New perspectives and strategies in the treatment of thromboembolic diseases

Uvod

Tromboembolijske bolesti su veliki javnozdravstveni pro-blem i jedan od glavnih uzroka pobola i smrtnosti u razvije-nim zemljama1,2. Procjenjuje se da u svijetu godiπnje ima 32milijuna srËanih i moædanih udara od Ëega 12,5 milijuna za-vrπava smrÊu. Udio osoba umrlih zbog kardiovaskularnihbolesti (KVB) u Hrvatskoj u ukupnom mortalitetu 2011. go-dine iznosio je 48,7%, a vodeÊe dijagnostiËke podskupine

2013;8(1-2):11. Cardiologia CROATICA

Pregledni rad / Review article

Nove perspektive i strategije u lijeËenju tromboembolijskih bolestiNew perspectives and strategies in the treatment ofthromboembolic diseasesAna BroniÊ1*, Jasna LeniËek Krleæa2

1 KliniËki bolniËki centar Sestre milosrdnice, Zagreb, Hrvatska 2 Klinika za djeËje bolesti Zagreb, Zagreb, Hrvatska1 University Hospital Centre Sestre milosrdnice, Zagreb, Croatia 2 Children’s Hospital Zagreb, Zagreb, Croatia

SAÆETAK: U prevenciji tromboembolijskih dogaajarazliËite etiologije, a stoga i kod pacijenata s fibrilacijomatrija (FA) te pacijenata s akutnim koronarnim sindro-mom (AKS) konvencionalno se primjenjuje acetilsalici-latna kiselina, heparini te antagonisti vitamina K. Ovisnoo indikaciji razliËite prednosti i nedostatci svake od ovihkategorija lijekova usmjeravaju ili ograniËavaju njihovuuporabu. Njihovom primjenom postignut je znatan na-predak u lijeËenju, meutim kako ipak imaju neke neæe-ljene karakteristike, a prevalencija trombotskih dogaajageneralno je joπ uvijek vrlo visoka, javila se potreba zarazvojem novih protuzgruπavajuÊih lijekova. U zadnjihnekoliko godina na træiπtu je predstavljena nova gene-racija protuzgruπavajuÊih lijekova Ëije je djelovanje us-mjereno na inhibiciju trombina ili aktiviranog faktora X.Rezultati provedenih kliniËkih istraæivanja istakli su po-tencijal direktnog inhibitora trombina dabigatrana te anti-Xa lijeka rivaroksabana u lijeËenju i prevenciji dubokevenske tromboze te moædanog udara povezanog s FA.Odnedavna je u mnogim zemljama njihova primjenaodobrena za navedene indikacije, a preliminarna istraæi-vanja kod pacijenata s AKS su ukazala na to da bi prim-jena pojedinih lijekova nove generacije mogla biti dobraalternativa za akutno zbrinjavanje ili blagotvorna u se-kundarnoj prevenciji ishemije. Ovdje dan kratak pregledspoznaja o farmakologiji novih lijekova, rezultatima klin-iËkih ispitivanja kod pacijenata s FA i AKS, kao i moguÊ-nostima njihovog monitoringa.

KLJU»NE RIJE»I: akutni koronarni sindrom, fibrilacijaatrija, tromboza, oralni antikoagulansi.

SUMMARY: In the prevention of tromboembolic eventsof different etiology and therefore in patients with atrialfibrillation (AF) and patients with acute coronary syndro-me (ACS) aspirin, heparins and vitamin K antagonistsare traditionally applied. Depending on the indication,various advantages and disadvantages of each of thesecategories of drugs direct or restrict their use. Their ap-plication has achieved considerable progress in thetreatment, but as some of them show undesired charac-teristcs and considering that general prevalence ofthrombotic events is generally still very high, a develop-ment of new antithrombotic drugs has been considered.In the last few years, a new generation of antithrombo-tic drugs with effects directed on the inhibition of throm-bin (FIIa) or activated factor X (FXa) has been develo-ped and introduced in the market. The results of theconducted clinical trials have demonstrated the potentialof these drugs in the treatment and prevention of deepvenous thrombosis and AF related stroke. In many coun-tries their application for the above mentioned indica-tions has been recently approved, while the preliminarytrials in patients with ACS have showed that the use ofparticular new generation drugs could be a good alter-native for the acute management or could be beneficialin the secondary prevention of ischemia. Here, we havepresented a short overview of insights about pharmaco-logy, results of clinical trials and possibilities of monito-ring of new antithrombotic drugs.KEYWORDS: acute coronary syndrome, atrial fibrilla-tion, thrombosis, antithrombotic drugs.CITATION: Cardiol Croat. 2013;8(1-2):11-23.

Introduction

Thromboembolic diseases are a major public health pro-blem and one of the major causes of morbidity and mortali-ty in developed countries1,2. It is estimated that there are 32millions of myocardial infarction and strokes on an annualbasis worldwide, of which 12.5 millions end up in death. Therate of deaths due to cardiovascular diseases (CVD) inCroatia with regard to overall mortality in 2011 was 48.7%;

2013;8(1-2):12.Cardiologia CROATICA

su i dalje ishemijska bolest srca (IBS) s udjelom od 21,3% tecerebrovaskularne bolesti s udjelom u ukupnom mortalitetuod 14,7%2. Pozitivan je pokazatelj to πto je ovo treÊa godinaza redom u kojoj je smanjen udio KVB u ukupnom mortalite-tu. Prema istraæivanjima provedenim u razliËitim populacija-ma, Ëak 44-76% smanjenja smrtnosti od IBS pripisuje seprevenciji i promjeni riziËnog ponaπanja, dok se 23-47%smanjenja smrtnosti pripisuje terapijskim intervencijama2. Uprevenciji trombotskih komplikacija kod visoko riziËnih paci-jenata do nedavno su u uporabi bile iskljuËivo dvije kategori-je protuzgruπavajuÊih lijekova: heparini (visoko- i nisko- mo-lekulski) i antagonisti vitamina K (VKA), dok se u smislu anti-agregacijske terapije primjenjivala acetilsalicilatna kiselina(ASK)3,4. Dakako, ovisno o indikaciji razliËite prednosti i ne-dostaci svake od ovih kategorija lijekova usmjeravaju iliograniËavaju njihovu uporabu. Primjenom ovih lijekova po-stignut je znatan napredak u lijeËenju, meutim, zbog nekihnjihovih ograniËenja poput odgoenog djelovanja, interakci-je s drugim lijekovima, potrebe za Ëestim laboratorijskim sli-jedom i titracijom doze, slabim odgovorom, hiperosjetljivostiili nuspojavama poput krvarenja te joπ uvijek visoke preva-lencije trombotskih dogaaja javila se potreba za razvojemnovih protuzgruπavajuÊih lijekova s poboljπanim farmako-kinetskim i farmakodinamskim profilom5,6. U zadnjih nekolikogodina osim nove generacije antiagregacijskih lijekova, raz-vijena je i na træiπtu predstavljena nova generacija protuz-gruπavajuÊih lijekova Ëije je djelovanje usmjereno na inhibi-ciju trombina (FIIa) ili faktora X (FXa). Za razliku od VKA,nova klasa protuzgruπavajuÊih lijekova selektivna je zajedan specifiËni faktor zgruπavanja, a srediπnja karakteristkaim je poboljπan farmakokinetski i farmakodinamski profil.Primjena direktnog inhibitora trombina dabigatrana te anti-Xa lijeka rivaroksabana odnedavna je u mnogim zemljamaodobrena u svrhu prevencije duboke venske tromboze(DVT) kod odraslih pacijenata koji su podvrgnuti elektivnomkirurπkom zahvatu ugradnje kuka ili koljena te moædanogudara (MU) i sistemskog embolizma povezanog s fibrila-cijom atrija (FA)4-6. Preliminarna istraæivanja kod pacijenata sakutnim koronarnim sindromom (AKS) su ukazala na to dabi primjena pojedinih lijekova nove generacije mogla biti al-ternativa za akutno zbrinjavanje ili blagotvorna u sekun-darnoj prevenciji ishemije6,7,. Ovdje dan kratak pregled spoz-naja o farmakologiji novih lijekova, rezultatima kliniËkih ispi-tivanja kod pacijenata s FA i AKS te moguÊnostima njihovogmonitoringa.

Farmakologija i mehanizam djelovanja novihprotuzgruπavajuÊih lijekova

Nova generacija protuzgruπavajuÊih lijekova je razvijana usmislu specifiËne inhibicije odreenog dijela ili enzima u ko-agulacijskoj kaskadi. Djelovanje im je usmjereno na inhibici-ju FIIa ili aktiviranog FXa. Trombin predstavlja atraktivan ciljzbog svoje srediπnje uloge u sustavu zgruπavanja u smislupretvorbe fibrinogena u fibrin te aktivacije brojnih drugih sup-strata poput trombocitnih receptora koji se aktiviraju pro-teazama te faktora V, VIII, XI i XIII. S druge strane, pozicijana poËetku tvz.”zajedniËkog puta” koagulacije Ëini FXatakoer vrlo atraktivnim ciljem4,8. Osnovne karakteristike po-jedinih novih lijekova su prikazane u Tablici 1.

the leading diagnostic subgroups were ischemic heart di-seases (IHD) and cerebrovascular diseases with mortalityrates of 21.3% and 14.7%, respectively2. It is a positive indi-cator that this is the third consecutive year in which the fre-quency of total CVD mortality has been decreased. Accor-ding to the trials conducted in different populations, even 44-76% of reduction in mortality from IHD is attributed to theprevention and changes in risk behavior, while 23-47% ofreduction in mortality is attributed to therapeutic interven-tions2. In the prevention of thrombotic complications in high-risk patients, until recently, only two categories of antithrom-botic drugs were in the use: heparins (high- and low-molec-ular weight heparins) and vitamin K antagonists (VKA), whileregarding the antiplatelet therapy, aspirin was applied3,4. So,depending on the indication, various advantages and disad-vantages of each of these categories of drugs direct or re-strict their use. The administration of these drugs has resul-ted in a significant progress in the treatment, however, dueto some of their limitations such as a delayed effect, interac-tions with other drugs, the need for frequent laboratory mon-itoring and titration of dose, low responsiveness, hypersen-sitivity or adverse events such as bleeding as well as due tostill very high prevalence of thrombotic events a need for thedevelopment of new antithrombotic drugs with improvedpharmacokinetic and pharmacodynamic profile has occur-red5,6. In the last few years, beside a new generation of anti-aggregation drugs, a new generation of antithrombotic drugswith effects directed on the inhibition of thrombin (FIIa) orfactor X (FXa) has been developed and introduced in themarket. Thus, unlike VKA, a new class of antithromboticdrugs is selective for one specific clotting factor, while thecentral characteristic is their improved pharmacokinetic andpharmacodynamic profile. Recently, in many countries, theapplication of the direct thrombin inhibitor dabigatran andanti-Xa drug rivaroxaban has been approved for the preven-tion of deep venous thrombosis (DVT) in adult patients whoundergo elective surgery of the hip or knee replacement aswell as for the stroke and systemic embolism related withatrial fibrillation (AF)4-6. Preliminary trials in patients withacute coronary syndrome (ACS) have showed that the useof particular new generation drugs could be an alternativesolution for the acute management or could be beneficial inthe secondary prevention of ischemia6,7. Here we have givena short overview of insights about pharmacology of newdrugs, the results of clinical trials in patients with AF andACS, as well as their influence on routine coagulation testsand possibilities of their monitoring.

Pharmacology and mechanism of the action ofnew antithrombotic drugs

A new generation of antithrombotic drugs has been deve-loped by means of specific inhibition of particular phase orenzyme in the coagulation cascade. Their action is directedon the inhibition of thrombin or activated coagulation FX.Thrombin is an attractive target due to its central role in thecoagulation system in terms of conversion of fibrinogen tofibrin and the activation of many other substrates such asplatelet receptors that are activated by proteases of factorsV, VIII, XI and XIII. On the other hand, the position at thebeginning of the so called ‘common pathway’ of coagulationmakes FXa also a very attractive target4,8. Some basic fea-tures of particular new drugs are shown in Table 1.


Dabigatran eteksilat je kompetitivni direktni inhibitor trombi-na koji se hidrolizira u jetri, a djelovanjem esteraza se brzo iu potpunosti pretvara u svoju aktivnu formu, dabigatran3,4,9.Bioraspoloæivost dabigatrana je mala, otprilike 6-7% i stogamu je neophodna kisela sredina za efikasnu resorpciju.Maksimalna koncentracija lijeka u plazmi se postiæe ~3 satanakon primjene, a poluvrijeme izluËivanja je od 9-13 sati, πtoomoguÊuje njegovu primjenu jednom ili dva puta dnevno.Oko 80% lijeka izluËuje se nepromijenjeno putem bubrega,a oko 20% putem æuËi nakon konjugacije u aktivne metabo-lite. Dabigatran stupa u relativno mali broj interakcijaobzirom da njegov metabolizam nije ovisan o sustavucitokroma P450 (CYP). Dabigatran eteksilat je meutim sup-strat za P-glikoprotein (P-gp), membranski transporter koji jeprisutan u tankom crijevu i bubrezima. Stoga je potrebanoprez pri istovremenoj primjeni dabigatrana s lijekovima kojiinhibiraju P-gp transporter, obzirom da mogu uzrokovatipoveÊanje njegove koncentracije u plazmi, a specifiËan anti-dot koji bi neutralizirao njegovo djelovanje ne postoji.Primjena dabigatrana takoer je kontraindicirana kod pacije-nata s teπkom insuficijencijom bubrega, kao i kod pacijena-ta s teπkom insuficijencijom jetre unatoË tome πto ne posto-

Dabigatran etexilate is a competitive direct thrombin inhibitorthat is hydrolyzed in the liver, whereas by means of action ofesterases it is rapidly and completely converted to its activeform, dabigatran3,4,9. The bioavailability of dabigatran is low,approximately 6-7%, and therefore it requires acidic environ-ment for efficient absorption. Maximum drug concentrationin plasma is achieved ~3 hours after its administration, andthe elimination half-life is between 9-13 hours, which ena-bles its administration once or twice a day. About 80% of thedrug is excreted unchanged by the kidneys, whereas about20% in the bile after conjugation into the active metabolites.Dabigatran comes in a relatively small number of interac-tions, as its metabolism is independent of the cytochromeP450 (CYP). Dabigatran etexilate is a substrate for P-glyco-protein (P-gp), a membrane transporter that is present in thesmall intestine and kidneys. Therefore, the caution is requi-red while co-administering dabigatran with drugs that inhibitP-gp transporter, because its concentration in plasma mayincrease and there is no specific antidote that could neutrali-ze its effect. In patients with severe renal insufficiency andin those with severe hepatic insufficiency, the use of dabiga-tran is contraindicated, although there is no evidence of its

Table 1. Main pharmacokinetic and pharmacodynamics properties of new anticoagulant agents.

Property Dabigatran Rivaroxaban Apixaban Edoxaban Otamixaban

Target Factor IIa Factor Xa Factor Xa Factor Xa Factor Xa

Approved indication Prevention of stroke Prevention of stroke Not yet FDA Under Under and embolism in and embolism in approved investigation investigationnonvalvular AF; nonvalvular AF; VTE prophylaxis VTE prophylaxis

Route Oral Oral Oral Oral Intravenous

Dosing and frequency 150 mg BID FA: 20 mg/daily 5 mg BID Once/day Bolus + infusionVTE prophylaxis:10 mg/daily

Renal dosage adjustment 75 -110 mg 15 mg/daily 2.5 mg — —

Prodrug Dabigatran is active No No No Nometabolite of dabigatran etexilate

Bioavailability (%) 6-7 80 66 45 NR

Protein binding (%) 35 > 90 87 40-59 NR

Tmax (hrs) 1-2 2-4 3 4 3 min

Half-life (hrs) 9-13h (GFR>80ml/min) Healthy: 5-9 8-15 9-11 Initial: 30 minUntil 18h Elderly: 9-13 Effective: 2-3 hrs(GFR30-50ml/min)

Mode of excretion (%) ~80 renal ~66 renal ~75 feces ~65 feces ~25 urine~20 fecal ~34 feces ~25 renal ~35 urine ~75 biliary

Substrate of CYP No Yes: CYP3A4, Yes: CYP3A4 Yes: CYP3A4 NRenzymes CYP2J2 (major drug (minor drug

interactions) interactions)

Substrate of P-gp Yes Yes Yes Yes NR

Adverse effect other Dyspepsia Elevated hepatic than bleeding GGT Nausea — —

Antidote No known No known NR NR NR

je dokazi o njegovoj hepatotoksiËnosti. U sluËaju predozi-ranja moæe se provesti dijaliza koja efikasno uklanja oko60% lijeka iz krvi tijekom 2-3 sata. Rivaroksaban je specifiËni, direktni inhibitor FXa. Primjenju-je se oralno, brzo se resorbira, a za njegovu aktivaciju nijepotrebno prisutstvo kofaktora3,4,10. Maksimalnu koncentracijalijeka u plazmi postiæe za 2-4 sata, a poluvrijeme æivota muiznosi 7-11 sati. U metabolizam rivaroksabana ukljuËen jeCYP3a4, a obzirom da je lijek takoer i supstrat za P-gptransporter, istovremena primjena snaænih inhibitoraCYP3a4 (npr. ketokonazol) ili P-gp je kontraindicirana, ob-zirom da moæe uzrokovati poveÊanje koncentracije lijeka uplazmi. ZahvaljujuÊi svojim farmakokinetskim i farmakodi-namskim osobinama, rivaroksaban se moæe primjeniti u fiks-nim dozama kod odraslih osoba bez potrebe za rutinskomkontrolom koagulacije. Apiksaban je visokoselektivni reverzibilni direktni inhibitorFXa3,11. Maksimalna koncentracija lijeka u plazmi postiæe se3-4 sata nakon njegove primjene. Poluvrijeme æivota mu je8-15 sati, a za doze viπe od 10mg bioraspoloæivost lijeka jeoko 50%. Apiksaban se metabolizira u jetri putem CYP3A4-ovisnih i neovisnih mehanizama, a oko 25% lijeka se izluËu-je nepromjenjeno. Edoksaban je takoer direktni inhibitor FXa. Primjenjuje seoralno, poluvrijeme æivota mu je 9-11 sati, a metabolizira seu jetri putem CYP3A4. Otamiksaban je parenteralni direktni inhibitor FXa kojeg ka-rakterizira brzo djelovanje, predvidljiv antikoagulantni uËinaki kratak poluæivot u plazmi, πto ga Ëini pogodnim kandidatomza zamjenu heparina kod pacijenata s AKS.

Novi antikoagulansi i fibrilacija atrija

Fibrilacija atrija (FA) predstavlja najuËestaliju srËanu aritmi-ju, koju prema procjenama ima πest milijuna osoba u Europi,a odgovorna je za oko 15-20% svih MU12-14. FA se smatrajednom od najvaænijih indikacija za primjenu VKA, meutimodabir vrste antitrombotske terapije Êe dakako ovisiti o pro-cjeni rizika od tromboembolijskih komplikacija13-14. U poËetnom istraæivanju o primjeni direktnog inhibitora trom-bina dabigatrana, studiji RE-LY (Randomized Evaluation ofLong-Term Anticoagulation Therapy Y) primjena dabigatra-na u dvije razliËite doze 110 mg i 150 mg dva puta dnevnousporeena je s primjenom varfarina kod 18.113 ispitanikas FA11,15,16. RE-LY je bilo multicentriËno randomizirano istraæi-vanja otvorenog tipa. ProsjeËna dob ispitanika ukljuËenih uistraæivanje iznosila je 71 godinu, dok je udio muπkih ispi-tanika iznosio 63,6%. Prema bodovnom sustavu CHADSprosjeËni rizik u istraæivanju je iznosio 2,1, a ispitanici supraÊeni tijekom dvije godine. Rezultati su pokazali da je uusporedbi s varfarinom primjena 150 mg dabigatrana pove-zana s niæom incidencijom MU, ali i sliËnim rizikom od veÊihkrvarenja, dok je primjena doze od 110 mg povezana sasliËnom incidencijom MU i embolije, ali i manjom incidenci-jom velikih krvarenja. Na temelju ovog istraæivanja dabiga-tran je odobren kao alternativa za varfarin u prevenciji ne-valvularne FA u mnogim zemljama diljem svijeta. Primjena rivaroksabana je testirana u istraæivanju RECORD(Rivaroxaban Once Daily Oral Direct Factor Xa InhibitionCompared with Vitamin K Antagonism for Prevention ofStroke and Embolism Trial in Atrial Fibrillation)17. Istraæivanjeje provedeno na visokoriziËnoj populaciji, a primjena riva-roksabana u prevenciji MU se pokazala efikasnom kao i onavarfarinom, ali uz neπto manji rizik krvarenja. U dvostruko


hepatotoxicity. In case of an overdose, the dialysis whicheffectively removes about 60% of the drug from the bloodduring 2-3 hours can be performed. Rivaroxaban is a specific and direct inhibitor of FXa. It isapplied orally and is rapidly reabsorbed. Its activation doesnot require the presence of cofactors3,4,10. The maximumplasma concentration is achieved within 2-4 hours, while itshalf-life is 7-11 hours. The metabolism of rivaroxaban inclu-des CYP3a4, and, since it is also a substrate for P-gp trans-porter, the co-administration with strong CYP3aA4 (e.g.ketoconazole) or P-gp inhibitors is contraindicated, as it maycause increased drug levels in plasma. Owing to its pharma-cokinetic and pharmacodynamic properties, rivaroxabancan be administered in fixed doses in adults without theneed for routine coagulation testing. Apixaban is highly selective reversible direct inhibitor ofFXa3,11. Maximum plasma concentration is achieved 3-4hours following the administration. Its half-life ranges from 8to 15 hours, while the bioavailability of the drug is around50% for doses exceeding 10mg. Apixaban is metabolized inthe liver via CYP3A4-dependent and independent mecha-nisms, while about 25% is excreted unchanged. Edoxaban is also the oral direct inhibitor of FXa. Its half-liferanges from 9 to 11 hours, and is metabolized in the liver viaCYP3A4. Otamixaban is a parenteral direct FXa inhibitor, which ischaracterized by fast action, predictable anticoagulant effectand short plasma half-life, which makes it a suitable replace-ment for heparin in patients with ACS.

New anticoagulants and atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhyth-mia, which affects about 6 million people in Europe and it isaccountable for about 15-20% of all strokes12-14. AF is con-sidered to be one of the most important indications for VKA;however, selection of the antithrombotic therapy type in AFdepends on the assessment of the thromboembolic risk13-14. In the initial trial on the application of the direct thrombin in-hibitor dabigatran, the RE-LY study (Randomized Evalua-tion of Long-Term Anticoagulation Therapy Y) the admini-stration of dabigatran in two different doses of 110 mg and150 mg twice a day was compared to the application of war-farin in 18,113 subjects suffering from AF11,15,16. RE-LY was amulticentre, randomized, open type study. The mean age ofthe patients included into the study was 71 years, whereasthe frequency of males was 63.6%. According to the CHADSscoring system, the average risk in the trial was 2.1, and thesubjects were followed-up for two years. The results showedthat in comparision with warfarin, the application of 150 mgdabigatran is associated with a lower incidence of strokeand a similar risk of major bleeding, while the application of110 mg was associated with a similar incidence of strokeand embolism, but with lower bleeding incidence. Based onthis study, dabigatran has been approved as an alternativeto warfarin in the prevention of non-valvular AF in manycountries around the world. The application of rivaroxaban was tested in the RECORDstudy (Rivaroxaban Once Daily Oral Direct Factor Xa In-hibition Compared with Vitamin K Antagonism for Preven-tion of Stroke and Embolism Trial in Atrial Fibrillation)17. Thestudy was conducted in high-risk population and the applica-tion of rivaroxaban in prevention of stroke proved to be aseffective as the application of warfarin, but with lower risk of

slijepom multicentriËnom randomiziranom istraæivanjuROCKET AF, (Rivaroxaban Once Daily Oral Direct FactorXa Inhibition Compared with Vitamin K Antagonism for Pre-vention of Stroke and Embolism Trial in Atrial Fibrillation) su-djelovalo je 14.264 ispitanika s umjerenim do visokim rizi-kom MU, a rivaroksaban je primjenjen u dvije doze: 20mgdnevno ili 15 mg za pacijente s klirensom kreatinina 30-49mL/min18-19. Udio muπkih ispitanika u istraæivanju je iznosio60,3%, a prosjeËna dob svih ispitanika 73 godine. Ispitanicisu praÊeni u prosjeku 1,9 godine, a prema bodovnom susta-vu CHADS oko 87% pacijenata je pokazalo rizik najmanje 3(u prosjeku 3,5). Razlika u primjeni rivaroksabana i varfarinau smislu redukcije MU i/ili tromboembolizma kod ispitanikanije se pokazala statistiËki znaËajnom.Prvi objavljeni rezultati o efikasnosti apiksabana, inhibitoraFXa, u prevenciji MU kod pacijenata s FA doπli su iz istraæi-vanja AVERROES (Apixaban VERsus acetylsalycilic acid topRevent strOkE in atrial fibrillation patientS who have failedor are unsuitable for vitaminK antagonist treatment). U is-traæivanje su bili ukljuËeni pacijenti s nevalvularnom FA i barjoπ jednim Ëimbenikom rizika, ali koji nisu bili kandidati zaprimjenu varfarina ili ga nisu htjeli uzimati. Istraæivanje jepokazalo da u usporedbi s ASK primjena apiksabana zna-Ëajno smanjuje rizik MU ili sistemskog embolizma bez zna-Ëajnog porasta rizika veÊeg i/ili intrakranijalnog krvarenja.Drugo veliko provedeno istraæivanje o primjeni apiksabanaje istraæivanje ARISTOTLE (Apixaban for Reduction in Stro-ke and Other Thromboembolic Events in Atrial Fibrillation)20.ARISTOTLE je bilo multicentriËno randomizirano, dvostrukoslijepo istraæivanje provedeno na 18.201 ispitanika s pro-sjeËnim rizikom od 2,1 prema bodovnom sustavu CHADS.ProsjeËna dob ukljuËenih ispitanika iznosila je 70 godina, audio muπkaraca meu ispitanicima je iznosio 64,7%. Api-ksaban je primjenjen u dozi 5 mg 2 x dnevno te u dozi od 2,5mg kod starijih ispitanika ili ispitanika s renalnom insuficijen-cijom. Ispitanici su praÊeni prosjeËno oko 1.8 godinu, a pre-ma rezultatima primjena apiksabana se pokazala superi-ornom nad varfarinom u smislu smanjenja incidencije MU,smrtnosti te rizika krvarenja. Prema rezultatima provedenih istraæivanja sva tri oralna an-tikoagulansa novije generacije pokazala su u najmanju rukujednaku efikasnost kao i VKA, sa sliËnim profilom neæeljenihnuspojava. UnatoË tome πto se ovi lijekovi kod pacijenata sne-valvularnom FA smatraju atraktivnom alternativom VKAili ASK treba imati na umu da se radi o rezultatima treÊe fazeispitivanja ovih lijekova te da rezultati dugotrajnog slijeda joπnisu objavljeni. Vrlo je teπko odgovoriti na pitanje koji od ovihlijekova je bolji obzirom da do danas nije provedeno istraæi-vanje u kojem se direktno usporeuje njihovo djelovanje.Pretpostavlja se da bi direktna usporedba u smislu procjeneefikasnosti ovih lijekova trebala ukljuËiti oko 50.000 pacije-nata. Na temelju provedenih istraæivanja usporedbu nije jed-nostavno napraviti prvenstveno zbog razlike u njihovom di-zajnu21. Istraæivanja RE-LY i ARISTOTLE su izvrπena naumjereno riziËnoj populaciji za razliku od ROCKET AF gdjeje uz to bila prisutna i neπto starija populacija, a vrijeme opti-malnog terapijskog raspona u smislu primjene varfarina jebilo neπto manje. U istraæivanjima su sudjelovali ispitanicirazliËite etniËke pripadnosti, a razlike postoje i u vremen-skom slijedu te definiciji krajnje toËke ovih istraæivanja. Indi-rektna usporedba efikasnosti ovih lijekova provedena je odstrane dvije skupine istraæivaËa, Mantha i sur.22 te Lip i sur.23.Oba istraæivanja se slaæu u tome da je malo argumenata kojibi istakli primjenu jednog lijeka nad drugim u smislu efikas-nosti, meutim zbog neπto manjeg broja zabiljeæenih nuspo-java favorizirana je uporaba apiksabana i dabigatrana u dozi


bleeding. In a double-blind randomized multicentre ROC-KET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhi-bition Compared with Vitamin K Antagonism for Preventionof Stroke and Embolism Trial in Atrial Fibrillation) study, riva-roxaban was administered in 14,264 patients with moderateto high risk of stroke in two doses of 20mg or 15mg a day forpatients with creatinine clearance 30-49mL/min18-19. The fre-quency of male patients included in the study was 60.3%,and the mean age of all patients was 73 years. The medianfollow-up of patients was 1.9 years and according to theCHADS scoring system approximately 87% of patients sho-wed a risk of minimum 3 (on average 3.5). Difference in theapplication of rivaroxaban and warfarin did not reach a sta-tistically significance in terms of reduction of stroke and/orthromboembolism in subjects. The first published results of the efficacy of apixaban as theFXa inhibitor for the prevention of stroke in patients with AFderived from the AVERROES study (Apixaban VERsus ace-tylsalycilic acid to pRevent strOkE in atrial fibrillation pa-tientS who have failed or are unsuitable for vitaminK antago-nist treatment). The study included patients with non-valvu-lar AF and at least one additional risk factor, but who werenot candidates for VKA application or did not want to take it.The trial has shown that apixaban significantly reduces therisk of stroke or systemic embolism compared with aspirin,with no significant increase in risk of major or intracranialhemorrhage. Another large trial conducted on apixaban ad-ministration was the ARISTOTLE study (Apixaban for Re-duction in Stroke and Other Thromboembolic Events in At-rial Fibrillation)20. ARISTOTLE was a multicenter, randomi-zed, double-blind trial in 18,201 patients with an averagerisk of 2.1 according to the CHADS scoring system. Themean age of included patients was 70 years with 64.7% ofmale patients. Apixaban was administered at a dose of 5 mgb.i.d. and 2.5 mg in elderly patients or those with renal insuf-ficiency. Median follow-up of patients was 1.8 years and ac-cording to the findings, the application of apixaban seems tobe superior to warfarin regarding lower incidence of stroke,mortality and the bleeding risk. According to the results of the conducted trials, all three oralanticoagulants of a new generation showed at least equalefficacy as VKA with a similar profile of side effects. Althoughconsidered to be attractive alternatives to VKA or aspirin inpatients with non-valvular AF, one should keep in mind thatthese are the results of Phase III trials of these drugs andthat long-term results have not yet been published. It is dif-ficult to answer the question as to which of these drugs isbetter since to date no trial on direct comparison of efficacyof these drugs has been conducted. It is assumed that thedirect comparison of these drugs should include about50,000 patients. According to existing trials, it is not easy tomake a comparison mainly due to their different design21.The RE-LY and ARISTOTLE studies were conducted onmoderate risk population unlike the ROCKET AF studywhich included some older population, with less time withinoptimal therapeutic range in terms of application of warfarin.The trials also included subjects from different ethnicgroups, and were different in the time line as well as in defi-nition of the trial end point. Indirect comparison of efficacy ofthese drugs was conducted by two groups of researchers,Mantha et al22 and Lip et al23. The both trials agree that thereare few arguments that emphasize the superiority of appli-cation of one drug over another in terms of efficacy, but dueto a smaller number of side effects the application of apixa-ban and dabigatran at a dose of 110 mg is preferred, which

od 110 mg, a πto se mora naravno promatrati i u kontekstutolerancije, cijene lijeka i sliËno.

Novi antikoagulansi i akutni koronarni sindrom

Akutni koronarni sindrom definira raspon ishemijskih stanjamiokarda koja ukljuËuju nestabilnu anginu i infarkt miokarda(IM) s elevacijom ST-segmenta (STEMI) ili bez elevacije ST-segmenta (NSTEMI), a najËeπÊe su posljedica akutne koro-narne tromboze. Pacijenti s AKS visoko su riziËni, a brzadijagnoza i primjena adekvatne terapije moæe znatno po-boljπati ishod gledajuÊi kratkoroËno i dugoroËno. Zbrinja-vanje AKS znatno je poboljπano zadnjih godina s predstav-ljanjem intervencijskih terapijskih strategija, potentnih lijeko-va inhibitora trombocita i reæimom lijeËenja u smislu sekun-darne prevencije7,24. UnatoË znatnom smanjenju mortaliteta imorbiditeta, rizik opetovanih ishemijskih dogaaja i dalje jevisok. Antiagregacijska terapija vaæna je sastavnica prevencijeAKS6,24-27. UnatoË dokazanom uËinku ASK i klopidogrela ulijeËenju AKS, jedan dio lijeËenih ne odgovara na primjen-jenu terapiju i razvija trombotske komplikacije. UËestalostneadekvatnog odgovora za ova dva lijeka kreÊe se u ras-ponu od 1-45%, a razlog je nedostatak definicije kojom seprocjenjuje odgovor na terapiju i razlike u laboratorijskim te-stovima (koncentracije agonista te (ne)definiranih “cut off”vrijednosti). Dosadaπnja istraæivanja su pokazala da supromjene vezane za COX-1, nedostatna koliËina lijeka napotrebnom mjestu djelovanja npr. zbog slabije apsorpcije li-jeka ili velikog obrtaja trombocita u odreenim bolestimaznaËajke rezistencije ASK28. U odnosu na ASK, mehanizamdjelovanja klopidogrela je razliËit. Njegov aktivni metabolit,ireverzibilni inhibitor trombocitnog P2Y12 ADP receptora na-staje u dvostupanjskom procesu koji ukljuËuje sustav enzi-ma citokroma P450. Sve je viπe podataka o tome da je uzrokvarijabilnosti odgovora na terapiju mehanizam pretvorbeklopidogrela u aktivni metabolit. Prema tome, odluka o nje-govoj primjeni u lijeËenju bi se trebala donijeti nakon πto seispita trombocitna funkcija, a dodatne informacije u smislurezistencije bi se mogle dobiti genotipizacijom pojedinihizoenzima CYP sustava koji su odgovorni za pretvorbu klo-pidogrela u aktivni metabolit. Za sada nema preporuke zasvakodnevnu praksu jer tek treba pronaÊi idealni laboratori-jski test koji bi dao odgovor na osnovno pitanje o kliniËkojkoristi primjene klopidogrela. Novija kliniËka istraæivanja su pokazala superiornu efikas-nost primjene CYP12 antagonista prasugrela i tikagrelora uzASK kod pacijenata koji prolaze koronarnu revaskularizacijute poboljπanu inhibiciju trombocita ex-vivo kod pacijenatakoji ne odgovaraju na primjenu klopidogrela. Meutim, kakosu tijekom lijeËenja pojedine podgrupe pacijenata pokazalerazliku u smislu efikasnosti terapije, æeljenog ishoda i nuspo-java poput krvarenja, kod odluke o njihovoj primjeni u sus-pektnom AKS u obzir bi trebalo uzeti pacijentov rizik zatrombozu (STEMI, prethodna stent tromboza), potrebni zah-vat (npr. kompleksna PCI, ugruπak in-situ) i Ëimbenike kojimogu utjecati na sigurnost (dob, teæina, prethodni MU, vjero-jatnost kirurπke revaskularizacije). StavljajuÊi u fokus indi-vidualni omjer rizika i koristi za pacijenta uz odgovarajuÊuprocjenu funkcije trombocita kada je to indicirano te nas-tavak istraæivanja uËinka prasuagrela i tikagrelora trebale bibiti kljuËne strategije u smislu primjene dvojne antitromboc-itne terapije. Lijekovi iz skupine VKA se rjee primjenjujukod pacijenata s AKS jer je slijed terapije vrlo opseæan. U

of course must be observed in the context of the patient’stolerance, price etc.

New anticoagulants and acute coronary syndrome

Acute coronary syndrome defines the range of myocardialischemic conditions that include unstable angina and myo-cardial infarction (MI) with ST-segment elevation (STEMI) ornon ST-segment elevation (NSTEMI), and are commonly aresult of acute coronary thrombosis. Patients with ACS arehigh risk patients, and a rapid diagnosis and application ofappropriate therapy can improve the short and long termoutcome7,24. The management of ACS has been significant-ly improved in recent years with the introduction of therapeu-tic intervention strategies, potent platelet inhibitors and thetreatment regime in terms of secondary prevention7,24. De-spite a significant reduction in mortality and morbidity, therisk of recurrent ischemic events still remains high. Antiaggregation therapy is an important component of pre-vention of ACS6,24-27. Despite the proven effect of aspirin andclopidogrel in the treatment of ACS, one part of the treatedpatients does not respond to the therapy and develop throm-botic complications. The frequency of inadequate responseto these two drugs ranges from 1 to 45%, and the reason isthe lack of definition used to assess the response to the the-rapy and differences in the laboratory tests (concentration ofagonist and (non)defined “cut off” value). Previous trialshave shown that the changes are attributable to COX-1, in-sufficient amount of the drug at the required point of action,for instance as a result of poor absorption of the drug or ahigh platelet turnover in certain diseases, ASC resistancefeatures28. Compared to aspirin the mechanism of clopido-grel action is different. Its active metabolite, irreversible inhi-bitor of the platelet P2Y12 ADP receptor occurs in a two-step process involving the cytochrome P450 enzyme sys-tem. There is an increasing number of information claimingthat the cause of the variability of response to the therapy isthe mechanism of conversion of clopidogrel into its activemetabolite. Accordingly, the decision on its application in thetreatment should be made after the platelet function hasbeen tested, while some additional information regarding theresistance could be obtained by genotypization of specificCYP isoenzymes that are responsible for the conversion ofclopidogrel into its active metabolite. Certainly for the timebeing, there is no recommendation for the daily practice, be-cause we should find an ideal laboratory test that would givean answer to the basic question about the clinical benefit ofapplication of clopidogrel. Recent clinical trials have demonstrated the superior effica-cy of CYP12 administration and antagonists such as prasug-rel and ticagrelor with aspirin in patients undergoing the co-ronary revascularization and improved platelet inhibition ex-vivo in patients who do not respond to clopidogrel admini-stration. However, during the time of treatment, specific sub-groups of patients showed a difference in the treatment effi-cacy, the desired outcome and side effects such as blee-ding, the patient’s risk for thrombosis (STEMI, previous stentthrombosis), required surgery (e.g. complex PCI, clot in-situ)and factors that may affect the safety (age, weight, previousstroke, the likelihood of surgical revascularization) shouldconsider when making a decision on their administration insuspected ACS. Focusing on the individual risk-benefit ratiofor the patient with an appropriate assessment of the plateletfunction when indicated and continuation of the investigationof the effects of prasuagrel and tickagrelor should be thecrucial strategies for the application of dual antiplatelet ther-apy.



tom smislu novi antikoagulansi moæda mogli pruæiti unapri-jeenje u lijeËenju AKS25,26.

Novi antikoagulansi u sekundarnoj prevencijiakutnog koronarnog sindroma

Kako bi se utvrdilo je li primjena dabigatrana, rivaroksabana,apiksabana te dareksabana kod ispitanika s NSTEMI i STE-MI uËinkovita u smislu smanjenja ponovnih ishemijskih do-gaaja provedena je faza II kliniËkih istraæivanja6,7,25. U istraæivanju RE-DEEM (Dose Finding Study for Dabiga-tran Etexilate in Patients With Acute Coronary Syndrome)kod pacijenata s AKS su primjenjene iste doze dabigatranakao i u istraæivanjima s FA (110 i 150 mg) pri Ëemu je, ovis-no o dozi, zabiljeæena veÊa uËestalost krvarenja iz gastroin-testinalnog trakta, ali ne i znaËajan rezultat u smislu isho-da29. U studiji ATLAS ACS-TIMI 46 (Rivaroxaban in CombinationWith Aspirin Alone or With Aspirin and a Thienopyridine inPatients With Acute Coronary Syndromes-Thrombolysis InMyocardial Infarction) kod ispitanika s AKS primjenom riva-roksabana su zabiljeæene kliniËki znaËajne komplikacije kr-varenja kod pacijenata koji su istovremeno primali ASK ilidvojnu antiagregacijsku terapiju30. U usporedbi s primjenomplaceba neπto manji omjer rizika zabiljeæen je primjenom ri-varoksabana u kontekstu ishoda, MU ili ponovne ishemijekoja zahtjeva revaskularizaciju. U treÊoj fazi istraæivanja(ATLAS ACS-TIMI 51) sa srednjim vremenom primjene riva-roksabana od 13,1 mjeseci, u dozi od 2,5 i 5 mg u uspored-bi s placebom zabiljeæena je znaËajno manja incidencija kar-diovaskularne smrti, IM i MU31.Primjena apiksabana u istraæivanju APPRAISE (Apixabanfor Prevention of Acute Ischemic and Safety Events) takoerje pokazala o dozi ovisan poveÊan rizik krvarenja kada segovori o dozama od 2,5 i 10 mg, a istraæivanja s dozamaveÊim od 10mg nisu nastavljena. Incidencija u smislu kardio-vaskularne smrti, IM, ponovne ishemije koja zahtjeva re-vaskularizaciju ili ishemijskog MU nije bila znaËajno manjapri primjeni 2,5 ili 10 mg apiksabana u odnosu na placebo.Meutim faza tri istraæivanja, tj. APPRISE-2 je brzo prekinu-ta zbog nuspojava poput kliniËki znaËajnog subkutanog kr-varenja, a bez dokazane koristi primjene lijeka. Istraæivanje RUBY-1 (Study Evaluating Safety, Tolerabilityand Efficacy of YM150 in Subjects With Acute CoronarySyndromes) dalo je obeÊavajuÊe rezultate u smislu primjenedareksabana u prevenciji ishemijskih dogaaja u AKS, me-utim njegova primjena zajedno s dvojnom antiagregacij-skom terapijom u odnosu na placebo pokazala je o doziovisno krvarenje, bez dodatnih izmjena u smislu sigurnostnjegove primjene, ali ni koristi32. Djelovanje jedinog novog parenteralnog antikoagulansa is-pitano je u istraæivanju SEPIA-ACS1 TIMI 42 (Otamixabanfor the treatment of patients with non-ST-elevation acutecoronary syndromes). Usporeeno je djelovanje 5 razliËitihdoza otamiksabana primjenom bolusa 0,08 mg/kg, a nakontoga infuzije od 0,035, 0,070, 0,105, 0,140 ili 0,175 mg/kg/h)kod 3.241 visokoriziËnog pacijenta s AKS bez ST-elevaci-je33. Za procjenu efikasnosti tijekom sedam dana praÊena jepojava ukupnog mortaliteta, ponovnog IM, ishemije koja jezahtijevala hitnu revaskularizaciju ili tromboembolijske kom-plikacije kod PCI. Ispitivanje s najmanjom dozom otamiksa-bana je prekinuto zbog neadekvatnog protuzgruπavajuÊegdjelovanja, a primjena bolusa otamiksabana u dozi 0,08mg/kg, uz nastavak infuzija od 0,105 ili 0,140 mg/kg/h je

Drugs from the VKA group are administered more rarely inpatients with ACS, because the therapy monitoring is verycomprehensive. It is believed that in this sense the new anti-coagulants may provide improvement in the treatment ofACS25,26.

New anticoagulants in secondary preventionof ACS

Phase II of clinical trail was conducted as to determinewhether the application of dabigatran, rivaroxaban, and api-xaban and darexaban in patients with NSTEMI and STEMIis effective in reducing recurrent ischemic events6,7,25. In the RE-Deem study (Dose Finding Study for DabigatranEtexilate in Patients With Acute Coronary Syndrome) thesame doses of dabigatran were applied as in AF trials (110and 150 mg) which resulted in a higher frequency of dose-dependent gastrointestinal bleeding, but not in a significantresult in terms of the outcome29. In the ATLAS ACS-TIMI 46 study (Rivaroxaban in Combina-tion With Aspirin Alone or With Aspirin and a Thienopyridinein Patients With Acute Coronary Syndromes-ThrombolysisIn Myocardial Infarction) the dose-dependent bleeding wasalso recorded in ACS patients receiving Rivaroxaban whosimultaneously received aspirin or dual therapy for plateletinhibition30. Compared with placebo, a slightly lower risk ratiohas been recorded by rivaroxaban administration regardingthe outcome, stroke or recurrent ischemia that requiresrevascularization. In the third phase of the study (ATLASACS-TIMI 51) mean time of applying rivaroxaban was 13.1months, and in comparisons of administration of drug doseof 2.5 and 5 mg with placebo, a significantly lower incidenceof cardiovascular death, MI and stroke was recorded31.The application of apixaban in the APPRAISE study (Apixa-ban for Prevention of Acute Ischemic and Safety Events)also showed a dose-dependant increased risk of bleedingwhen talking about the 2.5 and 10 mg doses, while the trialswith doses greater than 10 mg were discontinued. The inci-dence regarding the cardiovascular death, MI, recurrent is-chemia requiring revascularization, or ischemic stroke wasnot significantly lower while administering 2.5 or 10 mg api-xaban compared to placebo. However, phase three study,i.e. APPRISE-2 was prematurely discontinued as a conse-quence of side effects such as extensive subcutaneousbleeding, without any proven benefit. The RUBY-1 study (Study Evaluating Safety, Tolerability andEfficacy of YM150 in Subjects With Acute Coronary Syndro-mes) has shown promising results in respect of the darexa-ban application in the prevention of ischemic events in ACS,but its application with dual antiplatelet therapy has shown adose-dependant bleeding compared to placebo, withoutadditional changes related to safety of its application and nobenefits as well32. The efficacy of the only new parenteral anticoagulant wastested in SEPIA-ACS1 TIMI 42 study (Otamixaban for thetreatment of patients with non-ST-elevation acute coronarysyndromes). The study compared the efficacy of 5 differentdoses of otamixaban by using bolus of 0.08 mg/kg, followedby infusion of 0.035, 0.070, 0.105, 0.140, or 0.175 mg/kg/h)in 3,241 high-risk patients with non ST-segment elevationACS33. The combined end-point of total mortality, recurrentMI, ischemia requiring urgent revascularization, or thrombo-embolic complications in PCI were followed up to estimatethe efficacy during the seven days’ period. The investigationwith the lowest dose of otamixaban was early terminatedbecause of its inadequate antithrombotic efficacy, while theapplication of the otamixaban bolus in a dose of 0.08mg/kg,

followed by an infusion of 0.105 or 0.140mg/kg/h showedthe best efficacy and safety ratio, as well as reduction ofmortality and ischemic complications by 40% in comparisonwith heparin. The investigation of the above doses was in-cluded in the third phase of the investigation.All of the investigations conducted in patients with ACS weredesigned in the manner to assess the safety of receivingone to two doses of a drug daily throughout a period of 6months. Most of the patients received dual anti-aggregationtherapy (aspirin and clopidogrel) that consequently has re-sulted an upward trend in bleeding. According to the guide-lines of the European Society of Cardiology in the manage-ment of non ST-segment elevation ACS, more effectiveP2Y12 inhibitors prasugrel and ticagrelor are preferred anti-platelet drugs in combination with aspirin7,26. Prolonged treat-ment with prasugrel or ticagrelor is associated with a reduc-tion of undesired events compared with clopidogrel (tica-grelor also with decreased mortality) and a relatively smallincrease (30%) in the risk of major bleeding compared withthat published for FXa inhibitors. Therefore, the administra-tion of any of these new antiplatelet agents instead of clopi-dogrel seems to be better if we add them to FXa inhibitors.Certainly, when FXa inhibitors are added to the current anti-platelet therapy in patients with ACS, the possibility of unde-sirable bleeding should be kept in mind. It has not beenproven whether lower doses of any of the new anticoagu-lants may be useful in concomitant presence of any of thenew, more effective anti-platelet drugs. The current resultson the effect of FXa inhibitors in ACS will not result in achange of the clinical practice for the time being. They how-ever, open a new path for the investigation due to the evi-dence that they can reduce ischemic events in patients withcoronary heart disease. The challenge for the future investi-gation will be to identify the combination of antithromboticdrugs that are aimed at reduction of thrombotic events witha low risk of bleeding.

Laboratory monitoring of new anticoagulants

Irrespective of whether a therapy with heparin or warfarin isapplied in a patient, it must be regularly monitored due to do-se adjustment and the fact that excessive coagulation in-creases the risk of thrombosis, while the low level of coagu-lation increases the risk of bleeding. Today their monitoringis a routine procedure owing to the use of simple laboratorytests such as prothrombin time/international normalized ra-tio (PT/INR) and activated partial thromboplastin time (APTT). Due to stable and reproducible kinetics, the new anticoagu-lant drugs are considered to be the drugs that do not requiremonitoring34. Therefore, clinical trials of new drugs were de-signed in a manner that drugs were applied in a fixed dosewithout a laboratory monitoring. However, given that manypatients who undergo coagulation screening will take thesedrugs, it has to be known to what extent the coagulation isdelayed by means of the use of routine coagulation tests.Furthermore, there are numerous cases when we have toknow whether the active agent is present e.g. in case of hos-pitalization of a fainted patient with bleeding symptoms orurgent surgery where the presence of active anticoagulantsmay affect the risk of surgical bleeding, in case of thrombo-sis or hemorrhage while taking anticoagulation therapy inorder to estimate the error of the therapy, when switchingfrom one anticoagulant to another or identifying drug inter-actions35,36. All of this suggests a potential benefit of the ther-apy monitoring in some specific clinical situations37,38. Cur-rent insights regarding monitoring are scarce, and the beststrategy to control new drugs is to be revealed. In order to

pokazala najbolji omjer efikasnosti i sigurnosti, te smanjenjemortaliteta i ishemijskih komplikacija za 40% u usporedbi sheparinom. Istraæivanje navedenih doza uπlo je u treÊu fazuispitivanja.Sva navedena istraæivanja o djelovanju novih antikoagula-nasa u AKS dizajnirana su tako da se procjeni sigurnostprimjene jedne do dvije doze dnevno ovih lijekova u raz-doblju od πest mjeseci. U veÊini sluËajeva, pacijenti su pri-mali i dvojnu antiagregacijsku terapiju (ASK i klopidogrel),πto je rezultiralo trendom porasta krvarenja kod ovih pacije-nata. Prema vaæeÊim smjernicama Europskog kardioloπkogdruπtva u lijeËenju AKS bez elevacije ST-segmenta u kom-binaciji s ASK preferira se primjena P2Y12 inhibitora pra-sugrela i tikagrelora7,26. Dugotrajno lijeËenje prasugrelom ilitikagrelorom je povezano s smanjenjem neæeljenih dogaa-ja u usporedbi s primjenom klopidogrela (tikagrelor i s niæimmortalitetom) te relativno malim porastom rizika (30%) veli-kog krvarenja u usporedbi s rizikom objavljenim za inhibitoreFXa. Stoga, uporaba bilo kojeg od ovih antotrombocitnih lije-ka uz inhibitore FXa Ëini se bolja od primjene klopidogrela.Dakako, kod pacijenata s AKS pri dodavanju inhibitora FXatrenutnoj antitrombocitnoj terapiji treba razmiπljati i o mo-guÊem neæeljenom krvarenju. Nije dokazano mogu li niæedoze bilo kojeg od novih oralnih antikoagulansa biti korisneu prisutnosti bilo kojeg od navedenih antitrombocitnih lijeko-va. Trenutne spoznaje o djelovanju inhibitora FXa u AKS zasada neÊe rezultirati promjenama u kliniËkoj praksi. Oneipak, otvaraju novi put za istraæivanje zbog dokaza da mogureducirati ishemijske dogaaje kod pacijenata s koronarnombolesti srca. U buduÊnosti, izazov Êe biti identificirati kombi-naciju antitrombotika Ëija Êe primjena uz manju incidencijukrvarenja smanjiti broj trombotskih dogaaja.

Laboratorijski slijed novih antikoagulanasa

Neovisno o tome primjenjuje li se kod pacijenta terapija var-farinom ili heparinom, zbog prilagodbe doze lijeka i Ëinjeniceda prekomjerna koagulacija moæe poveÊati rizik tromboze, apreslaba rizik krvarenja ona se mora redovno pratiti. Danasje njihov monitoring rutinski u smislu uporabe jednostavnihlaboratorijskih testova poput protrombinskog vremena/inter-nacionalnog normalizirajuÊeg omjera (PV/INR) ili aktiviranogparcijalnog tromboplastinskog vremena (APTV). Novi protuzgruπavajuÊi lijekovi smatraju se lijekovima koji nezahtjevaju monitoring zbog svoje stabilne i reproducibilnekinetike34. Stoga su i kliniËka ispitivanja s novim lijekovimauglavnom dizajnirana tako da su lijekovi primjenjivani u fiks-noj dozi bez laboratorijskog monitoringa. Meutim, kako Êebrojni pacijenti koji prolaze koagulacijski probir koristiti ovelijekove, neophodno je znati kako i do kojeg je stupnja koa-gulacija odgoena u smislu koriπtenja rutinskih koagula-cijskih testova. Nadalje, brojni su sluËajevi u kojima trebaznati je li i u kojoj mjeri aktivni agens prisutan npr. kod hos-pitalizacije pacijenta bez svijesti radi krvarenja ili zbog hitneoperacije gdje prisutnost aktivnih antikoagulanasa moæe ut-jecati na rizik kirurπkog krvarenja, u sluËaju tromboze ili he-moragije dok je pacijent na antikoagulantnoj terapiji kako bise procijenila pogreπka terapije te kod prelaska s jednog nadrugi antikoagulans ili identifikacije interakcija lijekova35,36.Sve ovo ipak sugerira moguÊu korisnost slijeda terapije uspecifiËnim kliniËkim situacijama37,38. Spoznaje o monitoringuza sada nisu velike, a najbolja strategija kontrole terapije tektreba biti utvrena. Kako bi se izbjegla pogreπna interpre-tacija rezultata rutinskih koagulacijskih testova (PV, APTV,


TV i fibrinogen), potrebno je znati i na koji naËin novi anti-koagulansi djeluju na navedene testove.

Utjecaj novih antikoagulanasa na rutinskekoagulacijske testove

Utjecaj dabigatrana i rivaroksabana na rezultate rutinskihkoagulacijskih testova je otkriven pomoÊu in vitro istraæivan-ja dodajuÊi u plazmu normalnih uzoraka odreenu koncen-traciju aktivne komponente lijeka ili prikupljanjem plazmeispitanika (volontera/pacijenata) kod kojih je primjenjen lijek.Ex vivo je istraæen i utjecaj novih lijekova na globalne testo-ve zgruπavanja, a iako spoznaje nisu velike, izgleda da seneki globalni i specifiËni testovi mogu upotrijebiti za procjenunjihovog uËinka37,38,39.Inhibitori trombina i FXa utjeËu na test PV i to na naËin daproduæuju vrijeme u sekundama te poveÊavaju INR ovisno oprimjenjenoj dozi lijeka. Istraæivanja s rivaroksabanom i da-bigatranom su pokazala da je test PV osjetljiviji na primjenurivaroksabana nego dabigatrana, ali u oba sluËaja produ-æenje PV ovisi o upotrebljenom reagensu/tromboplastinu.Za razliku od primjene VKA gdje se osjetljivost razliËitihtromboplastina rjeπava primjenom INR, ovdje to nije mo-guÊe. Iako se vrijednost PV moæe koristiti kao relativno dos-tupan test za procjenu relativnog stupnja antikoagulacijekod pacijenata koji primaju rivaroksaban, on nije dovoljnoosjetljiv u smislu detekcije kliniËki relevantnih promjena ukoncentraciji lijeka. In vitro studije su pokazale da i apiksa-ban produæuje PV, meutim mjerenje inhibicije aktivnostiFXa dalo je bolji uvid u koncentracije apibaxana u plazmi odPV testa5,36,37.Primjena direktnih inhibitora faktora Xa ili inhibitora trombi-na takoer dovodi do produæenja vrijednosti APTV. Rezultatiistraæivanja su pokazali da je kod pacijenata koji dobivaju110-150 mg dabigatrana dva puta dnevno u piku koncen-tracije omjer APTV otprilike 1,4-1,8x veÊi od kontrole. Re-zultati dakako ovise primjenjenom reagensu te pripada-juÊem aktivatoru tj. sadræaju fosfolipida. Potrebne su daljnestudije kako bi se ustanovila relativna osjetljivost APTV nadabigatran i razvile preporuke o tome koji bi reagens bilobolje primjeniti. Rivaroksaban takoer pokazuje o dozi ovi-san odgovor na APTV. Njegova primjena u dozi od 20 mgkod zdravih muπkaraca uzrok je porasta APTV za otprilike1,5-1,8x u odnosu na kontrolnu vrijednost. Izgleda da je priprimjeni niskih koncentracija rivaroksabana i dabigatranatest osjetljiviji na dabigatran. U zdravih volontera, primjenaapixabana u dozi od 50 mg uzrokovala je produæenje APTVod oko 1,2x u odnosu na kontrolu, a produæeno APTV je po-kazalo korelaciju s koncentracijama apixabana odreenim uplazmi. Inhibitori FXa nemaju utjecaja na test trombinskog vremena(TV), meutim inhibitori trombina, direktni i indirektni, moguuzrokovati njegovo produæenje. TV se moæe koristiti za sli-jed terapije dabigatranom. Dakako, rezultat ovisi o primjen-jenom reagensu, a veÊina testova je preosjetljiva. Stoga seTV moæe koristiti kao osjetljiva metoda za odreivanje pri-sutnosti minimalnih koncentracija lijeka, a prisutnost lijekase moæe sa sigurnoπÊu iskljuËiti ako je TV normalno. Kakoje TV vrlo osjetljivo na ove inhibitore za slijed terapije arga-trobana te dabigatrana razvijena je i modifikacija testa na-zvana HemoClot5,36,37.Inhibitori FXa ne utjeËu na odreivanje fibrinogena me-todom po Claussu koja se bazira na dodatku suviπka trom-bina plazmi. Meutim, inhibitori trombina mogu uzrokovati

prevent misinterpretation of the results of routine coagula-tion tests (PT, APTT, TT, and fibrinogen) it is important toknow influence of the new anticoagulants to these tests.

The impact of new anticoagulants on routinecoagulation tests

The impact of dabigatran and rivaroxaban on the results ofroutine coagulation tests is discovered by in vitro studies byadding a certain concentration of the drug active componentto plasma of normal samples or by collecting the plasmafrom subjects (volunteers or patients) who take these drugs.Influence of the new oral anticoagulants on the global coa-gulation tests has been also investigated ex vivo after theadministration of these drugs and although the insights arenot extensive, it seems that some global and specific testscan be used to assess their effect37,38,39.Inhibitors of thrombin and FXa affect PT, by means of theprolongation of time in seconds and increase in the INR va-lue, dependently on the applied dose. Investigations with ri-varoxaban and dabigatran has shown that PT is more sensi-tive to the rivaroxaban than on to dabigatran administration,but in both cases prolongation of PT depends on used rea-gents/thromboplastin. Unlike the application of VKA wherethe sensitivity of various thromboplastins is solved by ap-plying INR, here it is not possible. Although the PT can beused as a relatively available test for the determination of re-lative intensity of anticoagulation due to rivaroxaban, it is nota sufficiently sensitive test that could detect clinically rele-vant changes in the drug concentration. In vitro studies haveshown that apixaban also prolongs PT, however, measuringof the inhibition of the FXa activity provides a better insightinto the concentrations of apibaxan in plasma than the PTtest5 36,37.With the use of the direct factor Xa inhibitors and thrombininhibitors prolongation of APTT has also occurred. Somestudies have shown that administration of 110 or 150 mg ofdabigatran b.i.d. at maximum of plasma concentration pro-longs APTV ratio approximately 1.4-1.8x. Certainly, the re-sult depends on used reagents, with corresponding activa-tor and certain content of phospholipids. However, furtherstudies are warranted in order to reveal relative sensitivity ofAPTT due to dabigatran and to develop recommendationsby means of the use of appropriate reagent. Rivaroxabanhas also influence on APTT prolongation in a dose depend-ent manner. The administration of 20mg of rivaroxaban inhealthy men has resulted in approximately 1.5-1.8x increaseof APTT ratio. It seems that at administration of low concen-trations of dabigatran and rivaroxaban APTT is much moresensitive to a dabigatran. In healthy volunteers, administra-tion of 50mg dose of apixaban has resulted in an increaseAPTT to approximately 1.2x and the prolonged APTT corre-lated with concentrations of apixaban determined in theplasma.The FXa inhibitors have no effect on the thrombin time (TT),however thrombin inhibitors, direct and indirect ones causeits prolongation. TT can be used for a monitoring of throm-bin inhibitors such as dabigatran. However, result dependson used reagents, and in most cases it is too sensitive tothese inhibitors. Therefore, TT can be used as relativelysensitive test for the determination of relative low concentra-tions of drug in the plasma. Presence of the dabigatran inthe plasma could be excluded if TT is normal. As TT is verysensitive to these inhibitors, a test modification namedHemoClot has been developed for the argatroban and dabi-gatran therapy monitoring5,36,37.


Inhibitors of FXa do not affect the determination of fibrino-gen by Clauss method, which is based on the addition ofexcess thrombin to the plasma. However, thrombin inhi-bitors may lead to false negative reduction of concentrationin some tests5,36,37.

The impact of new anticoagulants on theglobal and chromogenic coagulation tests

Thromboelastography is a global coagulation test and its po-tential use with new anticoagulants is still under investiga-tion. The results obtained so far have showed a good corre-lation between the concentration and prolonged clotting timefor several anticoagulants and in that sense the recommen-dations are expected. In sense of dabigatran monitoring, theEcarin clotting time (ECT) test has shown satisfactory re-sults. Dabigatran prolongs ECT in the way dependant on theapplied dose, and the test can be calibrated according to thedabigatran concentration. Due to its mechanism of action, ri-varoxaban is not expected to affect the ECT, whereas theimpact of the apixaban has not been tested yet or at leastthere are no published results. Chromogenic test that measures anti-Xa activity is used tomeasure the effect of LWMH if applied in patients with renalinsufficiency, obese people and pregnant women. Admini-stration of rivaroxaban also exerts concentration dependanteffect on these tests, and furthermore specific modificationof the test in order to measure effect of rivaroxaban in a wideconcentration span (20-660 ng/L) in plasma has been devel-oped. Chromogenic test for measuring anti-IIa activity of dabiga-tran is under investigation, whereas specific variant of theanti-FIIa activity test has been developed in order to assessthe activity of hirudin and argatroban.

Recommendations for monitoring new anticoagulants

The data related to the monitoring of new anticoagulants arelimited, and therefore general guidelines do not exist. Owingto a limited data, British Committee for Standards in Hema-tology has gave recommendation for monitoring the effect ofthe dabigatran and rivaroxaban39. Considering it, every labo-ratory that participated in evaluation of their effect has totake into account sensitivity of the reagents in use. For thedetermination of relative intensity of anticoagulation due todabigatran APTT could be used. APTT should not be usedfor the determination of the drug concentrations in the plas-ma, and in that sense TT could be helpful by means that nor-mal TT mean that drug concentration is very low. In terms ofthe assessment of the dabigatran effect, ECT or modifica-tion of TT test known as HemoClot could be used. For thedetermination of relative intensity of anticoagulation due torivaroxaban PT could be used, since it has higher sensitivi-ty on this drug in comparison to APTT. Furthermore, consi-dering both of the tests, PT and APTV, recommendation isto express results as a ratio of the clotting time in the patientplasma according to clotting time in normal plasma. Con-sidering INR values, the result could be taken into accountonly if INR was validated for the appropriate anticoagulants.If this is not a case, and INR is validated according to VKAsit should not be used as it dramatically shows non-repro-ducible results and the variability among the test reagents5,39.In order to assess concentration of particular drug, a highperformance liquid chromatography or mass spectrometrycould be used.


laæno negativno smanjenje koncentracije fibrinogena s ne-kim testovima5,36,37.

Utjecaj novih antikoagulanasa na globalne ikromogene testove zgruπavanja

Tromboelastografija je globalni test zgruπavanja Ëija se po-tencijalna uporaba kod novih antikoagulanasa tek istraæuje.Dosadaπnji rezultati su pokazali dobru povezanost koncen-tracije lijeka i produæenog vremena zgruπavanja za nekolikoantikoagulansa, i stoga se uskoro oËekuju i smjernice zanjezinu primjenu. U smislu monitoringa dabigatrana vrlo do-bre rezultate pokazao je test Ekarinskog vremena zgruπa-vanja (ECT). Dabigatran produæuje ECT ovisno o primjen-jenoj dozi, a test je moguÊe i kalibrirati prema koncentracija-ma dabigatrana. Prema svom mehanizmu djelovanja zarivaroksaban se ne oËekuje da Êe utjecati na ECT, dok utje-caj apiksabana nije ispitan ili o tome nema objavljenih rezul-tata. Kromogeni test koji mjeri anti-Xa aktivnost upotrebljava seza procjenu terapijskog uËinka LWMH pri primjeni lijeka kodpacijenata s renalnom insuficijencijom, pretilih osoba i trud-nica. Primjena rivaroksabana takoer moæe utjecati ovisno okoncentraciji na ove testove, a nadalje je razvijena i varijan-ta istog testa koja je specifiËna za rivaroksaban tj. pogodnaza mjerenje πirokog raspona njegovih koncentracija (20-660ng/L) u plazmi. Kromogeni test za mjerenje anti-IIa aktivnosti tj. dabigatranaje u razvitku, a varijanta ovog testa za procjenu aktivnosti hi-rudina i argatrobana moæe se veÊ neko vrijeme naÊi na træi-πtu.

Preporuke za monitoring novih antikoagulanasa

Podaci o monitoringu novih lijekova i njihovom utjecaju napostojeÊe testove su ograniËeni, a stoga joπ uvijek nisu raz-vijene opÊe smjernice. Na temelju ograniËenih podataka Bri-tish Comitee for Standards in Hematology je napravio pre-poruke za procjenu antikoagulacijskog uËinka dabigatrana irivaroksabana39. Smatra se da bi svaki laboratorij koji sud-jeluje u procjeni njihovog uËinka trebao uzeti u obzir osjetlji-vosti koagulacijskih testova koje koristi. Za relativnu proc-jenu antikoagulacijskog uËinka dabigatrana moæe se koristi-ti APTV. APTV se ne smije koristiti za procjenu koncentra-cije lijeka u plazmi, a u tom smislu normalno TV bi znaËiloda je njegova koliËina u plazmi izrazito niska. U smislu proc-jene uËinka dabigatrana moæe se koristiti i ECT-test ili mod-ificirani test TV, HemoClot. Za relativnu procjenu antikoa-gulacijskog uËinka rivaroksabana moæe se koristiti PV, ob-zirom da je neπto osjetljivije na ovaj lijek u odnosu na APTV.Nadalje, u oba sluËaja i kod PV i APTV preporuka je da serezultati izraze kao omjer vremena izmjerenog u pacijen-tovoj plazmi prema onome u normalnoj standardnoj plazmi.©to se vrijednosti INR tiËe, moæe se uzeti u obzir iskljuËivoako je validiran za lijek koji se testira. Meutim, ako je INRvalidiran prema VKA ne uzima se u obzir jer pokazuje dra-matiËno nereproducibilne rezultate i varijabilnost ovisnu oprimjenjenom reagensu5,39. U smislu procjene koncentracijelijeka moæe se koristiti visokotlaËna tekuÊinska kromatografi-ja ili masena spektrometrija.

Debate and conclusions

By introducing new antithrombotic drugs, an important steptowards a simpler, more efficient and safer treatment ofthrombosis has been made. Compared to conventionaldrugs, new oral anticoagulants have improved pharmacoki-netic and pharmacodynamic profile5, and currently availabledata suggests their different efficacy and safety profile fordifferent clinical indications.The current application of these new drugs began with anaim to prevent venous thromboembolism after orthopedicsurgical procedures, and they have been approved in manycountries for these indications and prevention of stroke inpatients with AF. The results at least showed that thesedrugs are as efficient as VKA and/or heparin for approvedindications. However, although the availability of an alterna-tive therapy represents a major breakthrough, we still needmore information about what are the patients that mostlybenefit from the new drugs. More information is also neededon the transition between the two drugs and discontinuationof the treatment procedure and/or surgical procedure anddosing in kidney patients. Due to a shorter half-life of neworal anticoagulants, the patients who stop taking them maybe at an increased risk for systemic embolism in a shorterperiod relative to the one when warfarin effects stop to beeffective. Also when switching e.g. from dabigatran to VKA,warfarin should be administered approximately 3 days be-fore a patient stops taking dabigatran under the assumptionthat the patient has normal creatinine clearance40,41. Besi-des, one must keep in mind any potential interactions of the-se drugs with some other drugs which proved to be impor-tant for the application in long term indications40. All inducersor inhibitors of CYP3A4 (e.g. macrolide antibiotics or calci-um channel blockers) or P-glycoprotein (immunosuppres-sants, calcium channel blockers ...) have to be applied witha great caution in patients receiving FXa inhibitors or theirsimultaneous administration should be avoided. The new anticoagulant drugs are introduced as drugs thatdo not require monitoring. Although this is considered to bea marketing advantage of these drugs, this disadvantagecan become very important for patients who experience anischemic event due to an error made in the therapy. As theywere not developed as drugs that require monitoring, the la-boratory tests for measuring their anticoagulant effect ordrug level in the serum still have to be standardized. Cur-rently, none of the tests has been validated as the optimaltest to measure their efficacy. More information is also war-ranted on how to follow up patients with bleeding becausethere are no specific antidote for any of these newagents40,41. So far, supportive therapy by the fresh frozenplasma, and the use of FVII concentrate, as well as the pro-thrombin complex is recommended. Recently conducted tri-als have shown that prothrombin complex can reverse theeffect of rivaroxaban, but not those of dabigatran. In case ofdabigatran, the hemodialysis may be effective in eliminatingas much as 60% of dabigatran from the blood during the pe-riod of 2-3 hours which can be exploited in terms of its toxi-city40,41. Expectations of the new therapy are great. Although moni-toring of the new drugs in comparison to warfarin can be re-duced, the number of patient’s visits can not be reduced,while a periodic assessment of his/her condition by meansof the exclusion of anemia, thrombocytopenia, liver or kid-ney disease as to avoid the bleeding complications is nec-essary as long as the patient receives the therapy. Ad-ditionally, high price of these drugs is certainly one of the


Diskusija i zakljuËci

Predstavljanjem novih protuzgruπavajuÊih lijekova naprav-ljen je vaæan je korak prema jednostavnijem, efikasnijem isigurnijem lijeËenju tromboze. U odnosu na konvencionalne,novi lijekovi poboljπanog su farmakokinetskog i farmakodi-namskog profila5, a trenutno dostupni podaci ukazuju na nji-hovu razliËitu efikasnost i sigurnosni profil kod razliËitih kli-niËkih indikacija. Primjena novih lijekova zapoËela je u smislu prevencije ven-skog tromboembolizma nakon ortopedskih zahvata, a za na-vedenu indikaciju kao i prevenciju MU kod pacijenata s FAnjihova primjena odobrena je u mnogim zemljama. Rezultatiistraæivanja su pokazali da su ovi lijekovi u najmanju rukuefikasni kao VKA i/ili heparin. Meutim, iako dostupnost al-ternative terapije predstavlja veliki napredak, potrebno jeviπe informacija o tome koji pacijenti imaju najveÊu korist odprimjene ovih lijekova. Viπe informacija potrebno je i o tran-ziciji izmeu dva lijeka te prekidu postupka lijeËenja i/ili indi-ciranog zahvata te njihovog doziranja kod bubreænih bo-lesnika. Zbog kratkog vremena poluæivota novih oralnih anti-koagulanasa, prestankom njihovog uzimanja pacijenti mogubiti pod veÊim rizikom sistemskog embolizma u razdobljurelativno kraÊem u onosu na prestanak uzimanja varfarina.Takoer kod prelaska npr. s dabigatrana na VKA, varfarin bise trebao primjeniti otprilike 3 dana prije prestanka uziman-ja dabigatrana uz pretpostavku da pacijent ima normalniklirens kreatinina40,41. Nadalje treba imati na umu i moguÊeinterakcije ovih lijekova s drugim lijekovima πto je vaæno zanjihovu primjenu u dugotrajnim indikacijama40. Svi induktoriili inhibitori CYP3A4 (npr. makrolidni antibiotici ili blokatorikalcijskih kanala) ili P-glikoproteina (imunosupresivi, bloka-tori kalcijskih kanala...) moraju se primjeniti s velikim opre-zom ili treba izbjeÊi njihovu istovremenu primjenu s inhibito-rima FXa.Novi antikoagulansi su na træiπtu su predstavljeni kao lijekovikoji ne zahtjevaju monitoring. Iako se to marketinπki navodikao njihova velika prednost, ovakav nedostatak moæe posta-ti vrlo vaæan kod pacijenata koji doæive ishemijski dogaajzbog pogreπke terapije. Kako nisu razvijani kao lijekovi kojizahtjevaju monitoring laboratorijski testovi za mjerenje nji-hovog protuzgruπavajuÊeg djelovanja tek se trebaju stan-dardizirati. Za sada, niti jedan od postojeÊih testova nije va-lidiran kao optimalan test za mjerenje njihovog djelovanja.Takoer viπe informacija je potrebno i o tome kako slijeditipacijenta s krvarenjem u smislu toksiËnosti lijeka, obziromda nema specifiËnog antidota za bilo koji od ovih lijekova40,41.Za sada, u sluËaju predoziranja, sugerira se suportivna tera-pija svjeæom smrznutom plazmom ili uporaba koncentrataFVII, kao i protrombinskog kompleksa. Nedavno provedenaistraæivanja su pokazala da protrombin kompleks moæe dje-lomice neutralizirati utjecaj rivaroksabana, ali ne i dabiga-trana. Hemodijaliza moæe biti efikasna u otklanjanju oko60% dabigatrana iz krvi tijekom 2-3h πto se moæe iskoristitiu smislu njegove toksiËnosti40,41. OËekivanja od nove terapije su velika. Iako potreba za njiho-vim monitoringom moæe biti manja u odnosu na onu za VKA,sve dok je na antikoagulantnoj terapiji broj posjeta pacijentalijeËniku se ne moæe smanjiti, a povremena procjena paci-jentovog stanja u smislu iskljuËenja anemije, trombocitope-nije, jetrene ili bubreæne bolesti kako bi se izbjegle komplika-cija krvarenja je neophodna. Osim toga, jedan od ograni-ËavajuÊih koraka u uporabi ovih lijekova je i njihova cijena.U EU je procijenjeno da se godiπnje po pacijentu s FApotroπi otprilike 1.500-3.200 EUR, a prema sistemskoj anali-


zi najveÊi udio troπkova otpada na hospitalizacije42. Tijekomzadnjih dekada troπkovi i broj hospitalizacija zbog FA su uporastu zbog sve starije populacije, a za oËekivati je da Êeprimjena novih antikoagulanasa poveÊati ove troπkove. Go-diπnja cijena terapije dabigatranom se procjenjuje na otpri-like 1.680 EUR, dok godiπnji troπkovi terapije s VKA iznoseotprilike 50-150 EUR tj. toËnije 12 EUR za lijek, a ostalo ovisio uËestalosti mjerenja INR. AmeriËko istraæivanje troπkovneuËinkovitosti metodom po Markovu je pokazalo da u odre-enim sluËajevima dabigatran moæe biti korisniji od varfari-na, npr. primjena dabigatrana u dozi od 150 mg dva putadnevno je korisnija kod pacijenata Ëiji INR nije idealan, astariji su od 65 god. te su visokoriziËni za MU (CHADS2Score ≥1), kao i onih s visokim rizikom hemoragije i MU(CHADS2 Score ≥3). Meutim, kod umjereno riziËnih paci-jenata primjena varfarina je korisnija, iako INR nije idealan.U Hrvatskoj, na osnovnoj listi lijekova HZZO registrirane sutablete rivaroksaban 10 mg u pakiranju od 30x10 mg i 10x10mg Ëija cijena prema zadnjim iznosi informacijama iznosi874,80 kn tj. 291,60 kn te tablete dabigatrana 75 mg u paki-ranju od 30x75 mg po cijeni 441,63 kn te tablete 110mg upakiranju 10x110 mg po cijeni 153,36 kn. Odluka o tome kojiÊe se protuzgruπavajuËi lijek prepisati ovisi o oËekivanoj ko-risti, riziku, troπkovima te pacijentovim sklonostima, a omjerrizika i koristi njihove primjene za pacijente u Hrvatskoj tekbi se trebao izraËunati. Za pacijente kod kojih se ne postiæeefikasnost u lijeËenju primjenom VKA, ovi lijekovi mogu bitialternativni izbor. Meutim, pacijenti s nestabilnim INR nemoraju biti idealni kandidati za nove lijekove. Stoga je po-trebno priËekati proπirenje spoznaja kako bi se ovi lijekovimogli primjenjivati i izvan klinika, a u meuvremenu, njihovaprimjena Êe ovisiti o Ëimbenicima vezanim za nuspojave,doziranju i cijeni te eventualnom zahtjevu za dodatnim te-stovima. Za sada, primjena varfarina u svakom sluËaju jejeftinija Ëak i kada se uzmu u obzir regularni troπkovi moni-toringa. Velike promjene se oËekuju u slijedeÊih nekoliko godina.Novi antikoagulansi su dobrodoπli u smislu nadilaæenja ne-dostataka tradicionalne protuzgruπavajuÊe terapije, a paælji-vo provedena faza IV kliniËkih studija osnova je za optimi-zaciju pozitivnih i negativnih dokaza iz faze III kliniËkih studi-ja. Spoznaje o sigurnosnom profilu novih lijekova Êe se pro-πiriti kako se bude πirila njihova uporaba, a pri tome je veli-ka odgovornost na lijeËnicima u smislu objave oËekivanih ineoËekivanih podataka o primjeni novih lijekova. Pri tome semora razmiπljati i u smislu razvoja lokalnih i globalnih pre-poruka za specijalne situacije koje zahtjevaju monitoringovih lijekova.

Received: 12th Jan 2013

*Address for correspondence: Klinika za traumatologiju, KBC Sestre milosrdnice ,DraπkoviÊeva 19, HR-10000 Zagreb, Croatia.

Phone: +386-1-4697-000

E-mail: [email protected]

reasons why their administration is limited. In EU, it is esti-mated that approximately EUR 1,500-3,200 is spent perpatient with AF on an annual basis, and according to the re-cent systematic analysis the hospitalizations are account-able for the largest portion of costs42. Costs and hospitaliza-tions for AF have increased over the last decade due to theaging population, and we could expect that the application ofnew anticoagulants will cause an increase in these costs.The annual cost of the therapy with dabigatran is estimatedat approximately EUR 1,680, while the annual costs of treat-ment with VKA are estimated at approximately EUR 50-150,that is, EUR 12 for the drug, while the remaining amount de-pends on INR measurement. An American investigation ofthe cost effectiveness by applying the Markov model hasshown that in certain cases dabigatran can be more usefulthan warfarin (e.g. in patients older than 65 who are at highrisk for stroke (CHADS2 Score ≥1) and those with a highrisk for hemorrhage and stroke (CHADS2 Score ≥3), where-as dabigatran at a 150 mg dose b.i.d. has a greater benefitfor patients whose INR is not ideal. However, in patients withmoderate-risk, the administration of warfarin is beneficial,although the INR is not ideal. The rivaroxaban 10 mg tabletsin 30x10 mg packs and 10x10 mg packs are registered onthe Croatian list of essential drugs which according to thelatest information are priced at HRK 874.80 or HRK 291.60and the abigatran 75 mg tablets in 30x75 mg packs arepriced at HRK 441.63, while 110 mg tablets in 10x110 mgpacks are priced at HRK 153.36. The clinical decision onwhich anticoagulant drug will be prescribed depends on theexpected benefit, risk, costs and patients’ preferences, andthe risk-benefit ratio for the Croatian patients still have to becalculated. These drugs may be an alternative choice forpatients in whom the efficacy is not achieved in the therapyby applying VKA. However, the patients with unstable INRmay not be the ideal candidates for new drugs. Therefore, itwill be necessary to wait for the more comprehensive in-sights in order to apply them outside of the clinic and in themean time, their administration will depend on side effects-related factors, dosing and pricing by the time as well as ondemands for some additional testing. So, far the administra-tion of warfarin is definitively cheaper even when taking intoaccount ordinary monitoring costs. Major changes are expected to be made in the next fewyears. New anticoagulants are welcome for the purpose ofovercoming deficiencies of traditional anticoagulant therapy,while carefully conducted Phases IV of clinical trials are thebasis for the optimization of positive and negative evidenceobtained from the Phase III of the clinical trials. The insightsabout the safety profile of the new drugs will broaden paral-lel with the expansion of their administration, whereas physi-cians will assume a great responsibility to report expectedand unexpected data on the application of the new drugs. Inthis sense, it is necessary to develop local and global rec-ommendations for special situations that require monitoringof these drugs.

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New perspectives and strategies in the treatment of thromboembolic diseases

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