New anticoagulants for the prevention of venous thromboembolism

Figures & data

Table 1 Risk stratification for the incidence of VTE

Risk level	Distal DVT	Prox DVT	Fatal PE	DVT total	Patients	Antithrombotic prophylaxis
Low	<10%	<1%	<0.1%	<10%	Minor surgery in mobile patients (eg, arthroscopic surgery)	Prophylaxis recommended only for patients with additional risk factors
				<10%	Medical patients who are fully mobile	No prophylaxis recommended
Moderate	10%–40%	1%–10%	0.1%–1%	10%–40%	General, gynecologic, urologic surgery	LMWH, UFH or fondaparinux
				10%–40%	Medical patients, bed rest, sick	LMWH, UFH or fondaparinux recommended for acutely ill hospitalized medical patients with additional risk factors*
High	40%–80%	10%–30%	>1%	40%–80%	Hip or knee arthroplasty	LMWH, fondaparinux or adjusted-dose vitamin K antagonists
				40%–80%	Hip fracture surgery
				40%–80%	Major trauma, spinal cord injury	LMWH or UFH

* Congestive heart failure, severe respiratory disease or who are confined to bed.

Abbreviations: DVT, deep vein thrombosis; LMWH, low molecular weight heparin; prox, proximal; PE, pulmonary embolism; UFH, unfractionated heparin.

Table 2 Main features of new anticoagulants

Drug	Class	Pro-drug	Route of administration	Bioavailability	Liver metabolism	Excretion	Drug or food interaction	Half life	Laboratory monitoring	Direct	Selective	Reversible	Competitive
Rivaroxaban^Citation19^–^Citation21	anti-Xa	no	oral	80%	CYP3A4	kidney 2/3 biliary 1/3	low	9 h in young 12–16 inelderly	no	yes	yes	yes	yes
Razaxaban^Citation29	anti-Xa	no	oral	NR	NR	kidney	NR	30 m–6 h	no	yes	yes	yes	NR
Apixaban^Citation22^–^Citation24	anti-Xa	no	oral	50%–80%	CYP3A4	biliary 75% kidney 25%	low	12 h	no	yes	yes	yes	NR
LY517717^Citation28	anti-Xa	no	oral	43%–88%	no	mainly GI	NR	25 h	no	yes	yes	NR	yes
Edoxaban^Citation26	anti-Xa	NR	oral	45%	NR	NR	NR	9–11 h	no	yes	yes	NR	yes
Betrixaban^Citation25	anti-Xa	no	oral	47%	no	biliary 85% kidney 5%	minimal	20 h	no	yes	yes	yes	yes
YM150^Citation27	anti-Xa	no	oral	25%–82%	NR	NR	low	NR	no	yes	yes	NR	NR
Eribaxaban^Citation30	anti-Xa	NR	oral	NR	NR	NR	NR	NR	no	yes	yes	yes	yes
TAK442^Citation33	anti-Xa	NR	oral	NR	NR	NR	NR	NR	no	yes	NR	NR	NR
GW813893	anti-Xa	NR	oral	NR	NR	NR	NR	NR	no	NR	NR	NR	NR
Dabigatran^Citation31	anti-II	yes	oral	6.5%	3.5%–5%	kidney 80%	amiodarone, chinidine	single dose: 7–9 h multiple doses: 15 h	no	yes	yes	yes	NR
AZD0837/AVE5026^Citation32	anti-Xa anti-II	yes	sc	NR	NR	NR	NR	16–20 h	no	NR	NR	yes	yes

Abbreviations: GI, gastrointestinal; h, hours; m, minutes; NR, not reported; Plt, piastrine; sc, subcutaneous.

Table 3 Efficacy and safety results with new Xa inhibitors in different clinical indications

Trial/drug	Phase	Drug	Comparator	Indication	Primary efficacy outcome	Major bleeding definition	Results
OdiXa-knee^Citation34	II	Rivaroxaban 2.5, 5, 10, 20, 30 bid	Enoxaparin 30 mg bid	TKR	Any DVT, nonfatal PE, all cause Mortality	Standard + bleeding warranting treatment cessation or leading to reoperation	All doses showed potential efficacy; dose effect for bleeding complications
OdiXa-hip^Citation35	II	Rivaroxaban 2.5, 5, 10, 20, 30 bid	Enoxaparin 40 mg od	THR			No significant dose-response relationship for efficacy significant dose-response relationship for safety
Rivaroxaban^Citation36	II	Rivaroxaban 5,10, 20, 30, 40 mg od	Enoxaparin 40 mg od	THR
RECORD1^Citation37	III	Rivaroxaban 10 mg, 5 weeks	Enoxaparin 40 mg od 5 weeks	THR	Any VTE, all cause mortality	Fatal, involved a critical organ, or required re-operation; or clinically extra-surgical site bleeding associated with a decrease in the hemoglobin level of ≥2 g/dL or requiring infusion ≥2 units of blood	Superior efficacy of rivaroxaban similar safety
RECORD2^Citation33	III	Rivaroxaban 10 mg, 5 weeks	Enoxaparin 40 mg od 10–14 days	THR
RECORD3^Citation38	III	Rivaroxaban 10 mg, 10–14 days	Enoxaparin 40 mg od 10–14 days	TKR
RECORD4^Citation40	III	Rivaroxaban 10 mg, 10–14 days	Enoxaparin. 30 mg bid, 10–14 days	TKR
Meta-analysis RECORD^Citation41,Citation42		Rivaroxaban 10 mg	Enoxaparin 40 mg od enoxaparin 30 mg bid	THR, TKR	Symptomatic VTE, cardiovascular events, all-cause mortality and major bleeding		Superior efficacy of rivaroxaban similar safety
Razaxaban^Citation29	II	Razaxaban 25–50–75–100 mg	Enoxaparin 30 mg bid	TKR	DVT and symptomatic VTE	Major bleeding	Effective at any dosage; highest doses ... 5 associated with more bleedings
Apixaban^Citation44	II	Apixaban 5, 10, 20 mg od or bid divided dose	Enoxaparin 30 mg bid warfarin (INR 1.8–3)	TKR	Any VTE, all cause mortality	Standard + need to discontinue study medication	Effective dose effect in efficacy and safety
ADVANCE 1^Citation45	III	Apixaban 2.5 mg bid 10–14 days	Enoxaparin 30 mg bid, 10–14 days	TKR	Any VTE all cause mortality	Standard + bleeding into operated joint, requiring re-operation; intramuscular bleeding with compartment syndrome	Apixaban inferior to enoxaparin improved safety
ADVANCE 2^Citation46	III	Apixaban 2.5 mg bid	Enoxaparin 40 mg	TKR		Standard + bleeding into operated joint requiring re-operation, need to discontinue study medication; pericardial	Superior efficacy of apixaban
EXPERT^Citation47	II	Betrixaban 15/40 mg bid, 10–14 days	Enoxaparin 30 mg bid, 10–14 days	TKR	Any VTE	Fatal; involving vital organs; requiring additional surgery or a new therapeutic procedure; BI ≥ 2 and clinically significant nonmajor bleeding	Good safety and efficacy profile
Edoxaban^Citation48	II	Edoxaban 5, 15, 30, 60 mg	Placebo	TKR	Any VTE	Major and clinical relevant bleeding	Dose effect for safety and
STARTS II^Citation49	II	Edoxaban 15, 30, 60,90 mg	Dalteparin	THR		Major and clinically relevant bleeding	Dose effect for safety bleedings only with edoxaban
ONYX 1^Citation27	II	YM 150 3, 10, 30 and 60 mg	Enoxaparin 40 mg	THR	Any VTE	Standard + attributable BI ≥ 2.0 or CRNM	Safe and effective
ONIX II^Citation50	II	YM150 5, 10, 30, 60, 120 mg	Enoxaparin 40 mg	THR	DVT, symptomatic VTE, PE, death	Standard + attributable BI ≥ 2.0 or CRNM	Dose effect for efficay
LY517717^Citation28	II	LY517717 25, 50, 75, 100, 125, 150 mg	Enoxaparin 40 mg	THR TKR	Any VTE	Standard + associated with a BI ≥ 2 or required surgical intervention	Noninferiority similar safety
Eribaxaban ^Citation30	II	Eribaxaban 0.1,0.3, 0.5, 1.0, 2.5, 4.0,10 mg	Enoxaparin 30 mg bid	TKR	Any VTE	Total bleeding	Nonsignificant increase of total bleeding
TREK^Citation32	II	AVE5026 5, 10, 20, 40, 60 mg qd	Enoxaparin 40 mg	TKR	Any VTE	Standard + surgical or nonsurgical site bleeding leading to intervention; nonsurgical site overt bleeding with a BI ≥ 2	Dose effect of AVE5026 for efficacy and safety

Notes: Standard: clinically overt bleeding associated with a fall in hemoglobin >2 g/dL within 24 hours, leading to transfusion of ≥2 units of blood; fatal bleeding; bleeding into a critical organ (including retroperitoneal, intracranial, intraocular, or intraspinal bleeding).

Abbreviations: BI, bleeding index (number of blood units transfused + pre-bleeding minus post-bleeding hemoglobin (g/dL); bid, twice daily; CRNM, clinically relevant nonmajor bleeding; DVT, deep vein thrombosis; qd, four times daily; THR, total hip replacement; TKR, total knee replacement.

Table 4 Efficacy and safety results with new II inhibitors in different clinical indications

Trial/drug	Phase	Drug	Comparator	Indication	Primary efficacy outcome	Major bleeding definition	Results
BISTRO I^Citation51	II	Dabigatran 12.5, 25, 50,100,150, 200, 300 mg bid or 150, 300 mg od	No comparator	THR	Any DVT	Standard	Effective with no dose effect no major bleedings
BISTRO II^Citation52	II	Dabigatran 50,150, 225 mg bid or 300 mg od	Enoxaparin 40 mg od	THR TKR	Any VTE	Standard + surgical or nonsurgical site bleeding warranting treatment cessation or re-operation	Dose-dependent efficacy and safety VTE lower in 150, 225 mg bid and 300 mg od
RE-MODEL^Citation54	III	Dabigatran 150 or 220 mg 28–35 days	Enoxaparin 40 mg 6–10 days	TKR	Any VTE and death from all causes		Noninferiority of dabigatran similar safety
RE-MOBILIZE^Citation55	III	Dabigatran 150–220 mg 28–35 days	Enoxaparin 30 mg bid 12–15 days	TKR			Inferiority of dabigatran similar safety
RE-NOVATE^Citation53	III	Dabigatran 150–220 mg 28–35 days	Enoxaparin 40 mg 28–35 days	THR			Noninferiority of dabigatran similar safety
Dabigatran metanalysis^Citation56		Dabigatran 220 mg, 150 mg	Enoxaparin 40 mg Enoxaparin 30 mg	TKR THR	Any VTE and death from all causes		Noninferior to enoxaparin 40 mg Similar safety

Notes: Standard: clinically overt bleeding associated with a fall in hemoglobin >2 g/dL within 24 hours, leading to transfusion of ≥2 units of blood; fatal bleeding; bleeding into a critical organ (including retroperitoneal, intracranial, intraocular, or intraspinal bleeding).

Abbreviations: THR, total hip replacement; TKR, total knee replacement; VTE, venous thromboembolism.

Table 5 Ongoing phase II and III studies

Drug	Dose	Comparator	Duration of therapy	Phase	Indication
Apixaban	2.5 mg bid	Enoxaparin 40 mg	35 days	III	THR
YM 150	NR	Enoxaparin	NR	II III	THR (ONIX3)
YM 150	NR	Enoxaparin	NR	II	TKR (PEARL1)
YM 150	NR	Enoxaparin	NR	II III	TKR
YM 150	NR	Warfarin	NR	II	TKR (PEARL)
YM 150	NR	NR	NR	II III	THR
YM 150	NR	NR	NR	III	Hip fracture, lower extremities surgery
TAK442	10–20–40–80 mg bid or 40–80 mg od	Enoxaparin	NR	II	TKR
GW813893	NR	NR	NR		TKR
AVE5026	20 mg	Enoxaparin	7 to 10 days	III	TKR (SAVE KNEE)
AVE5026	NR	Enoxaparin	7 to 10 days	III	THR (SAVE-HIP 1)
AVE5026	NR	Enoxaparin 40 mg	7 to 10 days	III	Hip fracture surgery (SAVE-HIP 2)
Dabigatran	110 mg followed by 220 mg od	Enoxaparin 40 mg	28–35 days	III	THR (RE-NOVATE II)
AVE5026	NR	Enoxaparin 40 mg	NR	III	Major abdominal surgery
YM 150	NR	Mechanical prophylaxis	NR	III	Major abdominal surgery
Apixaban	5 mg od	Placebo	12 week	II	Metastatic cancer
AVE5026	NR	Placebo	NR	III	Cancer and chemotherapy (SAVE ONCO)
Rivaroxaban	10 mg	Enoxaparin 40 mg	31–39 days enoxaparin 6–14 days	III	Medical ill patients (MAGELLAN)
Apixaban	2.5 mg bid	Enoxaparin 40 mg	Apixaban 30 days vs enoxaparin 14 days	II	Medical ill patients (ADOPT)
AVE5026	NR	Enoxaparin	NR	III	Medical ill patients with restricted mobility

Abbreviations: bid, twice daily; NR, not reported (the studies have been described according to data reported on the web, www.clinicaltrials.gov); od, once daily.

KubitzaDBeckaMWensingGVoithBZuehlsdorfMSafety, pharmacodynamics and pharmacokinetics of BAY 59-7939, an oral, direct, Factor Xa inhibitor after multiple dosing in healthy male subjectsEur J Clin Pharmacol20056187388016328318

 PubMed Web of Science ®Google Scholar

WeinzCSchwartzTPleissJMetabolism and distribution of BAY 59-7939 – an oral, direct factor Xa inhibitor - in rat, dog and humanDrug Metab Rev200436196

 Web of Science ®Google Scholar

LassenMDavidsonBGallusAA Phase II randomized double blind, five-arm, parallel group, dose response study of a new oral acting Factor Xa inhibitor, razaxaban, for the prevention of deep vein thrombosis in knee replacement surgeryBlood200310215

 Web of Science ®Google Scholar

SpyropoulosACBrave new world: The current and future use of novel anticoagulantsThrombosis Research200812329S35S

 Web of Science ®Google Scholar

KanHBingHGraceJEPreclinical pharmacokinetics and metabolism of apixaban, a potent and selective factor Xa inhibitorBlood2006108273

 Web of Science ®Google Scholar

AgnelliGHaasSGinsbergJKruegerKDmitrienkoABrandtJA phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacementJ Thromb Haemost2007574675317408408

 PubMed Web of Science ®Google Scholar

ZafarMVorcheimerDGaztanagaJAntithombotic effects of factor Xa inhibition with DU-176b: Phase I study of an oral direct factor Xa inhibitor using an ex-vivo flow chamberThromb Haemost20079888388817938815

 PubMed Web of Science ®Google Scholar

TurpieAGGNew oral anticoagulants in atrial fibrillationEur Heart J20082915516518096568

 PubMed Web of Science ®Google Scholar

ErikssonBTurpieALassenMA dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacementJ Thromb Haemost200751660166517663737

 PubMed Web of Science ®Google Scholar

CohenAArmstrongDGazdzikTAn adaptative-design doseranging study of PD 0348292, a new oral factor Xa inhibitor, for the prophylaxis after total knee replacement surgeryBlood2008112 Abstr 980

 Google Scholar

PerzbornEFactor Xa inhibitors. New anticoagulants for secondary haemostasisHamostaseologie20092926026719644596

 PubMedGoogle Scholar

StangierJRathgenKStahleHGansserDRothWThe pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjectsBr J Clin Pharmacol20076429230317506785

 PubMed Web of Science ®Google Scholar

LassenMDahlOMismettiPDestréeDTurpieAGAVE5026, a new hemisynthetic ultra-low-molecular-weight heparin for the prevention of venous thromboembolism in patients after total knee replacement surgery-TREK: A dose-ranging studyJ Thromb Haemost2009756657219187076

 PubMed Web of Science ®Google Scholar

TurpieAFisherWBauerKBAY 59-7939: An oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging studyJ Thromb Haemost200532479248616241946

 PubMed Web of Science ®Google Scholar

ErikssonBIBorrisLDahlOEOral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacementJ Thromb Haemost2006412112816409461

 PubMed Web of Science ®Google Scholar

ErikssonBIBorrisLDahlOEA once-daily oral, direct Factor Xa inhibitor, Rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacementCirculation20061142374238117116766

 PubMed Web of Science ®Google Scholar

ErikssonBIBorrisLCFriedmanRJRivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplastyN Engl J Med20083582765277518579811

 PubMed Web of Science ®Google Scholar

LassenMRAgenoWBorrisLCRivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplastyN Engl J Med200835826

 Web of Science ®Google Scholar

TurpieALassenMDavidsonBRivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD 4): A randomized trialLancet20093731673168019411100

 PubMed Web of Science ®Google Scholar

BauerKATurpieAGGLassenMRKakkarAKErikssonBIGentMEffect on age, weight, gender and renal function in a pooled analysis of four rivaroxaban studies. [abstract]J Thromb Haemost2009

 Google Scholar

TurpieAGGLassenMRKakkarAKErikssonBIGentMPooled analysis of four rivaroxaban studies: effects on symptomatic events and bleeding. [abstract]Blood2008San Francisco CA

 Google Scholar

LassenMRDavidsonBLGallusAPineoGAnsellJDeitchmanDThe efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacementJ Thromb Haemost200752368237517868430

 PubMed Web of Science ®Google Scholar

LassenMRRaskobGEGallusAPineoGChenDPortmanRJApixaban or enoxaparin for thromboprophylaxis after knee replacementN Engl J Med200936159460419657123

 PubMed Web of Science ®Google Scholar

LassenMGallusAPineoGRaskobGThe advance-2 study: A randomized double-blind trial comparing apixaban with enoxaparin for thromboprophylaxis after total knee replacement. [abstract]J Thromb Haemost2009

 Google Scholar

TurpieABauerKDavidsonBA randomized evaluation of betrixaban, an oral factor Xa inhibitor for prevention of thrombolic events after total knee replacement (EXPERT)Thromb Haemost2009101687619132191

 PubMed Web of Science ®Google Scholar

FujiTFujitaSTachibanaSRandomized, double-blind, multidose efficacy, safety and biomarker study of the oral factor Xa inhibitor DU-176b compared with placebo for prevention of venous thromboembolism in patients after total knee arthroplastyBlood20081123418436740

 PubMed Web of Science ®Google Scholar

RaskobGCohenAErikssonBRandomized double-blind multidose trial of the oral factor Xa inhibitor DU-176b versus LMW heparin (dalteparin) for prevention of venous thromboembolism after total hip replacementEur Heart J20082960918310671

 PubMed Web of Science ®Google Scholar

ErikssonBITurpieAGLassenMRPrevention of venous thromboembolism with an oral Factor Xa inhibitor, YM150, after total hip arthroplasy. A dose-finding study (ONYX-2)J Thromb Haemost2010 Epub ahead of print. Blood. 2007;110:A309

 Web of Science ®Google Scholar

ErikssonBIDahlOEAhnfeltLKäleboPDose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO IThromb Haemost2004215731580

 Web of Science ®Google Scholar

ErikssonBIDahlOEBüllerHRHettiarachchiRA new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: The BISTRO II randomized trialJ Thromb Haemost2005310311115634273

 PubMed Web of Science ®Google Scholar

ErikssonBIDahlOERosencherNDabigatran etexilate versus enoxaparin for the prevention of venous thromboembolism after total knee replacement: The RE-MODEL randomized trialJ Thromb Haemost200752178218517764540

 PubMed Web of Science ®Google Scholar

The RE-MOBILIZE Writing CommitteeOral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regime for prevention of venous thromboembolism after knee arthroplasty surgeryThe Journal of Arthroplasty2009241

 Web of Science ®Google Scholar

ErikssonBIDahlOERosencherNDabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: A randomised, double-blind, non-inferiority trialLancet200737094995617869635

 PubMed Web of Science ®Google Scholar

WolowaczSERoskellNSPlumbJMCapriniJAErikssonBIEfficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysisThromb Haemost2009101778519132192

 PubMed Web of Science ®Google Scholar