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1. Introduction
2. Rivaroxaban
3. Conclusion
4. Expert opinion
Drug Evaluation
Rivaroxaban in the contemporarytreatment of acute coronarysyndromesDeepu Alexander & Allen Jeremias†
State University of New York--Stony Brook School of Medicine, Health Sciences Centre Division of
Cardiovascular Medicine, NY, USA
Introduction: Rivaroxaban is the first orally bioavailable direct factor Xa
inhibitor and its role in acute coronary syndrome is not fully understood.
A significant residual risk of recurrent ischemia remains in patients with
acute coronary syndrome despite optimal medical therapy. Warfarin has
demonstrated modest benefit that is offset by the risk of bleeding and
complexity in its management. Rivaroxaban may be an attractive agent
for the treatment of acute coronary syndromes given its predictable
pharmacodynamics and favorable safety profile.
Areas covered: The current guideline-based antithrombotic and adjunctive
medical therapies in acute coronary syndrome are summarized in this
review. Rivaroxaban’s drug profile, its current applications, ongoing trials
and experience in patients with acute coronary syndrome are also described.
Expert opinion: Current experience of rivaroxaban in acute coronary
syndrome demonstrates its safety and a trend towards benefit when added
to current optimal medical therapy. The benefits were observed primarily in
patients receiving aspirin monotherapy and increased bleeding among those
receiving dual anti-platelet therapy. This suggests that there may be a narrow
window between the optimal clinically achievable antithrombotic effect and
the point where bleeding risk outweighs the benefits. Though promising, it
remains to be seen if this drug will achieve the right balance between
efficacy and bleeding risk.
Keywords: acute coronary syndrome, anti-thrombotic agent, direct factor Xa inhibitor,
rivaroxaban
Expert Opin. Investig. Drugs (2011) 20(6):849-857
1. Introduction
Acute coronary syndrome (ACS) encompasses a spectrum of presentations of myocar-dial ischemia that range from unstable angina (UA) and non-ST segment elevationmyocardial infarction (NSTEMI) to ST segment elevation myocardial infarction(STEMI) and is responsible for > 1.4 million hospitalizations yearly in the USalone [1,2]. Contemporary treatment of ACS based on clinical evidence involves theuse of the early invasive strategy (defined as immediate cardiac catheterization andcoronary revascularization if necessary without the need for previous stress testing)along with the use of long-term dual anti-platelet therapy, statins, b-blockers, ACEinhibitors and short-term anti-thrombotic agents prior to and during percutaneouscoronary intervention (PCI) [3,4]. However, despite these therapies, the risk of recur-rent cardiovascular events including death or myocardial infarction ranges from10.2 to 11.1% [5,6]. This not only poses a significant risk to the patient but also exertsa significant burden on the healthcare system. The total yearly hospital costs for car-diovascular disease, stroke and related conditions are estimated to be $155.7 billionand are the most costly as a diagnostic group [7]. The significant morbidity, mortality
10.1517/13543784.2011.580274 © 2011 Informa UK, Ltd. ISSN 1354-3784 849All rights reserved: reproduction in whole or in part not permitted
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as well as the monetary impact of ACS emphasize the need toconstantly optimize treatment strategies in light of emergingdrug and device therapies.
1.1 Current anti-thrombotic agents in ACS1.1.1 AnticoagulantsUnfractionated heparin is a mixture of sulfated mucopoylsac-charides that exerts its anticoagulant effect by binding to anti-thrombin and augmenting its inhibition of factors IXa, Xaand thrombin, thereby limiting the formation of fibrin [8].While no randomized trial clearly demonstrated the superiorityof heparin over placebo, meta-analysis showed that unfractio-nated heparin compared to placebo conferred a 33% relativereduction in the rate of death or myocardial infarction [9]. Itsanticoagulant response is variable and needs to be closely mon-itored. Although heparin prevents clot formation, it has limitedeffect on existing thrombus as the site needed to bind theheparin--anti-thrombin complex is occupied by the fibrin--thrombin complex. As opposed to heparin, direct thrombininhibitors do not require anti-thrombin to exert its anticoagu-lant effect. The site it needs to bind to on thrombin is not occu-pied by the fibrin--thrombin complex and thereby directthrombin inhibitors can inactivate clot bound thrombus.Another disadvantage with the use of unfractionated heparinis the development of heparin-induced thrombocytopeniawhere there is an immune-mediated activation of platelets viaIgG antibodies against heparin--platelet factor 4 complex andsubsequent arterial and venous thrombosis [10].The utility of low molecular weight heparins such as
enoxaparin has been mixed. Its beneficial effect for the treat-ment of ACS is most pronounced with an early conservativestrategy (defined as initial medical management with stress
testing prior to potential coronary angiography) as in theEfficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) and Thrombolysis InMyocardial Infarction (TIMI) 11B trials where there was arobust reduction in the rate of death, myocardial infarctionor recurrent ischemic events at the expense of a small increasein bleeding [11,12]. In comparison, there was little difference inoutcomes in the patients treated with an early invasive strategyas seen in the Superior Yield of the New Strategy of Enoxa-parin, Revascularization and Glycoprotein IIb -- IIIa Inhibi-tors (SYNERGY) trial [13]. In the presence of these mixedstudy results and the increasing prevalence of an early invasivestrategy where monitoring of low molecular weight heparin inthe cardiac catheterization lab is not possible, its impact hasbeen blunted.
The latest addition to the low molecular weight heparins,fondaparinux, is a synthetic pentasaccharide that binds toanti-thrombin III and inhibits factor Xa. It has no effect onthrombin. It has predictable pharmacokinetics and has along half-life, allowing for once daily dosing [14]. It has beenshown to have lower mortality and bleeding rates when com-pared to enoxaparin [15]. However, fondaparinux has beenassociated with a higher rate of intracoronary thrombosis dur-ing PCI in the Fifth Organization to Assess Strategies inIschemic Syndromes (OASIS-5) study reducing its value inthe setting of ACS when PCI is used [16].
1.1.2 Anti-platelet agentsThe second major group of pharmaceutical agents for the treat-ment of ACS is anti-platelet drugs. In order to limit thrombusformation, platelet activation and thrombin generation must behalted. Aspirin, an irreversible COX-1 inhibitor, prevents the
Box 1. Drug summary.
Drug name RivaroxabanPhase IIIIndication Acute coronary syndromesPharmacology description Direct factor Xa inhibitor
Protease/peptidase inhibitorSerine protease inhibitorFactor Xa inhibitor
Route of administration AlimentaryChemical structure
NO
O
NO
O
N
O
SCI
Pivotal trial(s) ACS thrombolysis in myocardial infarction 46 (ATLAS ACSTIMI 46) trial and ATLAS ACS 2-TIMI 51 trial
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and
Citeline (http://informa.citeline.com).
Rivaroxaban
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formation of thromboxane A2, a potent platelet aggregator [17].Aspirin has been shown to reduce death, myocardial infarctionand vascular events in patients with coronary heart diseaseand peripheral vascular disease and serves as the cornerstoneof anti-platelet drug therapy [18,19].
Thienopyridines irreversibly block the P2Y12 component ofADP receptors on the platelet surface, which prevents activationof the glycoprotein IIb -- IIIa receptor complex, thereby reducingplatelet aggregation. Currently available agents are ticlopidine,clopidogrel and prasugrel. Ticlopidine, a first generation thieno-pyridine, has been found to reduce recurrent ischemic events;however, currently it is only rarely used due to its adverse eventprofile of causing agranulocytosis and rash [20,21].
Clopidogrel, a second generation thienopyridine, is currentlythe most widely used anti-platelet agent. Its efficacy has beenestablished across the spectrum of ACS. In STEMI, a 600 mgloading dose of clopidogrel achieves a more rapid platelet inhi-bition. The added anti-ischemic benefit of clopidogrel comes ata moderate risk of increased major bleeding [22]. Evidence isemerging on the role of platelet function testing in patientson dual anti-platelet therapy. Poor responders to clopidogrelcan now be identified; the variability in the clinical responseto clopidogrel has been observed and it has now been shownthat reduced function of the CYP2C19 variants of the cyto-chrome P450 system is associated with worse clinical outcomes.Though controversial, genetic testing can be done in suspectedpatients and, if identified, the therapy can be switched to prasu-grel that is not affected by the CYP2C19 variants [23]. However,this anti-platelet strategy remains to be tested in a prospectivefashion. Moreover, new trial data suggest no role for doubledose of clopidogrel in patients with a poor response to thedrug; rather, prasugrel or ticagrelor may have a role [24].
Prasugrel, a recently approved thienopyridine that is an irre-versible adenosine diphosphate P2Y12 receptor blocker, hasmore potent anti-platelet activity when compared to clopidogreland this translates to a 19% relative risk reduction of death fromcardiovascular causes, nonfatal myocardial infarction or nonfatalstroke at the expense of an increased rate of major bleeding [25].An initial loading dose of 60mg followed by 10mgmaintenancedose is currently approved by the FDA with the exception ofpatients with active pathological bleed such as from a peptic ulceror intracranial hemorrhage or a history of transient ischemicattack or stroke. A lower dose of prasugrel can be used in patientsolder 75 years or who weigh < 60 kg to minimize the riskof bleeding.
Cangrelor, a non-thienopyridine intravenous reversible aden-osine diphosphate P2Y12 receptor blocker, has been shown tohave potent and predictable anti-platelet activity but in clinicaltrials was not found to be superior to 600 mg loading dose ofclopidogrel and is yet to find utility in clinical practice [26-29].However, ticagrelor, an oral non-thienopyridine adenosinediphosphate P2Y12 receptor blocker, demonstrated a 22%reduction in mortality without a significant increase in majorbleeding when compared to clopidogrel in patients withACS [6,30].
Glycoprotein IIb -- IIIa inhibitors are potent anti-plateletagents that prevent platelet aggregation at its final commonpathway [31]. The available agents are abciximab, eptifibatideand tirofiban. The mechanism of action, pharmacokineticsand pharmacokinetics of the three agents are different. Abcix-imab is a mAb with a short half-life that has strong affinity toglycoprotein IIb -- IIIa receptors on the platelet plasma mem-brane; eptifibatide is a cyclic heptapeptide that reversiblybinds to glycoprotein IIb -- IIIa receptor; whereas, tirofibanis a synthetic non-peptide that reversibly binds to glycopro-tein IIb -- IIIa receptor. The use of glycoprotein IIb -- IIIainhibitors in ACS has produced mixed results. In the settingof STEMI, PCI facilitated by the combination of glycoproteinIIb -- IIIa inhibitors and thrombolytics prior to PCI showedno mortality benefit but was associated with a higher inci-dence of major and minor bleeding complications [32,33].Hence, glycoprotein IIb -- IIIa inhibitors are not currentlyused in combination with thrombolytic therapy. However,there may be a role for its use upstream in STEMI (i.e., priorto cardiac catheterization) where an improved coronary flowwas seen in the infarct related artery prior to primary PCIthat may be associated with improved outcomes, althoughthe evidence for this is controversial [34,35]. In UA/NSTEMI,the use of glycoprotein IIb -- IIIa inhibitors has been shownto have more favorable outcomes when used either upstreamor during PCI [36]. However, no clear benefit was seen whena non-invasive strategy was being pursued [37].
1.2 Other adjunct medical therapyAdjunct drug therapies include the use of nitrates that neitherhas shown any survival benefit nor reduced the rate of recur-rent myocardial infarction [38,39]. They can be used to relieverefractory ischemia when there is adequate perfusion pressureand is to be avoided in inferior wall myocardial infarctionwhere right ventricular involvement is suspected. b-Blockersdecrease myocardial oxygen demand and improve coronaryperfusion. They should be given acutely and continued longterm unless contraindicated. Patients with left ventricular dys-function appear to gain the most benefit from b-blockertherapy [40-44].
2. Rivaroxaban
Rivaroxaban, formerly known as BAY 59-7939, is the firstorally bioavailable factor Xa inhibitor (Box 1) [45]. It is asmall molecule oxazolidinone derivative that selectivelybinds to factor Xa and thus inhibiting the conversion ofpro-thrombin to thrombin. In animal models, rivaroxabanwas found to be very effective in the prevention of the for-mation and progression of thrombus [45]. It is not knownto have any direct activity on thrombin or platelets.
2.1 Pharmacokinetics [46]
Rivaroxaban is rapidly absorbed with the peak plasmaconcentration 2 -- 4 h after an oral dose of 10 mg. The
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bioavailability is high at 80 -- 100% for the 10 mg dose [47],and remains unaffected by the intake of food [48]. Theabsorption is linear up to 15 mg after which there is adecreased absorption rate with increased dose. The inter-indi-vidual variability in the pharmacokinetics is moderate at30 -- 40%. Rivaroxaban is heavily bound to plasma proteinat 92 -- 95%. Two-thirds of the administered dose undergometabolic degradation, of which roughly 50% is renallyexcreted and the other half fecally. The remaining one-third of the dose that does not undergo metabolic degradationis excreted renally as unchanged active substance in the urine,mainly via active renal secretion. Rivaroxaban is metabolizedvia CYP3A4, CYP2J2 and CYP-independent mechanisms.Elimination of rivaroxaban from plasma occurs with terminalhalf-lifes of 5 -- 9 h in young individuals and with terminalhalf- lifes of 11 -- 13 h in the elderly. Dose adjustment isnot necessary in the elderly, different weight categories or dif-ferent ethnic groups. It is contraindicated in patients withhepatic disease associated with coagulopathy and clinicallyrelevant bleeding risk. Its use in patients with a creatinineclearance of < 15 ml/min is not recommended. Because rivar-oxaban is heavily bound to plasma protein, it is not expectedto be dialyzable.
2.2 PharmacodynamicsThere is a dose-dependent inhibition of factor Xa [49]. Also,the prothrombin time is affected by rivaroxaban in a dose-dependent manner. There is a close correlation between itsplasma concentration and the prothrombin time if neoplastinis used as the reagent [47,50]. When aspirin was studied in nor-mal subjects on rivaroxaban, no clinically significant interac-tions were observed. Rivaroxaban’s inhibition of factor Xaactivity was not affected by aspirin. Platelet aggregation andbleeding time were not affected by rivaroxaban either [51].The concomitant use of rivaroxaban with azole antifungals(except for fluconazole) and HIV protease inhibitors is notrecommended. Other inhibitors of cytochrome P450 can beco-administered. Because rivaroxaban has a favorable safetyprofile when combined with other medications in its clinicaluse, there is no need to routinely monitor coagulation param-eters (Figure 1). In the event of a life threatening bleedrecombinant factor VII or activated prothrombin-complexconcentrate can be used; however, these strategies have notbeen evaluated prospectively.
2.3 Experience in ACSAmong the optimal medical therapy for patients with recentACS is the use of long-term dual anti-platelet therapy. How-ever, despite optimal contemporary medical therapy there is asignificant residual risk of major adverse cardiovascular eventsin this high-risk population. To mitigate this risk, warfarinhas been considered in clinical studies with mixed results.Rivaroxaban has been considered as an additional therapy inpatients with ACS to further attenuate recurrent ischemicevents. The anti-Xa therapy to lower cardiovascular events
in addition to aspirin with or without thienopyridine therapyin subjects with ACS thrombolysis in myocardial infarction46 (ATLAS ACS TIMI 46) trial was a Phase II randomized,double-blind, placebo-controlled study that evaluated thesafety and optimal dosing strategy of long-term rivaroxabanuse in patients with recent ACS [52]. A total of 3491 sub-jects were enrolled from 297 centers worldwide between2006 and 2008. Randomization occurred within a week ofbeing admitted for ACS. Of the patients studied, 761 werephysician assigned to the aspirin only stratum and the restin the aspirin plus thienopyridine stratum. Within the stra-tum, subjects randomly received either placebo or escalatingdoses, once daily or twice daily (same total dose), of rivaroxa-ban and studied for 6 months. Baseline characteristics werewell matched across the two strata and among treatmentgroups within each stratum. When compared to placebo,the use of long-term rivaroxaban was associated with a nonsig-nificant reduction in the primary efficacy outcome of death,myocardial infarction, stroke or severe recurrent ischemiarequiring revascularization (5.6 vs 7%; hazard ratio0.79 (0.60 -- 1.05), p = 0.10) [52]. However, rivaroxaban hadsignificant benefits when compared with placebo for thepre-specified secondary end points of death, myocardialinfarction or stroke (3.9 vs 5.5%; hazard ratio 0.69, 95% CI0.50 -- 0.96, p = 0.0270). This benefit of rivaroxaban waslargely confined, however, to patients that received aspirinalone. There was a dose-dependent risk of clinically signifi-cant bleeding (Table 1). The absolute rates of clinically signif-icant bleeding were categorised as requiring medical attention,11% TIMI major and 6% TIMI minor, and there was no var-iability when age, creatinine clearance, weight or diabetic sta-tus is taken into consideration. However, one of the majoradvantages of rivaroxaban over warfarin is its fixed dose regi-men and its predictable anticoagulant effect. Based on rivar-oxaban’s favorable outcome and bleeding profile of its lowertested doses, twice daily 2.5 and 5 mg doses have been selectedfor further assessment in a large, Phase III clinical trial(ATLAS ACS -TIMI 51) that is ongoing. It is important tonote that other oral antithrombotic agents have yet to showcombined safety and efficacy. Ximelagatran demonstrated areduction in recurrent ischemia when added to dual anti-platelet therapy but was at the expense of significant hepato-toxicity [53]. Dabigatran, though found to be safe in thePhase II trial when used in addition to dual anti-platelet therapy for ACS, is yet to be tested for efficacy endpoints [54]. The trial to test the efficacy of apixaban in ACSwas halted prematurely as the bleeding risks outweighed thereduction in ischemic end points.
2.4 Current applicationsRivaroxaban is currently approved in > 100 countries for theprevention of deep vein thrombosis (DVT) and pulmonaryembolus (PE) in adult patients undergoing elective totalknee or hip replacement surgery. This is based on thestrength of the four REgulation of Coagulation in
Rivaroxaban
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ORthopaedic surgery to prevent Deep vein thrombosis andpulmonary embolism (RECORD) trials. The RECORD1 and 2 trials demonstrated superiority of either short-term or extended term 10 mg rivaroxaban over 40 mg ofdaily enoxaparin in preventing DVT or PE in patientsundergoing elective hip replacement [55,56]. Rivaroxabanwas found to be superior to the approved doses of enoxa-parin for venous thromboembolism prophylaxis in Europeand the US in patients undergoing total knee replace-ment [57,58]. This benefit comes without a significantlyincreased risk of bleeding in all four trials. In the US, theFDA has put the decision to approve rivaroxaban for theprevention of venous thromboembolism on hold.
2.5 Ongoing, recently published and unpublished
studiesThe recent release of two important trials further highlights theusefulness of rivaroxaban. The EINSTEIN-DVT trial thatinvestigated the usefulness of rivaroxaban in patients with acutesymptomatic DVT was recently published. It showed that
rivaroxaban was non-inferior to initial enoxaparin followed bywarfarin therapy in patients with acute DVT (2.1 vs 3% for pri-mary efficacy end point, hazard ratio 0.68 (95%CI 0.44 -- 1.04),p < 0.001 for non-inferiority) [59]. The second trial, theEINSTEIN-EXT compared the continued use of rivaroxabanversus placebo for an additional 6 to 12 months in patientswho had completed 6 to 12 months of treatment for venousthromboembolism. The results demonstrate the superiority(1.3 vs 7.1% events, p < 0.001) and safety (0.7 vs 0%,p = 0.11) of rivaroxaban when used for an extended period oftime; however, the choice of placebo rather than warfarin castsa shadow on the strength of evidence in using rivaroxaban foran extended period of time.
Another area of interest for the use of rivaroxaban is theprevention of embolic complications in non-valvular atrialfibrillation. The Rivaroxaban- Once daily, oral, direct fac-tor Xa inhibition Compared with vitamin K antagonismfor prevention of stroke and Embolism Trial in AtrialFibrillation (ROCKET AF) trial was recently presented atthe American Heart Association meeting in November
Contact activation pathway Tissue factor pathway
XII XXII a
IX a
IX
VII a
Xa
VII
Platelet activation
Platelets
TXA 2
Thrombin
ADP
Activatedplatelets
Prothrombin
Direct action on XaRivaroxaban apixaban
Indirect action on XaFonduparinux LMWH
Gp2b 3a inhibitors
Plateletaggregation
Fibrinogen TiclopidineClopidogrelTicagrelorEnalagrel
Indirect thrombin inhibitorUFH + antithrombin
Fibrin
Cross linkedfibrin clot
ASA
Direct thrombininhibitor
DabigatranXimelgatranBivalirudin
Figure 1. Coagulation cascade with sites of inhibition by various pharmaceuticals in shaded boxes.
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2010. A feature of the study was its double-blind trialdesign with computer generated sham INR values in therivaroxaban group and the high-risk population enrolledin the study. Patients with atrial fibrillation receiving activetreatment with rivaroxaban had a significantly reduced riskof stroke and other systemic embolism versus warfarin(1.71 vs 2.16 events per 100 patient years, p < 0.001),with similar rates of bleeding (3.6 vs 3.45 events per 100patient years, p < 0.576 for major bleeding).
3. Conclusion
Rivaroxaban, a small molecule oxazolidinone derivative, isthe first orally bioavailable factor Xa inhibitor that iscurrently being used clinically in postoperative thrombo-prophylaxisin patients undergoing elective hip or kneereplacement surgery. Its antithrombotic properties are cur-rently being tested in a variety of clinical settings includingACS. In a Phase IIb dose finding study, it has shown a trendtowards benefit along with harm when used at higher doses.The ongoing Phase III ATLAS ACS 2-TIMI 51 trial willgive us an insight into whether rivaroxaban will have a rolein the treatment of ACS.
4. Expert opinion
Despite the advances in pharmacotherapy and PCI over the pastdecade, a substantial residual risk of death from cardiovascularcauses, myocardial infarction, stroke and refractory ischemiaremains in high-risk patients with ACS [6]. Current long-termdual anti-platelet treatment strategy blocks the thromboxaneA2 and ADP mediated pathways leaving the thrombin medi-ated platelet activation pathway uninterrupted. Warfarin, apotent antithrombotic agent, has been studied in ACS withmixed results [60-63]. Though there are improved ischemic endpoints, the bleeding risk and its narrow therapeutic windowlimit its widespread use. Moreover, other pharmaco-therapyin ACS including the use of aggressive statin therapy does notcompletely prevent the progression of atherosclerosis and recur-rent ischemic events. It is in this setting where there might be arole for newer potent antithrombotic agents that can be used toattenuate long-term cardiovascular risk.
?A3B2 tlsb=-0.01w?>Rivaroxaban may be poised to fill thevoid where warfarin would have played a role in reducingischemic events. Its safety profile and tolerability when com-bined with other agents may prove to be advantageous overwarfarin. The ATLAS ACS TIMI 46 trial, though a dose find-ing study, demonstrates its safety and a trend towards benefitwhen rivaroxaban is added to current optimal medical ther-apy. However, the benefits were observed primarily inpatients stratified to single-agent anti-platelet therapy withaspirin. This suggests there may be a narrow window betweenthe degree of anti-platelet and antithrombotic effect that canbe achieved clinically and the point where the bleeding riskoutweighs the benefits. However, it is to be noted thatT
able
1.Riskofclinicallysignificantbleeding.
Dose
(mg)
Pooledplacebo
KM
rate
(percent)
Once
daily
dosing
Twicedaily
dosing
Primary
endpoint
Bleeding
KM
rate
(percent)
HR
(95%
CI)
KM
rate
(percent)
HR
(95%
CI)
PE
Bleeding
PE
Bleeding
PE
Bleeding
PE
Bleeding
57
3.3
8.7
7.4
1.01(0.56--1.83)
2.73(1.38--5.37)
5.3
4.8
0.60(0.29--1.25)
1.71(0.76--3.85)
10
73.3
5.3
10.8
0.77(0.5
--1.20)
3.35(2.21--5.09)
4.4
11
0.63(0.39--1.01)
3.36(2.21--5.09)
20
73.3
5.2
16
0.69(0.40--1.20)
5.32(3.46--8.18)
6.5
14.6
0.87(0.53--1.44)
4.80(3.09--7.45)
Primary
endpointofdeath,myocardialinfarction,strokeorrecurrentischemia
requiringrevascularization.
HR:Hazard
ratio;KM:KaplanMeier;PE:Primary
endpoint.
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ximelagatran demonstrated a reduction in ischemia drivenend points in patients with recent ACS who were on dualanti-platelet therapy [53].
The bleeding risk at higher doses was significantwhen considering any bleeding that required medical atten-tion with a trend towards higher rates of TIMI major bleed-ing. In an effort to reduce major bleeding, the rivaroxabandoses chosen to be tested in the ongoing ATLAS ACS2-TIMI 51 trial are on the low end of the spectrum and
may limit the efficacy of rivaroxaban in the population stud-ied. Though promising, it remains to be seen if this drugwill achieve the right balance between efficacy and bleedingrisk in the treatment of high-risk ACS.
Declaration of interest
The authors state no conflict of interest and have received nopayment in preparation of this manuscript.
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AffiliationDeepu Alexander MD &
Allen Jeremias† MD MSc†Author for correspondence
State University of New York--Stony Brook
School of Medicine,
Health Sciences Centre Division of
Cardiovascular Medicine,
T16-080, Stony Brook,
NY 11794, USA
Tel: +1 631 444 1064; Fax: +1 631 444 1054;
E-mail: [email protected]
Alexander & Jeremias
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