Role of novel oral anticoagulants in the management and prevention of venous thromboembolism

Table 1 Comparative pharmacology of novel oral anticoagulants

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Target	IIa (thrombin)	Xa	Xa	Xa
Bioavailability	8%	66% without food	50%	62%
		100% with food
Time to peak level (h)	1.25-3	2-4	1-4	1-2
Half life (h)	12-17	5-9 young	12	9-11
		11-13 elderly
Trough	12-24	16-24	12-24	12-24
Drug interactions	Proton pump inhibitors	Potent CYP3A4 and P- glycoprotein inhibitors	Potent CYP3A4 and P- glycoprotein inhibitors	P- glycoprotein inhibitors
Renal excretion	80%	35%	25%	50%
Coagulation test effect	aPPT > 2 × ULN at trough → increased bleeding	Prolonged PT may indicate excess bleeding risk but local calibration required	PT and aPTT prolonged but no known relation to bleeding risk	PT and aPTT prolonged but no known relation to bleeding risk
	dTT at trough > 200 ng/mL or > 65 s → excess bleeding	Anti-FXa chromogenic assays: quantitative but no data on threshold values for bleeding or thrombosis	Anti-FXa chromogenic assays: quantitative but no data on threshold values for bleeding or thrombosis	Anti-FXa chromogenic assays: quantitative but no data on threshold values for bleeding or thrombosis

dTT: Diluted thrombin test.

Table 2 Phase 3 novel oral anticoagulant trials

	RECOVER and RECOVER II	EINSTEIN DVT	EINSTEIN PE	AMPLIFY	Hokusai VTE
Drug	Dabigatran	Rivaroxaban	Rivaroxaban	Apixaban	Edoxaban
N	5128	3449	4832	5395	8240
Indication	VTE	DVT	PE	VTE	VTE
Heparin bridge	Yes	No	No	No	Yes
Duration (mo)	6	3, 6, 12	3, 6, 12	6	3, 6, 12

DVT: Deep vein thrombosis; PE: Pulmonary embolism; VTE: Venous thromboembolism.

Table 3 Efficacy and safety

	Incidence of recurrent VTE			Incidence of major bleeding
	NOAC	Warfarin	HR (95%CI)	NOAC	Warfarin	HR (95%CI)
RE-COVER	2.4%	2.1%	1.10 (0.65-1.84)	1.6%	1.9%	0.82 (0.45-1.48)
RE-COVER II	2.3%	2.2%	1.08 (0.45-1.48)	1.2%	1.9%	0.69 (0.36-1.32)
RE-MEDY1	1.8%	1.3%	1.44 (0.78-2.64)	0.9%	1.8%	0.52 (0.27-1.02)
EINSTEIN DVT	2.1%	3.0%	0.68 (0.45-1.48)	0.8%	1.2%	0.65 (0.33-1.30)
EINSTEIN PE	2.1%	1.8%	1.12 (0.75-1.68)	1.1%	2.2%	0.49 (0.31-0.79)
AMPLIFY	2.3%	2.7%	0.84 (0.60-1.18)	0.6%	1.8%	0.31 (0.17-0.55)
HOKUSAI-VTE	3.2%	3.5%	0.89 (0.70-1.13)	1.4%	1.6%	0.84 (0.59-1.21)

¹Extended treatment study. NOAC: Novel oral anticoagulant; DVT: Deep vein thrombosis; PE: Pulmonary embolism; VTE: Venous thromboembolism.

Table 4 Practical guide to use

When considering the use of a NOAC, there are important steps that should be considered:

(1) Consideration as to whether anticoagulation is necessary

Does the patient have a confirmed indication for anticoagulation?

Did the patient have a transient risk factor for VTE that has resolved or did they have an unprovoked VTE and should be considered for extended treatment?

(2) Consideration as to whether a NOAC is the most appropriate choice

Does the patient have normal renal and liver function?

Does the patient have an underlying malignancy for which LMWH may be a more appropriate alternative?

(3) Review of any other medications that may be contra-indicated or pose unfavourable drug-drug interactions

Potent inhibitors: ketoconazole, itraconazole, voriconazole, posaconazole

Potent inducers: rifampicin, carbamazepine, phenytoin, phenobarbital, HIV protease inhibitors

(4) Education regarding the importance of compliance and bleeding risk

Due to the short half life, there is a rapid decline in protective anticoagulation

(5) Regular follow-up to assess:

Therapy adherence

Potential thromboembolic event

Any adverse events

Bleeding events

Co-medications

Blood tests for haemoglobin, renal and hepatic function

(6) Assessment to determine whether ongoing anticoagulation is necessary and beneficial

NOAC: Novel oral anticoagulant; LMWH: Low molecular weight heparin; HIV: Human immunodeficiency virus; VTE: Venous thromboembolism.