy male subjects at a dose of 50 IU/kg (administered as a slow IV injection) (Eerenberg et al., 2011).
• Rivaroxaban and apixaban are highly protein-bound and hence NOT dialysable.