New Oral Anticoagulants (NOACs)

Clinical Summary
	Dabigatran (Pradaxa)	Rivaroxaban (Xarelto)	Apixaban (Eliquis)
Dose	150mg bd (standard) 110mg bd If CrCl 30-50 OR Age >75	20mg once daily (standard) 15mg daily If CrCl 30-50	5mg bd 2.5 mg bd If 2 of: - Weight <60 kg - Age >80 years - Serum Cr >133 umol/L
Pregnancy and breastfeeding	Cat C (limited data) Not recommended	Cat C (limited data) Not recommended	Cat C (limited data) Not recommended
Caution/CI	CrCl <30 Liver enzymes >2ULN Ketaconazole Verapamil	CrCl <30 Azoles	CrCl <25 Severe liver disease
Adverse		peripheral oedema, itch, skin blisters, muscle spasm	Nausea Abnormal LFTs Thrombocytopaenia
Pack (see PBS Criteria)	60tabs 5rpts (for both sizes)	28tabs, 5rpts	60tabs, 5rpts
	Dabigatran (Pradaxa)	Rivaroxaban (Xarelto)	Apixaban (Eliquis)
Tmax	2h	2.5-4h	1-3h
T1/2	12-17h	5-9h 11-13h elderly	8-15h
Metabolism	P-gp	P-gp CYP3A4 CYP 2J2	P-gp CYP3A/5 Many minor CYPs
Use after stroke Disabling Any	>6months >14days	>3months >14days	? >7days
Measuring anticoagulation effect
	Dabigatran (Pradaxa)	Rivaroxaban (Xarelto)	Apixaban (Eliquis)
INR/PT	Insensitive	PT elevated - but highly variable result INR not useful	No clear data
APTT	Somewhat sensitive (may underestimate high levels)	Prolonged in dose dependent manner, less sensitive than PT	Insensitive
Thrombin time (TT)	Oversensitive (need special kit)	Insensitive	Insensitive
Significant anticoagulant effect unlikely	APTT and TT normal	PT Normal (using sensitive reagent)	PT normal (using sensitive reagent)
Anticoagulant effect present	TT prolonged APTT prolonged	PT prolonged	PT prolonged
Drug effect likely (confirmation)	HEMOCLOT prolonged	Modified anti-Xa positive	Modified anti-Xa positive
Changing Anticoagulants
	Dabigatran (Pradaxa)	Rivaroxaban (Xarelto)	Apixaban (Eliquis)
Switching from Warfarin	Start day after INR is 2.5 or less	Start day after INR is 2.5 or less	Start day after INR is 2.5 or less
Switching to Warfarin GFR >50 GFR30-50 GFR15-30	Stop after: 3 days 2 days 1 day	Stop after: 4days 3days 2days	Stop after: 4days 3days 2days
Conversion from LMWH	Start at time next LMWH is due	Start at time next LMWH is due	Start at time next LMWH is due
Conversion from Heparin	Immediately on infusion cessation	Immediately on infusion cessation	Immediately on infusion cessation
Conversion from NOAC to LMWH/heparin	GFR >30 start after 12-48h GFR <30 start after 48h	12-24h	12-24h
NOACs and surgery
	Dabigatran (Pradaxa)	Rivaroxaban (Xarelto)	Apixaban (Eliquis)
High bleeding risk GFR >50 GFR <50	48-72h 96h	48-72h 72h	48-72h 72h
Low bleeding risk GFR >50 GFR <50	24h 48-72	24h 48h	24h 48h
Restarting after surgery:
High bleeding risk	48-72h	48-72h	48-72h
Low bleeding risk	24h	24h	24h
Pre spinal catheter	24h	24h	24h
Restarting after spinal	Not recommended	22-26h	26-30h
Time b/n spinal removal and next dose	6h	6h	6h

PBS Criteria

(for all three agents)

Streamline code: 4269

Prevention of stroke or systemic embolism

Clinical criteria:

Patient must have non-valvular atrial fibrillation,

AND

Patient must have one or more risk factors for developing stroke or systemic embolism.

Risk factors for developing stroke or systemic ischaemic embolism are:

(i) Prior stroke (ischaemic or unknown type), transient ischaemic attack or non-central nervous system (CNS) systemic embolism;

(ii) age 75 years or older;

(iii) hypertension;

(iv) diabetes mellitus;

(v) heart failure and/or left ventricular ejection fraction 35% or less.

Evidence comparison

	Dabigatran 110mg	Dabigatran 150mg	Rivaroxaban 20mg	Apixaban 5mg/2.5mg bd	Warfarin
	RE-LY		ROCKET-AF	ARISTOTLE
% stroke/TIA patients in trials			55	19
Stroke or systemic embolism RR (95% CI)	0.91 (0.74-1.11)	0.66 (0.53-0.82)	HR 0.79 (0.66-0.96)	HR 0.79 (0.66-0.95)
ARR	0.16% (1.69-1.53)	0.58% (1.69-1.11)	0.3% (2.4vs2.1%)	0.33% (1.27vs1.6%)
NNT	625	172	333	303
ICH RR	0.31 (0.2-0.47)	0.4 (0.27-0.6)	1.03 (NS)	0.42 (0.3-0.58)
ARR	0.51% (0.74-0.23)	0.44% (0.74-0.3)	0.2% (0.7vs0.5%)	0.47% 0.33vs0.8%
NNT	196	227	500 (to harm)	212
Major and clinically relevant Bleeding ARR			-0.4% (14.9 vs14.5)	1.94% 4.07vs6.01%
Major Bleeding			-0.2$ 3.6vs 3.4%	0.96% 2.13vs3.09%
GI bleeding			3.2vs2.2%	0.76vs0.86%
Net clinical benefit (ARR)	0.55% (7.64-7.09)	0.73% (7.64-6.91)		1.07% (6.13vs7.20%)
NTT	181	137		93
Death				0.42% 3.52vs3.94% NNT - 238
Cost/month Cost/year		$96 $1152		$103 $1235	$8.50 $102 (Based on 5mg/day)
	RE-LY		ROCKET-AF	ARISTOTLE
% stroke/TIA patients in trials	20		55	19
Median age	71
CHADS	2.1		3.5	2.0
Exclusion

Dabigatran

· Direct thrombin inhibitor

· Pharmacology

o 80% renal excretion

o Contraindicated if GFR <30

o If GFR 30-50 – lower dose – 110mg bd

RE-LY trial

· Trialled at high 150mg and low dose 110mg

· Similar efficacy to warfarin low dose, greater efficacy in high dose

· Major bleeding was less in low dose and equivalent to warfarin in high dose

· ICH reduced in both doses ~70%.

Subgroups:

· If the time in therapeutic range (TTR) for warfarin was >57%

o Then there was no difference in primary endpoint

o No difference in major bleeding at high dose

o Still a slightly lower risk of bleeding at lower dose

o Australian centres had avg. TTR of 74%

· Patients over 75yrs

o Greater rate of extracranial major bleeding

· Conclusions about subgroups – best for:

o Younger patients with normal renal function

o Patients or centers who have poorly controlled INRs

· Reference: Dabigatran, who benefits? Editorial Int Med Journal 42 (2012)p113

Rivaroxaban

· ROCKET AF trial

· 20mg daily vs Warfarin

· Avg CHADS 3.5

· 55% of pts had prior stroke/TIA/embolism

· >75yrs old – 31%

· Median age – 70

· Stoke –

· Major bleeding similar

Apixaban

· ARISTOTLE trial

· CHADS avg 2.0

· >75yrs old – 31%

· Median age - 70

· 19% had previous stroke/TIA/embolism

· Absolute reduction in stroke embolism 0.3%

· Absolute reduction in major bleeding of 1%