Antigos e Novos Anticoagulantes Schattauer

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Hmostaseologie 1/2011

21 Schattauer 2011Review

Old and new anticoagulantsU. HarbrechtInstitute of Experimental Haematology and Transfusion Medicine and Rheinische Friedrich Wilhelms Universitt, Bonn,Germany

KeywordsVitamin K antagonists, heparins, direct oralthrombin inhibitors, factor Xa inhibitors,clinical trials

SummaryVitamin-K-antagonists (VKA) and heparinshave been complementary anticoagulants forprevention and treatment of thrombosis for

almost 70 years. In contrast to heparins, VKAhave not been modified pharmacologically,however treatment surveillance has improvedby introducing INR and self-monitoring/man-agement. Disclosure of the molecular basis ofinteraction with VKORC1, the target enzymeof VKA, has helped to better understand cou-marin sensitivity and resistance. New oralanticoagulants have now been approved andstimulated expectations in patients and phys-icians to get rid of the burdening frequentcontrols of VKA without loss of efficacy andsafety.

This review will summarize the developmentand profile of the new substances. Main dif-ference compared to VKA is their direct modeof action against one clotting factor which isfactor IIa in dabigatran and factor Xa in rivar-oxaban and other xabanes currently underintensive investigation. Half lifes of the newanticoagulants are much shorter than that ofthe mainly used coumarins (phenprocoumon,warfarin), making anticoagulation bridgingunnecessary before surgery. Therapeuticwidth of direct thrombin inhibitors and factor

Xa inhibitors is broader and they are given atfixed doses. Clinical studies in thrombopro-phylaxis, thromboembolism and atrial fibril-lation indicate at least non-inferiority or evensuperior efficacy compared with enoxaparin

Correspondence to:

Ursula Harbrecht, MDInstitute of Experimental Haematology and TransfusionMedicine, University of BonnSigmund-Freud-Str. 25, 53105 Bonn, GermanyTel. +49/(0)228/287 67 28, Fax +49/(0)228/287 60 87E-mail: [email protected]

and VKA at comparable safety outcomes. Limi-tations of the new substances may arise fromgastrointestinal side effects, mode of metab-olism and route of elimination. Specific anti-dots are not available for none of them.Undoubtedly, the new oral anticoagulants arevery promising. But, although thousands ofstudy patients already have been treated, thereare questions to be answered such as treat-

ment adherence in absence of monitoring,safety and efficacy in risk patients, dosage ad-justment and interactions with other drugs, be-fore conclusions can be drawn towards theirpotential to replace VKA.

SchlsselwrterVitamin-K-Antagonisten, Heparine, direkteorale Thrombininhibitoren, Faktor-Xa-Inhibito-ren, klinische Studien

Zusammenfassung

Vitamin-K-Antagonisten (VKA) und Heparinewaren fast 70 Jahre lang komplementre Anti-koagulanzien fr die Prvention und Therapievon Thrombosen. Im Gegensatz zu den Hepari-nen wurden die VKA pharmakologisch nichtverndert, aber die Mglichkeiten der Thera-pieberwachung verbesserten sich mit Einfh-rung des INR-Bestimmung und des Selbstmoni-torings. Die Entdeckung der molekularenGrundlagen des Vitamin-K-Epoxid-Reduktase-Komplexes (VKORC1), dem Schlsselenzym derInteraktion mit VKA, hat das Verstndnis frPhnomene wie Cumarinsensitivitt und -re-sistenz entscheidend erweitert. Neue Substan-zen wurden mittlerweile entwickelt und zuge-lassen. Sie haben sowohl bei Patienten als auchrzten groe Erwartungen geweckt, in naher

Alte und neue Antikoagulanzien

Hmostaseologie 2011; 31: 2127

doi:10.5482/ha-1149

Zukunft die hufigen und belastenden INR-Kontrollen nicht mehr zu bentigen.Diese bersichtsarbeit fasst die Entwicklungund das Profil der neuen Substanzen zusam-men. Ihr wesentlicher Unterschied im Ver-gleich zu den VKA besteht darin, dass sie di-rekt gegen einen einzelnen Gerinnungsfaktorgerichtet sind, Faktor IIa (Thrombin) im Fallevon Dabitgatran und Faktor Xa bei Rivaroxa-

ban und anderen Xabanen, die derzeit in-vensiv untersucht werden. Die Halbwertzei-ten der neuen Antikoagulanzien sind wesent-lich krzer als die der berwiegend verwende-ten VKA (Phenprocoumon, Warfarin), womitein Antikoagulations-Bridging z. B. prope-rativ unntig wrde. Die therapeutische Brei-te von Thrombin- und Faktor-Xa-Inhibitorenist grer und sie werden in fixer Dosierungappliziert. Klinische Studien aus den Berei-chen Thromboseprophylaxe, Therapie vonThromboembolien und Vorhoffflimmern wei-sen zumindest Nicht-Unterlegenheit, wennnicht sogar bessere Effektivitt im Vergleichzu Enoxaparin und VKA nach, bei vergleichba-ren Sicherheitsendpunkten. Limitierungen derneuen Substanzen knnten sich auf Grundgastrointestinaler Nebenwirkungen, Art derMetabolisierung und dem Eliminierung erge-ben. Ein spezifisches Antidot steht fr keineder Substanzen zur Verfgung.Unzweifelhaft sind die neuen oralen Anti-koagulanzien sehr vielversprechend. Dennochbleiben offene Fragen, obwohl schon tausen-de von Patienten unter Studienbedingungen

behandelt wurden, z. B. die nach der Therapie-adhrenz bei nicht mehr erfolgendem Moni-toring, Effektivitt und Sicherheit bei Risiko-patienten sowie Dosisanpassung und Inter-aktion mit anderen Medikamenten. Erst nachderen Beantwortung wird eine abschlieendeBewertung mglich sein, ob die neuen Sub-stanzen geeignet sind, die Vitamin-K-Antago-nisten zu ersetzen.


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22 U. Harbrecht: Old and new anticoagulants

In 2010, an estimated number of one mil-lion patients (according to patient net-works) were treated with oral anticoagu-lants in Germany due to atrial fibrillation, deep vein thrombosis, pulmonary embolism, heart valve prosthesis, few other indications.

Another estimated one million patientswith atrial fibrillation is supposed to bene-fit from antithrombotic therapy. For manydecades vitamin K antagonists (VKA) havebeen the only choice for long-term treat-ment (1, 2). After more than 30 years of re-

search new substances such as directthrombin inhibitors and direct factor Xainhibitors have been designed and moreand more of them are approved. The prin-ciple expectation of patients and physiciansis focussed on long term treatment withthese substances instead of VKA whichhopefully would relief them from theburden of frequent INR-controls and fearof bleeding due to the narrow therapeuticwindow of VKA.

This short review will summarize thedevelopment and profile of the new oralanticoagulants and compare them with theold agents in terms of pharmacology,mechanism of action, efficacy and safety.An overview of the relevant clinical trialswill be given together with a careful projec-tion of what we might expect in future.

Old anticoagulants

Vitamin K antagonists and heparins areused complementary for antithrombotic

treatment. Unfractionated heparins withtheir short half-life, quick onset and paren-teral mode of administration are safe andwell controllable in thromboprophylaxisand/or acute treatment of thrombosis. Butneed of frequent applications in the s.c.route (twice to three times daily) andrequirement of monitoring of intravenoustherapeutic doses due to considerableintra- and interindividual variability makestherapy unpredictable and inappropriatefor long-term use. Heparins inhibit all ser-

ine proteases to various extents with pre-dominant inhibition of thrombin (factor

IIa) and factor Xa requiring antithrombinas cofactor.

Further development of unfractionatedheparin (UFH) by shortening the glycos-

aminoglycan chain resulted in low-molec-ular-weight heparin (LMWH) with higherbioavalability and therefore better pre-dictability of effect and without need ofroutine monitoring. Longer half-life ofLMWH (24 hours after single s.c. injec-tion) allow once daily injection for throm-boprophylaxis or twice daily for treatmentof thrombosis (3).

Long-term anticoagulation is still doneby VKA, which are therapeutically usedcoumarins, acting indirectly by inhibition

of carboxylation of the vitamin K depend-ent factors II, VII, IX and X and proteins C,S and Z, thereby abolishing their potentialto be activated on phospholipid surfacesafter calcium-dependent binding. Car-boxylation does not take place because vit-amin K is needed in this reaction and VKAinhibit regeneration of vitamin K by inter-fering with vitamin K epoxide reductase(VKOR).

The gene was discovered in 2004 and en-codes several isoforms, collectively termedVKOR complex 1 (VKORC1) (4, 5). Sinceintroduction of dicumarol in 1941 in theUS and phenprocoumon (Marcumar)1954 in Germany these compounds havenot been altered pharmacologically. How-ever, much has been done to improve treat-ment surveillance. Increasing knowledge ofmechanism of VKA-action as well as in-sights into interaction with foods and otherdrugs rendered them more predictable. In-troduction of INR and self-measurement/monitoring and more careful and individ-ually tailored loading doses have further in-

creased safety (6, 7). Recognition ofVKORC1 as the target of VKA and sub-sequent disclosure of mutations and poly-morphisms in VKORC1 as well as inCYP2C9 have contributed substantially tounderstand phenomena of coumarin sen-sitivity and resistance (8, 9).

Common characteristics ofnew anticoagulants

The new anticoagulants are syntheticallyproduced small molecules that act against

one clotting factor. In contrast to heparinsand fondaparinux their effect is indepen-dent of antithrombin. They are binding se-lectively and with high affinity to the active

site of the enzyme, thereby competitivelyinhibiting the turnover of the natural sub-strates. Reversible binding to the enzymesis thought to be important for lowering thebleeding risk. Whether factor IIa or factorXa inhibitors are better remains to be inves-tigated. Prinicple of factor Xa inhibition isreduction of thrombin burst in the propa-gation phase of coagulation, an approachwith a straightforward effect. Inhibition ofthrombin itself, which is the key enzyme inthe coagulation cascade with many other

functions such as platelet activation, inter-action with fibrinolysis, inflammatory pro-cesses, and cell proliferation is less predict-able as it may affect all properties of throm-bin, however, this pleotropic effect mayprovide advantages, too (10).

Direct thrombin inhibitors

Direct thrombin inhibitors (DTI) selec-tively block the activity of the proteasethrombin (soluble and fibrin-bound) re-sulting in inhibition of fibrin generationand thrombus formation. DTI were in-itially only available for parenteral use, laterfollowed by orally applicable substances.Development was accompanied by severedraw backs, the most surprising was with-drawal of the first oral DTI ximelagatran(Exanta) in 2006 due to suspected livertoxicity after it had been introduced on themarkets in 2004 (11). Lepirudin (Reflud-an) and argatroban (Argatra) have beenimplemented already some years ago as al-

ternative anticoagulants in heparin-in-duced thrombocytopenia type II. Desiru-din (Revasc) is approved for thrombopro-phylaxis in hip and knee replacement sur-gery and bivalirudin (Angiox) for percut-aneous coronary interventions.

Dabigatran (Pradaxa)

Dabigatran is a nonpeptide small moleculeacting as reversible inhibitor of thrombin.In contrast to factor Xa inhibitors dabigat-

ran is a very polar, permanently chargedhydrophilic molecule, which itself has no


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23U. Harbrecht: Old and new anticoagulants

Schattauer 2011 Hmostaseologie 1/2011

bioavailability after oral administration.Hence, a double prodrug was generated,dabigatran etexilate (Pradaxa), by ma-sking the polar amidinium moiety as a car-

bamate ester and by turning the carboxy-late into an ester group which allows bio-availability of 6.5%. After resorption of theprodrug, both polar groups of dabigatranare restored quickly in plasma and liver byesterase-mediated hydrolysis leading torapid onset of action with peak plasmaconcentrations after 1 to 2 hours after in-gestion. Terminal half-life is 1417 hours.Galenism of the drug was constructed withtartaric acid allowing for solubility and re-sorption in an acidic milieu. This however

accounts for gastrointestinal side effects,mainly dyspepsia, and leads to reduction ofapproximately 30% of bioavailability of da-bigatran when combined with protonpump inhibitors. Dabigatran is not meta-bolized by cytochrome P450, reveales lowinteractions with other drugs and no inter-actions with foods. It is excreted renally, ap-proximately 85% as active drug (Tab. 1)(12, 13).

Factor Xa inhibitors

Factor Xa inhibitors can be indirect (e. g.fondaparinux, idraparinux, idrabiotapari-nux) or direct (e. g. rivaroxaban, apixaban,edoxaban) depending on the requirement ofantithrombin to exert their antithromboticeffect. They reduce thrombin burst duringpropagation of coagulation. Whereas fonda-parinux was rapidly integrated into clinicaluse and the xabanes have started to follow,idraparinux as a derivate of fondaparinuxwith longer half-life (80 hours) was investi-

gated for treatment of deep vein thrombosisand pulmonary embolism with a onceweekly subcutaneous administration, how-ever it revealed increased bleeding compli-cations and is no longer followed (14).

Fondaparinux (Arixtra)

Fondarinux was the first substance of thefactor Xa inhibiting group, syntheticallygenerated, further condensating the low-molecular heparin structure to the essential

pentasaccharid motif, responsible for bind-ing to antithrombin. The fondaparinux-

mediated conformational change of anti-thrombin results in reversible binding tofactor Xa with 700-fold higher affinitycompared to heparins. Its administration is

once daily subcutaneously, half-life is1417 hours and it is exctreted renally (15).Fondaparinux is approved since 2002,meanwhile with a broad spectrum of indi-cations comparable to that of enoxaparin,including thromboprophylaxis, treatmentof venous thrombosis, pulmonary embol-ism and unstable angina pectoris (16).However, like all heparins, it is dependenton the presence and functionality of anti-thrombin. Nevertheless, the favourableprofile and convincing outcomes in clinical

trials in comparison to low-molecular-weight heparins, mainly enoxaparin, hasstimulated a lot of work on factor Xa aspromising target for antithrombitic agents.

Rivaroxaban (Xarelto)

Rivaroxaban is the first and most advancedrepresentative of the direct oral factor Xa in-hibitors with 10 000-fold higher selectivityfor factor Xa than for other serine proteases.It is an oxazolidininon derivate which is alsoused in some antibiotics. Inhibition of factorXa is concentration-dependent and affectsprothrombinase complex-bound as well asclot-associated factor Xa. Pharmacokineticand pharmacodynamics have been shown to

be predictable across 5 to 80 mg daily inges-tion. Range of mean plasma concentrationwas 12 to 201 ng/ml after daily intake of 5 to20 mg of rivaroxaban. Peak plasma concen-

trations are achieved after 2 to 4 hours. Bioa-vailability is 80100% and terminal half-lifeof 711 hours is between that of LMWH andfondaparinux. Two third of the drug aremetabolised, one third is excreted un-changed. Two third are eliminated renally,one third through faeces. Rivaroxaban ismetabolised in the liver involving cytoch-rome P450 (CYP3A4, CYP2J2) (17, 18). Ofthe coagulation assays it affects prothrombintime more than aPTT and it can be moni-tored by anti-factor-Xa assays if desired (19).

Apixaban

Pharmacokinetics of apixaban have beenstudied in healthy human males after ad-ministration of a single 20 mg oral dose ofradiolabeled [14C]apixaban (20) and inother species including rabbits (21). Bioa-valability in humans is more than 50% andpeak plasma concentrations are reached in3 to 4 hours (22). Other properties are sum-marized inTable 1.

Edoxaban (DU-176b)

Pharmacokinetics and pharmacodynamicsof edoxaban have been investigated in ani-

Tab. 1 Pharmacological characteristics of the direct thrombin inhibitor dabigatran and the oral fac-tor Xa inhibitors rivaroxaban, apixaban and edoxaban

Dabigatran(Pradaxa)

Rivaroxaban(Xarelto)

Apixaban Edoxaban(DU-176b)

molecular mass

[g/mol]

628/472* 436 460 548

protein binding [%] 3435 9295 ca. 87 ?

bioavailability [%]reduction by PPI

6.530%

80100no

> 50no

4550unlikely

T(max) [h] 12 24 34 12

terminal half-life [h] 1417 711 1014 911

metabolismCYP450 dependent

ca. 20%no

ca. 66% (liver)ca. 32% CYP3A4, CYP2J2

?CYP3A4

?

ca. 6% ca. 33% ca. 56% ca. 62%

*prodrug/drug

excretion ca. 85%(active)

ca. 66%(ca. 33% active)



urine

faeces


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mal studies (23) and in a clinical safetystudy in healthy volunteers. Peak plasmaconcentrations are observed after 12hours and terminal half-life is 56 hours.

Oral factor Xa inhibitors

Many other substances are currently inves-tigated in clinical trials such as PRT-054021(betrixaban), eribaxaban, LY 517717,TAK-442, YM150.

Clinical trials

Clinical trials are listed for the most ad-

vanced new oral anticogulants with variousindications (Tab. 2) and results are pres-ented briefly. Additionally, further pro-grams are under way concerning other in-dications including medically ill patients,paediatric cases, haemodialysis, electivepercuteanous interventions.

Thromboprophylaxis in hip andknee arthroplasty

Dabigatran

Dabigatran was compared with enoxaparinin three phase III trials (RE-NOVATE, RE-MODEL, RE-MOBILIZE) including morethan 8000 patients (25, 26, 27). Patients

were randomly assigned to receive 220 mgor 150 mg dabigatran once daily, starting 1to 4 hours with a half-dose after surgery, orenoxaparin (40 mg once daily or 30 mg

bid), beginning the evening before surgery.A pooled analysis with 6200 evaluable pa-tients revealed comparable efficacy andbleeding outcomes. The composite out-comes of major VTE (proximal deep veinthrombosis and/or pulmonary embolism)and VTE-related mortality occurred in3.3% of the enoxaparin group versus 3.0%of the dabigatran 220 mg and 3.8% of thedabigatran 150 mg group (proof of non-in-feriority). Major bleeding occurred in 1.4% of the enoxaparin group versus 1.4% in

the 220 mg and 1.1% in the 150 mg dabig-atran group (28).

Direct factor Xa inhibitors

Rivaroxaban was investigated in knee andhip arthroplasty in the RECORD 14 pro-gram (2932). Patients were randomly as-signed to 10 mg rivaroxaban once daily be-ginning 68 hours after surgery or enox-aparin (40 mg once daily or 30 mg bid),starting the evening before surgery in the40 mg studies or beginning 1224 hoursafter surgery in 2 x 30 mg study (RECORD4). A pooled analysis of the four studies(12 729 patients) revealed better efficacy ofrivaroxaban, but higher, though not signifi-cantly different, bleeding rates. Composite

endpoint of symptomatic VTE and all-cause mortality in the day 12 2 activetreatment pool occurred in 29/6183 pa-tients receiving rivaroxaban (0.5%) versus

60/6200 patients receiving enoxaparin(1.0%; p = 0.001). Major bleeding was ob-served in 21 (0.3%) versus 13 (0.2%) pa-tients, p = 0.23, major plus non-majorclinically relevant bleeding in 176 (2.8%)versus 152 (2.5%) and any bleeding in 409(6.6%) versus 384 (6.2%) patients, p =0.38, respectively (33).

Huisman and co-workers compared En-oxaparin versus dabigatran and rivar-oxaban by pooling 6 phase III trials (18 405participants) and came to the conclusion

that enoxaparin and dabigatran show simi-lar rates of efficacy and bleeding, whereasenoxaparin was less effective than rivar-oxaban but had a lower risk of bleeding(34).

Apixaban was assessed in knee replace-ment surgery in the ADVANCE-2 studywith 3057 patients randomly allocated tooral apixaban 2.5 mg twice daily starting 12to 24 hours after wound closure orenoxaparin 40 mg once daily starting 12hours before surgery. In the recently pub-lished analysis, 1973 patients were select-able for primary outcome (composite ofasymptomatic and symptomatic DVT,non-fatal PE and all-cause mortality)which occurred in 147/976 (15%) patientsreceiving apixaban versus 243/997 (24%)



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

Dabigatran

(Boehringer)

Rivaroxaban(Bayer)

Apixaban(Pfizer/Bristol-Myers Sqibb)

Edoxaban(DU-176b)(Daiichi Sankyo)

DVT: deep vein thrombosis; PE: pulmonary embolism; ACS: acute coronary syndrome; * results of study published

DVT-prophylaxis

phase III

RE-NOVATE* (25)RE-MODEL* (26)RE-MOBILIZE* (27)

phase IIIRECORD 13* (2931)RECORD 4* (32)

phase IIIADVANCE-2* (35)ADOPT ongoing (37)

phase IIISTARS E-3 (38)completed

DVT/PE treatment

phase III

RE-COVER* (39)RE-MEDY (40) completedRE-SONATE (41) ongoing

phase IIIEINSTEIN-DVT (42) completedEINSTEIN-PE (42) recruitingEINSTEIN-Extension (42) completed

phase IIBOTTICELLI* (43)completed

phase IIIHOKUSAI-VTE (44)recruiting

ACS

phase II

RE-DEEMcompleted (45)

phase IIIATLAS ACS TIMI 51 (46)

phase IIIAPPRAISE-2 (47)completed

atrial fibrillation

phase III

RE-LY* (48)

phase IIIROCKET-AF (49)completed

phase IIIARISTOTLE (51) ongoing, not recruitingAVERROES (50) ongoing, not recruiting

phase IIIENGAGE AF TIMI 48 (52)recruiting

substance indication


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enoxaparin (p < 0.0001). Major or clini-cally relevant bleeding was observed in 53(4%) of 1501 patients receiving apixabanand 72 (5%) of 1508 patients treated with

enoxaparin. The investigators concludefrom the study that apixaban 2.5 mg twicedaily, starting on the morning after surgery,offers a more effective alternative to enox-aparin without increased bleeding (35). Ina meta-analysis of patients with total kneearthroplasty it is concluded, that apixabanis non-inferior to enoxaparin when usedfor the same duration, but with consider-able advantage regarding safety profile(36). In the phase III ADOPT study apixa-ban (2.5 mg bid) is investigated for preven-

tion of thrombosis-related events in pa-tients with acute medical illness during andafter hospitalisation in comparison toenoxaparin and placebo (37).

Edoxaban 30 mg once daily was com-pared in the STARS E-3 trial with enoxapa-rin 20mg twice daily for VTE prevention inknee arthroplasty (38). An interim analysisrevealed DVT in 7.4% of edoxaban treatedpatients versus 13.9% of patients receivingenoxaparin. Major and clinically relevantbleedings were not significantly different.

Treatment of deep vein thrombosisand pulmonary embolism

Several study programs have been initiatedand are awaiting completion, analysis/in-terpretation and publication (Tab.1).The comparators are therapeutic doses ofUFH/LMWH/fondaparinux and VKA.

Dabigatran

Dabigatran has already shown non-in-feriority in treatment of DVT and PE com-pared to warfarin. In the RE-COVER study2564 patients with DVT (~70%), PE(~20%) or both (~10%) were randomly as-signed after initial treatment with thera-peutic LMWH, UFH or fondaparinux for 9days to receive 150 mg dabigatran twicedaily or warfarin (INR 2.03.0) and fol-lowed for 6 months. Primary endpoints(recurrence of thromboembolism and/ordeath) were observed in 30/1274 (2.4%)

patients treated with dabigatran versus27/1265 (2.1%) under warfarin. Major

bleeding episodes occurred in 1.6% versus1.9% in dabigatran and warfarin, respect-ively. However, discontinuation of thestudy drug due to adverse events, among

these diarrhoea and dyspepsia (signifi-cant), was more frequent in dabigatran(9.0%) than in warfarin (6.8%, p = 0.05),(39). RE-MEDY (40) will look at long term(18 months) secundary prophylaxis aftersymptomatical VTE in comparison to war-farin in patients with successful initialtreatment for 3 to 6 months. RE-SONATE(41) is a placebo-controlled trial in patientswith recurrent VTE who have completed 6to 18 months of treatment.

Direct factor Xa inhibitors

Rivaroxaban is currently investigated inthe EINSTEIN-DVT and EINSTEIN-PEprogram at a dosage of 15 mg twice dailyfor proof of non-inferiority compared tostandard treatment with LMWH/VKA. Inthe EINSTEIN-extension-study, patients ofthe DVT- and PE-program will be furtherfollowed after 6 or 12 months of treatmentin a placebo controlled arm receiving 20 mgonce daily rivaroxaban (42).

Apixaban was investigated in a dose-finding phase II study (BOTTICELLI-DVT) at dosages of 5 mg twice-daily, 10 mgtwice-daily or 20 mg once-daily comparedto LMWH followed by VKA (43).

Edoxaban is currently under investi-gation in the phase III HOKUSAI-VTEstudy comparing LMWH/edoxaban tosyl-ate (DU-176b) with LMWH/warfarin. Ed-oxaban is given once daily 60 mg (44).

Acute coronary syndrome

Dose-finding studies in patients with acutecoronary syndrome (ACS) have not shownuniform risk reduction. In case of equal orsuperior efficacy by trend they tended tohave increased bleeding risks in com-bination with single or dual anti-platelettherapy. RE-DEEM (45) evaluated 4 dosesofdabigatran twice daily and placebo in ad-dition to dual antiplaelet therapy. In theplacebo controlled ATLAS-TIMI 51 studyrivaroxaban is assessed with 2.5 mg and 5

mg twice daily additionally to aspirin aloneor aspirin and clopidogrel (46). The AP-

PRAISE-2 study is a placebo-controlledstudy, too, investigating apixaban 5 mgtwice daily aganist placebo additionally tostandard care for ACS (47).

Atrial fibrillation

Atrial fibrillation (AF) is the predominantindication for long-term anticoagulation.Though it is no causal therapy, antithrom-botic treatment represents basic care forstroke prevention. Greatest expectationswith the new substances are focussed onlong-term anticoagulation with hope thatthey finally may replace VKA. According to

AF-guidelines, indication for anticoagu-lation in atrial fibrillation follows theCHADS2 score or the more recently pro-posed CHA2DS2-VASc score usually recom-mended when 2 points are given. Amongthe new anticoagulants dabigatran is so farthe most intensively studied substance in at-rial fibrillation. In the RE-LY study 18113patients had received dabigatran 110 mg or150 mg twice daily in comparison to ad-

justed-dose warfarin (INR 2.03.0). MeanCHADS2 score was 2.1. Primary outcomewas stroke or systemic embolism and wasobserved after a median follow up period of2 years in 1.69% of patients treated with war-farin compared to 1.53% in the group thatreceived 110 mg dabigatran (p75 years andwith reduced renal function. Gastrointesti-nal side effects, mainly dyspepsia, were morethan twice as frequently as with dabigatran(11.8% and 11.3%) compared to warfarin(5.8%) and accounted for 21% of discon-

tinuation of the study drug in the dabigatrangroup compared to 17% in warfarin (48).

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More than 14 000 patients have been rando-mised in the ROCKET AF study to 20 mgonce daily rivaroxaban or dose-adjustedwarfarin (INR 2.0 3.0). Follow up is

planned until 405 primary outcomes are ob-served (49). In the ARISTOTLE study 18 206patients with AF have been randomised toapixaban 5 mg twice daily with warfarin ascomparator. At least 448 primary efficacyoutcomes will be awaited (50). The AVER-ROES trial investigates apixaban 5 mg twicedaily compared to acetylsalicylic acid(81324 mg) in AF patients with at least onerisk factor for stroke and who have failed orare unsuitable for VKA therapy (51).

Conclusions, perspectives

After decades of constant and nearly un-changed options for antithrombotic treat-ment new competitive and innovative sub-stances are rushing on the markets backedwith very promising results of historicallylarge clinical trials. Most data at present areavailable for the direct thrombin inhibitordabigatran and the factor Xa inhibitor ri-varoxaban, being catched up by other fac-tor Xa inhibitors as apixaban and edox-aban. Although already thousands of pa-tients have been treated under study con-ditions, the new substances have to befurther followed carefully and intensivelyin post-approval studies when a broadspectrum of patients will be treated inorder to clarify open questions such as treatment adherence in absence of

monitoring, safety aspects in patients with renal/he-

patic impairment and multimorbidity, side effects (e. g. gastrointestinal) and

drug interactions, monitoring of risk patients, interpretation of coagulation tests (e. g.

before surgery).

Answering these questions will be one pre-requisite before conclusions can be drawntowards the potential of the new substancesto replace vitamin K antagonists. If they indeed turn out to be superior and/or saferthan VKA in routine use with no need ofdrug monitoring at regular intervals would

implicate a great step in the direction ofsubstantially improved medical care.



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