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Review © Schattauer 2011 21

Old and new anticoagulants

U. Harbrecht
Institute of Experimental Haematology and Transfusion Medicine and Rheinische Friedrich Wilhelms Universität, Bonn,

Keywords and VKA at comparable safety outcomes. Limi- Zukunft die häufigen und belastenden INR-
Vitamin K antagonists, heparins, direct oral tations of the new substances may arise from Kontrollen nicht mehr zu benötigen.
thrombin inhibitors, factor Xa inhibitors, gastrointestinal side effects, mode of metab- Diese Übersichtsarbeit fasst die Entwicklung
clinical trials olism and route of elimination. Specific anti- und das Profil der neuen Substanzen zusam-
dots are not available for none of them. men. Ihr wesentlicher Unterschied im Ver-
Summary Undoubtedly, the new oral anticoagulants are gleich zu den VKA besteht darin, dass sie di-
Vitamin-K-antagonists (VKA) and heparins very promising. But, although thousands of rekt gegen einen einzelnen Gerinnungsfaktor
have been complementary anticoagulants for study patients already have been treated, there gerichtet sind, Faktor IIa (Thrombin) im Falle
prevention and treatment of thrombosis for are questions to be answered such as treat- von Dabitgatran und Faktor Xa bei Rivaroxa-
almost 70 years. In contrast to heparins, VKA ment adherence in absence of monitoring, ban und anderen „Xabanen“, die derzeit in-
have not been modified pharmacologically, safety and efficacy in risk patients, dosage ad- vensiv untersucht werden. Die Halbwertzei-
however treatment surveillance has improved justment and interactions with other drugs, be- ten der neuen Antikoagulanzien sind wesent-
by introducing INR and self-monitoring/man- fore conclusions can be drawn towards their lich kürzer als die der überwiegend verwende-
agement. Disclosure of the molecular basis of potential to replace VKA. ten VKA (Phenprocoumon, Warfarin), womit
interaction with VKORC1, the target enzyme ein „Antikoagulations-Bridging“ z. B. präope-
of VKA, has helped to better understand cou- rativ unnötig würde. Die therapeutische Brei-
marin sensitivity and resistance. New oral Schlüsselwörter te von Thrombin- und Faktor-Xa-Inhibitoren
anticoagulants have now been approved and Vitamin-K-Antagonisten, Heparine, direkte ist größer und sie werden in fixer Dosierung
stimulated expectations in patients and phys- orale Thrombininhibitoren, Faktor-Xa-Inhibito- appliziert. Klinische Studien aus den Berei-
icians to get rid of the burdening frequent ren, klinische Studien chen Thromboseprophylaxe, Therapie von
controls of VKA without loss of efficacy and Thromboembolien und Vorhoffflimmern wei-
safety. Zusammenfassung sen zumindest Nicht-Unterlegenheit, wenn
This review will summarize the development Vitamin-K-Antagonisten (VKA) und Heparine
nicht sogar bessere Effektivität im Vergleich
and profile of the new substances. Main dif- waren fast 70 Jahre lang komplementäre Anti-
zu Enoxaparin und VKA nach, bei vergleichba-
ference compared to VKA is their direct mode koagulanzien für die Prävention und Therapie
ren Sicherheitsendpunkten. Limitierungen der
of action against one clotting factor which is von Thrombosen. Im Gegensatz zu den Hepari-
neuen Substanzen könnten sich auf Grund
factor IIa in dabigatran and factor Xa in rivar- nen wurden die VKA pharmakologisch nicht
gastrointestinaler Nebenwirkungen, Art der
oxaban and other “xabanes” currently under verändert, aber die Möglichkeiten der Thera-
Metabolisierung und dem Eliminierung erge-
intensive investigation. Half lifes of the new pieüberwachung verbesserten sich mit Einfüh-
ben. Ein spezifisches Antidot steht für keine
anticoagulants are much shorter than that of rung des INR-Bestimmung und des Selbstmoni-
der Substanzen zur Verfügung.
the mainly used coumarins (phenprocoumon, torings. Die Entdeckung der molekularen
Unzweifelhaft sind die neuen oralen Anti-
warfarin), making “anticoagulation bridging” Grundlagen des Vitamin-K-Epoxid-Reduktase-
koagulanzien sehr vielversprechend. Dennoch
unnecessary before surgery. Therapeutic Komplexes (VKORC1), dem Schlüsselenzym der
bleiben offene Fragen, obwohl schon tausen-
width of direct thrombin inhibitors and factor Interaktion mit VKA, hat das Verständnis für
de von Patienten unter Studienbedingungen
Xa inhibitors is broader and they are given at Phänomene wie Cumarinsensitivität und -re-
behandelt wurden, z. B. die nach der Therapie-
fixed doses. Clinical studies in thrombopro- sistenz entscheidend erweitert. Neue Substan-
adhärenz bei nicht mehr erfolgendem Moni-
phylaxis, thromboembolism and atrial fibril- zen wurden mittlerweile entwickelt und zuge-
toring, Effektivität und Sicherheit bei Risiko-
lation indicate at least non-inferiority or even lassen. Sie haben sowohl bei Patienten als auch
patienten sowie Dosisanpassung und Inter-
superior efficacy compared with enoxaparin Ärzten große Erwartungen geweckt, in naher
aktion mit anderen Medikamenten. Erst nach
deren Beantwortung wird eine abschließende
Bewertung möglich sein, ob die neuen Sub-
Correspondence to: Alte und neue Antikoagulanzien stanzen geeignet sind, die Vitamin-K-Antago-
Ursula Harbrecht, MD Hämostaseologie 2011; 31: 21–27 nisten zu ersetzen.
Institute of Experimental Haematology and Transfusion doi:10.5482/ha-1149
Medicine, University of Bonn
Sigmund-Freud-Str. 25, 53105 Bonn, Germany
Tel. +49/(0)228/287 67 28, Fax +49/(0)228/287 60 87

Hämostaseologie 1/2011
22 U. Harbrecht: Old and new anticoagulants

In 2010, an estimated number of one mil- IIa) and factor Xa requiring antithrombin one clotting factor. In contrast to heparins
lion patients (according to patient net- as cofactor. and fondaparinux their effect is indepen-
works) were treated with oral anticoagu- Further development of unfractionated dent of antithrombin. They are binding se-
lants in Germany due to heparin (UFH) by shortening the glycos- lectively and with high affinity to the active
● atrial fibrillation, aminoglycan chain resulted in low-molec- site of the enzyme, thereby competitively
● deep vein thrombosis, ular-weight heparin (LMWH) with higher inhibiting the turnover of the natural sub-
● pulmonary embolism, bioavalability and therefore better pre- strates. Reversible binding to the enzymes
● heart valve prosthesis, dictability of effect and without need of is thought to be important for lowering the
● few other indications. routine monitoring. Longer half-life of bleeding risk. Whether factor IIa or factor
LMWH (2–4 hours after single s.c. injec- Xa inhibitors are better remains to be inves-
Another estimated one million patients tion) allow once daily injection for throm- tigated. Prinicple of factor Xa inhibition is
with atrial fibrillation is supposed to bene- boprophylaxis or twice daily for treatment reduction of thrombin burst in the propa-
fit from antithrombotic therapy. For many of thrombosis (3). gation phase of coagulation, an approach
decades vitamin K antagonists (VKA) have Long-term anticoagulation is still done with a straightforward effect. Inhibition of
been the only choice for long-term treat- by VKA, which are therapeutically used thrombin itself, which is the key enzyme in
ment (1, 2). After more than 30 years of re- coumarins, acting indirectly by inhibition the coagulation cascade with many other
search new substances such as direct of carboxylation of the vitamin K depend- functions such as platelet activation, inter-
thrombin inhibitors and direct factor Xa ent factors II, VII, IX and X and proteins C, action with fibrinolysis, inflammatory pro-
inhibitors have been designed and more S and Z, thereby abolishing their potential cesses, and cell proliferation is less predict-
and more of them are approved. The prin- to be activated on phospholipid surfaces able as it may affect all properties of throm-
ciple expectation of patients and physicians after calcium-dependent binding. Car- bin, however, this pleotropic effect may
is focussed on long term treatment with boxylation does not take place because vit- provide advantages, too (10).
these substances instead of VKA which amin K is needed in this reaction and VKA
hopefully would relief them from the inhibit regeneration of vitamin K by inter-
burden of frequent INR-controls and fear fering with vitamin K epoxide reductase Direct thrombin inhibitors
of bleeding due to the narrow therapeutic (VKOR).
window of VKA. The gene was discovered in 2004 and en- Direct thrombin inhibitors (DTI) selec-
This short review will summarize the codes several isoforms, collectively termed tively block the activity of the protease
development and profile of the new oral VKOR complex 1 (VKORC1) (4, 5). Since thrombin (soluble and fibrin-bound) re-
anticoagulants and compare them with the introduction of dicumarol in 1941 in the sulting in inhibition of fibrin generation
old agents in terms of pharmacology, US and phenprocoumon (Marcumar®) and thrombus formation. DTI were in-
mechanism of action, efficacy and safety. 1954 in Germany these compounds have itially only available for parenteral use, later
An overview of the relevant clinical trials not been altered pharmacologically. How- followed by orally applicable substances.
will be given together with a careful projec- ever, much has been done to improve treat- Development was accompanied by severe
tion of what we might expect in future. ment surveillance. Increasing knowledge of draw backs, the most surprising was with-
mechanism of VKA-action as well as in- drawal of the first oral DTI ximelagatran
sights into interaction with foods and other (Exanta®) in 2006 due to suspected liver
Old anticoagulants drugs rendered them more predictable. In- toxicity after it had been introduced on the
troduction of INR and self-measurement/ markets in 2004 (11). Lepirudin (Reflud-
Vitamin K antagonists and heparins are monitoring and more careful and individ- an®) and argatroban (Argatra®) have been
used complementary for antithrombotic ually tailored loading doses have further in- implemented already some years ago as al-
treatment. Unfractionated heparins with creased safety (6, 7). Recognition of ternative anticoagulants in heparin-in-
their short half-life, quick onset and paren- VKORC1 as the target of VKA and sub- duced thrombocytopenia type II. Desiru-
teral mode of administration are safe and sequent disclosure of mutations and poly- din (Revasc®) is approved for thrombopro-
well controllable in thromboprophylaxis morphisms in VKORC1 as well as in phylaxis in hip and knee replacement sur-
and/or acute treatment of thrombosis. But CYP2C9 have contributed substantially to gery and bivalirudin (Angiox®) for percut-
need of frequent applications in the s.c. understand phenomena of coumarin sen- aneous coronary interventions.
route (twice to three times daily) and sitivity and resistance (8, 9).
requirement of monitoring of intravenous Dabigatran (Pradaxa®)
therapeutic doses due to considerable
intra- and interindividual variability makes Common characteristics of Dabigatran is a nonpeptide small molecule
therapy unpredictable and inappropriate new anticoagulants acting as reversible inhibitor of thrombin.
for long-term use. Heparins inhibit all ser- In contrast to factor Xa inhibitors dabigat-
ine proteases to various extents with pre- The new anticoagulants are synthetically ran is a very polar, permanently charged
dominant inhibition of thrombin (factor produced small molecules that act against hydrophilic molecule, which itself has no

Hämostaseologie 1/2011 © Schattauer 2011

U. Harbrecht: Old and new anticoagulants 23

bioavailability after oral administration. mediated conformational change of anti- be predictable across 5 to 80 mg daily inges-
Hence, a double prodrug was generated, thrombin results in reversible binding to tion. Range of mean plasma concentration
dabigatran etexilate (Pradaxa®), by ma- factor Xa with 700-fold higher affinity was 12 to 201 ng/ml after daily intake of 5 to
sking the polar amidinium moiety as a car- compared to heparins. Its administration is 20 mg of rivaroxaban. Peak plasma concen-
bamate ester and by turning the carboxy- once daily subcutaneously, half-life is trations are achieved after 2 to 4 hours. Bioa-
late into an ester group which allows bio- 14–17 hours and it is exctreted renally (15). vailability is 80–100% and terminal half-life
availability of 6.5%. After resorption of the Fondaparinux is approved since 2002, of 7–11 hours is between that of LMWH and
prodrug, both polar groups of dabigatran meanwhile with a broad spectrum of indi- fondaparinux. Two third of the drug are
are restored quickly in plasma and liver by cations comparable to that of enoxaparin, metabolised, one third is excreted un-
esterase-mediated hydrolysis leading to including thromboprophylaxis, treatment changed. Two third are eliminated renally,
rapid onset of action with peak plasma of venous thrombosis, pulmonary embol- one third through faeces. Rivaroxaban is
concentrations after 1 to 2 hours after in- ism and unstable angina pectoris (16). metabolised in the liver involving cytoch-
gestion. Terminal half-life is 14–17 hours. However, like all heparins, it is dependent rome P450 (CYP3A4, CYP2J2) (17, 18). Of
Galenism of the drug was constructed with on the presence and functionality of anti- the coagulation assays it affects prothrombin
tartaric acid allowing for solubility and re- thrombin. Nevertheless, the favourable time more than aPTT and it can be moni-
sorption in an acidic milieu. This however profile and convincing outcomes in clinical tored by anti-factor-Xa assays if desired (19).
accounts for gastrointestinal side effects, trials in comparison to low-molecular-
mainly dyspepsia, and leads to reduction of weight heparins, mainly enoxaparin, has Apixaban
approximately 30% of bioavailability of da- stimulated a lot of work on factor Xa as
bigatran when combined with proton promising target for antithrombitic agents. Pharmacokinetics of apixaban have been
pump inhibitors. Dabigatran is not meta- studied in healthy human males after ad-
bolized by cytochrome P450, reveales low Rivaroxaban (Xarelto®) ministration of a single 20 mg oral dose of
interactions with other drugs and no inter- radiolabeled [14C]apixaban (20) and in
actions with foods. It is excreted renally, ap- Rivaroxaban is the first and most advanced other species including rabbits (21). Bioa-
proximately 85% as active drug (씰Tab. 1) representative of the direct oral factor Xa in- valability in humans is more than 50% and
(12, 13). hibitors with 10 000-fold higher selectivity peak plasma concentrations are reached in
for factor Xa than for other serine proteases. 3 to 4 hours (22). Other properties are sum-
It is an oxazolidininon derivate which is also marized in 씰Table 1.
Factor Xa inhibitors used in some antibiotics. Inhibition of factor
Xa is concentration-dependent and affects Edoxaban (DU-176b)
Factor Xa inhibitors can be “indirect” (e. g. prothrombinase complex-bound as well as
fondaparinux, idraparinux, idrabiotapari- clot-associated factor Xa. Pharmacokinetic Pharmacokinetics and pharmacodynamics
nux) or “direct” (e. g. rivaroxaban, apixaban, and pharmacodynamics have been shown to of edoxaban have been investigated in ani-
edoxaban) depending on the requirement of
antithrombin to exert their antithrombotic
effect. They reduce thrombin burst during Tab. 1 Pharmacological characteristics of the direct thrombin inhibitor dabigatran and the oral fac-
propagation of coagulation. Whereas fonda- tor Xa inhibitors rivaroxaban, apixaban and edoxaban
parinux was rapidly integrated into clinical
Dabigatran Rivaroxaban Apixaban Edoxaban
use and the “xabanes” have started to follow,
(Pradaxa®) (Xarelto®) (DU-176b)
idraparinux as a derivate of fondaparinux
with longer half-life (80 hours) was investi- molecular mass 628/472* 436 460 548
gated for treatment of deep vein thrombosis [g/mol]
and pulmonary embolism with a once protein binding [%] 34–35 92–95 ca. 87 ?
weekly subcutaneous administration, how- bioavailability [%] 6.5 80–100 > 50 45–50
ever it revealed increased bleeding compli- reduction by PPI 30% no no unlikely
cations and is no longer followed (14).
T(max) [h] 1–2 2–4 3–4 1–2

Fondaparinux (Arixtra®) terminal half-life [h] 14–17 7–11 10–14 9–11

metabolism ca. 20% ca. 66% (liver) ? ?
Fondarinux was the first substance of the CYP450 dependent no ca. 32% CYP3A4, CYP2J2 CYP3A4
factor Xa inhibiting group, synthetically
excretion urine ca. 85% ca. 66% ca. 25% ca. 35%
generated, further condensating the low- (active) (ca. 33% active) (ca. 22% active) (ca. 24% active)
molecular heparin structure to the essential
pentasaccharid motif, responsible for bind- faeces ca. 6% ca. 33% ca. 56% ca. 62%
ing to antithrombin. The fondaparinux- *prodrug/drug

© Schattauer 2011 Hämostaseologie 1/2011

24 U. Harbrecht: Old and new anticoagulants

mal studies (23) and in a clinical safety were randomly assigned to receive 220 mg endpoint of symptomatic VTE and all-
study in healthy volunteers. Peak plasma or 150 mg dabigatran once daily, starting 1 cause mortality in the day 12 ± 2 active
concentrations are observed after 1–2 to 4 hours with a half-dose after surgery, or treatment pool occurred in 29/6183 pa-
hours and terminal half-life is 5–6 hours. enoxaparin (40 mg once daily or 30 mg tients receiving rivaroxaban (0.5%) versus
bid), beginning the evening before surgery. 60/6200 patients receiving enoxaparin
Oral factor Xa inhibitors A pooled analysis with 6200 evaluable pa- (1.0%; p = 0.001). Major bleeding was ob-
tients revealed comparable efficacy and served in 21 (0.3%) versus 13 (0.2%) pa-
Many other substances are currently inves- bleeding outcomes. The composite out- tients, p = 0.23, major plus non-major
tigated in clinical trials such as PRT-054021 comes of major VTE (proximal deep vein clinically relevant bleeding in 176 (2.8%)
(betrixaban), eribaxaban, LY 517717, thrombosis and/or pulmonary embolism) versus 152 (2.5%) and any bleeding in 409
TAK-442, YM150. and VTE-related mortality occurred in (6.6%) versus 384 (6.2%) patients, p =
3.3% of the enoxaparin group versus 3.0% 0.38, respectively (33).
of the dabigatran 220 mg and 3.8% of the Huisman and co-workers compared En-
Clinical trials dabigatran 150 mg group (proof of non-in- oxaparin versus dabigatran and rivar-
feriority). Major bleeding occurred in 1.4 oxaban by pooling 6 phase III trials (18 405
Clinical trials are listed for the most ad- % of the enoxaparin group versus 1.4% in participants) and came to the conclusion
vanced new oral anticogulants with various the 220 mg and 1.1% in the 150 mg dabig- that enoxaparin and dabigatran show simi-
indications (씰Tab. 2) and results are pres- atran group (28). lar rates of efficacy and bleeding, whereas
ented briefly. Additionally, further pro- enoxaparin was less effective than rivar-
grams are under way concerning other in- Direct factor Xa inhibitors oxaban but had a lower risk of bleeding
dications including medically ill patients, (34).
paediatric cases, haemodialysis, elective Rivaroxaban was investigated in knee and Apixaban was assessed in knee replace-
percuteanous interventions. hip arthroplasty in the RECORD 1–4 pro- ment surgery in the ADVANCE-2 study
gram (29–32). Patients were randomly as- with 3057 patients randomly allocated to
signed to 10 mg rivaroxaban once daily be- oral apixaban 2.5 mg twice daily starting 12
Thromboprophylaxis in hip and ginning 6–8 hours after surgery or enox- to 24 hours after wound closure or
knee arthroplasty aparin (40 mg once daily or 30 mg bid), enoxaparin 40 mg once daily starting 12
starting the evening before surgery in the hours before surgery. In the recently pub-
Dabigatran 40 mg studies or beginning 12–24 hours lished analysis, 1973 patients were select-
after surgery in 2 x 30 mg study (RECORD able for primary outcome (composite of
Dabigatran was compared with enoxaparin 4). A pooled analysis of the four studies asymptomatic and symptomatic DVT,
in three phase III trials (RE-NOVATE, RE- (12 729 patients) revealed better efficacy of non-fatal PE and all-cause mortality)
MODEL, RE-MOBILIZE) including more rivaroxaban, but higher, though not signifi- which occurred in 147/976 (15%) patients
than 8000 patients (25, 26, 27). Patients cantly different, bleeding rates. Composite receiving apixaban versus 243/997 (24%)

Tab. 2 Overview of clinical trials with new oral anticoagulants for prevention and treatment of thromboembolism

substance indication
DVT-prophylaxis DVT/PE treatment ACS atrial fibrillation
Dabigatran phase III phase III phase II phase III
(Boehringer) RE-NOVATE* (25) RE-COVER* (39) RE-DEEM RE-LY* (48)
RE-MODEL* (26) RE-MEDY (40) completed completed (45)
RE-MOBILIZE* (27) RE-SONATE (41) ongoing
Rivaroxaban phase III phase III phase III phase III
(Bayer) RECORD 1–3* (29–31) EINSTEIN-DVT (42) completed ATLAS ACS TIMI 51 (46) ROCKET-AF (49)
RECORD 4* (32) EINSTEIN-PE (42) recruiting completed
EINSTEIN-Extension (42) completed
Apixaban phase III phase II phase III phase III
(Pfizer/ ADVANCE-2* (35) BOTTICELLI* (43) APPRAISE-2 (47) ARISTOTLE (51) ongoing, not recruiting
Bristol-Myers Sqibb) ADOPT ongoing (37) completed completed AVERROES (50) ongoing, not recruiting
Edoxaban phase III phase III Ø phase III
(DU-176b) STARS E-3 (38) HOKUSAI-VTE (44) ENGAGE AF TIMI 48 (52)
(Daiichi Sankyo) completed recruiting recruiting
DVT: deep vein thrombosis; PE: pulmonary embolism; ACS: acute coronary syndrome; * results of study published

Hämostaseologie 1/2011 © Schattauer 2011

U. Harbrecht: Old and new anticoagulants 25

enoxaparin (p < 0.0001). Major or clini- bleeding episodes occurred in 1.6% versus PRAISE-2 study is a placebo-controlled
cally relevant bleeding was observed in 53 1.9% in dabigatran and warfarin, respect- study, too, investigating apixaban 5 mg
(4%) of 1501 patients receiving apixaban ively. However, discontinuation of the twice daily aganist placebo additionally to
and 72 (5%) of 1508 patients treated with study drug due to adverse events, among standard care for ACS (47).
enoxaparin. The investigators conclude these diarrhoea and dyspepsia (signifi-
from the study that apixaban 2.5 mg twice cant), was more frequent in dabigatran
daily, starting on the morning after surgery, (9.0%) than in warfarin (6.8%, p = 0.05), Atrial fibrillation
offers a more effective alternative to enox- (39). RE-MEDY (40) will look at long term
aparin without increased bleeding (35). In (18 months) secundary prophylaxis after Atrial fibrillation (AF) is the predominant
a meta-analysis of patients with total knee symptomatical VTE in comparison to war- indication for long-term anticoagulation.
arthroplasty it is concluded, that apixaban farin in patients with successful initial Though it is no causal therapy, antithrom-
is non-inferior to enoxaparin when used treatment for 3 to 6 months. RE-SONATE botic treatment represents basic care for
for the same duration, but with consider- (41) is a placebo-controlled trial in patients stroke prevention. Greatest expectations
able advantage regarding safety profile with recurrent VTE who have completed 6 with the new substances are focussed on
(36). In the phase III ADOPT study apixa- to 18 months of treatment. long-term anticoagulation with hope that
ban (2.5 mg bid) is investigated for preven- they finally may replace VKA. According to
tion of thrombosis-related events in pa- Direct factor Xa inhibitors AF-guidelines, indication for anticoagu-
tients with acute medical illness during and lation in atrial fibrillation follows the
after hospitalisation in comparison to Rivaroxaban is currently investigated in CHADS2 score or the more recently pro-
enoxaparin and placebo (37). the EINSTEIN-DVT and EINSTEIN-PE posed CHA2DS2-VASc score usually recom-
Edoxaban 30 mg once daily was com- program at a dosage of 15 mg twice daily mended when ≥ 2 points are given. Among
pared in the STARS E-3 trial with enoxapa- for proof of non-inferiority compared to the new anticoagulants dabigatran is so far
rin 20mg twice daily for VTE prevention in standard treatment with LMWH/VKA. In the most intensively studied substance in at-
knee arthroplasty (38). An interim analysis the EINSTEIN-extension-study, patients of rial fibrillation. In the RE-LY study 18113
revealed DVT in 7.4% of edoxaban treated the DVT- and PE-program will be further patients had received dabigatran 110 mg or
patients versus 13.9% of patients receiving followed after 6 or 12 months of treatment 150 mg twice daily in comparison to ad-
enoxaparin. Major and clinically relevant in a placebo controlled arm receiving 20 mg justed-dose warfarin (INR 2.0–3.0). Mean
bleedings were not significantly different. once daily rivaroxaban (42). CHADS2 score was 2.1. Primary outcome
Apixaban was investigated in a dose- was stroke or systemic embolism and was
finding phase II study (BOTTICELLI- observed after a median follow up period of
Treatment of deep vein thrombosis DVT) at dosages of 5 mg twice-daily, 10 mg 2 years in 1.69% of patients treated with war-
and pulmonary embolism twice-daily or 20 mg once-daily compared farin compared to 1.53% in the group that
to LMWH followed by VKA (43). received 110 mg dabigatran (p<0.001 for
Several study programs have been initiated Edoxaban is currently under investi- non-inferiority), and 1.11% in the 150 mg
and are awaiting completion, analysis/in- gation in the phase III HOKUSAI-VTE dabigatran group (p < 0.001 for superior-
terpretation and publication (씰Tab.1). study comparing LMWH/edoxaban tosyl- ity). Major bleeding complications were not
The comparators are therapeutic doses of ate (DU-176b) with LMWH/warfarin. Ed- significantly different in warfarin compared
UFH/LMWH/fondaparinux and VKA. oxaban is given once daily 60 mg (44). to higher dose of dabigatran (3.11 vs 3.36%
per year) but were significantly lower in the
Dabigatran patients that received 110 mg dabigatran
Acute coronary syndrome (2.71%, p = 0.003). The rate of haem-
Dabigatran has already shown non-in- orrhagic stroke per year was lower with both
feriority in treatment of DVT and PE com- Dose-finding studies in patients with acute dabigatran doses (110 mg bid 0.12%; 150 mg
pared to warfarin. In the RE-COVER study coronary syndrome (ACS) have not shown bid 0.10%) as compared to warfarin (0.38%;
2564 patients with DVT (~70%), PE uniform risk reduction. In case of equal or p < 0.001). However, gastrointestinal bleeds
(~20%) or both (~10%) were randomly as- superior efficacy by trend they tended to were 50% higher (p < 0.001) in the 150 mg
signed after initial treatment with thera- have increased bleeding risks in com- dabigatran group compared to warfarin and
peutic LMWH, UFH or fondaparinux for 9 bination with single or dual anti-platelet this was related to patients >75 years and
days to receive 150 mg dabigatran twice therapy. RE-DEEM (45) evaluated 4 doses with reduced renal function. Gastrointesti-
daily or warfarin (INR 2.0–3.0) and fol- of dabigatran twice daily and placebo in ad- nal side effects, mainly dyspepsia, were more
lowed for 6 months. Primary endpoints dition to dual antiplaelet therapy. In the than twice as frequently as with dabigatran
(recurrence of thromboembolism and/or placebo controlled ATLAS-TIMI 51 study (11.8% and 11.3%) compared to warfarin
death) were observed in 30/1274 (2.4%) rivaroxaban is assessed with 2.5 mg and 5 (5.8%) and accounted for 21% of discon-
patients treated with dabigatran versus mg twice daily additionally to aspirin alone tinuation of the study drug in the dabigatran
27/1265 (2.1%) under warfarin. Major or aspirin and clopidogrel (46). The AP- group compared to 17% in warfarin (48).

© Schattauer 2011 Hämostaseologie 1/2011

26 U. Harbrecht: Old and new anticoagulants

More than 14 000 patients have been rando- 20. Raghavan N, Frost CE, Yu Z et al. Apixaban metab-
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