Old and new anticoagulant drugs: A minireview

Figures & data

Table I. Comparative advantages and disadvantages of traditional anticoagulant and corresponding clinical consequences.

Comparative advantage or disadvantage	Consequence
LMWH versus UH:
Better bioavailability	Subcutaneous administration
Less binding to endothelium	Longer half-life, which permits once-daily administration
Less binding to plasma proteins	More predictable anticoagulant response, which obviates need for monitoring
Less binding to platelet factor 4	Lower risk of thrombocytopenia
Less binding to bone cells	Lower risk of osteoporosis
Protamine sulphate less effective as antidote	Less rapid reversal in case of overdose and/or bleeding complications
Fondaparinux versus LMWH :
Improved safety	No risk of biological contamination; lower risk of thrombocytopenia and osteoporosis
Defined target	Single target (factor Xa) versus multiple targets
Less potent inhibition of factor Xa than heparin	Risk of catheter thrombosis in acute coronary syndromes, unless supplemental heparin is administered
Vitamin K antagonists versus LMWH and fondaparinux:
Oral administration	Easier outpatient treatment
Interaction with food, drugs and genetic polymorphisms	Need of regular laboratory control for dose adjustment
Longer plasma half-life	Less rapid reversal in case of overdose and/or bleeding complication

LMWH = low-molecular-weight heparins; UH = unfractionated heparin.

Figure 1. Mechanism of interaction between coagulation factors and corresponding active enzymes (solid lines) and drugs inhibiting enzymatic activity (broken lines).

Table II. Pharmacokinetic and pharmacodynamic characteristics of new and traditional anticoagulants.

	UH	Warfarin	LMWHs	Fondaparinux	Rivaroxaban	Dabigatran
Target	Factor Xa and thrombin	All vitamin-K-dependent coagulation factors and inhibitors	Factor Xa and thrombin	Factor Xa	Factor Xa	Thrombin
Administration	Subcutaneous	Oral	Subcutaneous	Subcutaneous	Oral	Oral
Antidote	Yes	Yes	Partial	No	No	No
Source	Biological	Synthetic	Biological	Synthetic	Synthetic	Synthetic
Bioavailability (%)	30	90	90	100	60–80	4–10
Degree of renal excretion	Low	Low	High	High	High	High
Half-life (hours)	1	15–44	4	17	6–9	14–17
Rate of thrombocytopenia	<5%	No	<1%	?	No	No

Table III. Dabigatran etexilate for thromboprophylaxis in major orthopedic surgery: results of the phase III trials.

				Primary efficacy outcome^a			Primary safety outcome^b
Study (ref.)	Patients	Surgery	Study arms	Enoxaparin	Dabigatran 150 mg (P)	Dabigatran 220 mg (P)	Enoxaparin	Dabigatran 150 mg (P)	Dabigatran 220 mg (P)
RE-NOVATE (28)	3494	Hip arthroplasty	Enoxaparin 40 mg o.d., 28–35 days	6.7%	8.6%	6.0%	1.6%	1.3%	2.0%
			Dabigatran etexilate 150 mg o.d., 28–35 days		(<0.0001)^c	(<0.0001)^c		(0.60)	(0.44)
			Dabigatran etexilate 220 mg o.d., 28–35 days
RE-MODEL (29)	2076	Knee arthroplasty	Enoxaparin 40 mg o.d., 6–10 days	37.7%	40.5%	36.4%	1.3%	1.3%	1.5%
			Dabigatran etexilate 150 mg o.d., 6–10 days		(0.017)^c	(0.0003)^c		(–)	(0.82)
			Dabigatran etexilate 220 mg o.d., 6–10 days
RE-MOBILIZE (30)	2715	Knee arthroplasty	Enoxaparin 30 mg b.i.d., 12–15 days	25.3%	33.7%	31.7%	1.4%	0.6%	0.6%
			Dabigatran etexilate 150 mg b.i.d., 12–15 days		(0.0009)^d	(0.02)^d		(NA)	(NA)
			Dabigatran etexilate 220 mg b.i.d., 12–15 days

o.d. = once daily; b.i.d. = twice daily; NA = not available.

^aComposite of total (venographic and symptomatic) VTE and death from all causes.

^bIncidence of major bleeding on treatment.

^cNon-inferior to enoxaparin.

^dInferior to enoxaparin.

Table IV. Rivaroxaban for thromboprophylaxis in major orthopedic surgery: results of the phase III trials.

				Primary efficacy outcome^a			Primary safety outcome^b
Study (ref.)	Patients (n)	Surgery	Study arms	Rivaroxaban	Enoxaparin	P	Rivaroxaban	Enoxaparin	P
RECORD 1 (31)	4541	Hip arthroplasty	Rivaroxaban 10 mg o.d. 5 weeks	1.1%	3.7%	<0.001	0.3%	0.1%	0.18
			Enoxaparin 40 mg o.d. 5 weeks
RECORD 2 (32)	2509	Hip arthroplasty	Rivaroxaban 10 mg o.d. 5 weeks	2.0%	9.3%	<0.001	0.1%	0.1%	–
			Enoxaparin 40 mg o.d. 10–14 days
RECORD 3 (33)	2531	Knee arthroplasty	Rivaroxaban 10 mg o.d. 10–14 days	9.6%	18.9	<0.001	0.6%	0.5%	0.77
			Enoxaparin 40 mg o.d. 10–14 days
RECORD 4 (34)	2300	Knee arthroplasty	Rivaroxaban 10 mg o.d. 10–14 days	6.9%	10.1%	0.012	0.7%	0.3%	0.11
			Enoxaparin 30 mg b.i.d. 10–14 days

o.d. = once daily; b.i.d. = twice daily.

^aComposite of total VTE (any DVT, non-fatal PE) and death from all causes up to the end of treatment period.

^bIncidence of major bleeding on treatment.

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