Rivaroxaban (Xarelto) is an oraldirect factor Xa inhibitor. It was

licensed in 2008 for prophylaxis ofvenous thromboembolism (VTE)after knee or hip replacement sur-gery at a dose of 10mg daily. It isnow also licensed (as 15mg and20mg tablets) for the prevention ofstroke and systemic embolism inadults with nonvalvular atrial fibril-

lation (AF) and one or more riskfactors (eg congestive heart failure,hypertension, age ≥75 years, dia-betes mellitus, prior stroke or tran-sient ischaemic attack), and astreatment of deep vein thrombosis(DVT) and prevention of recurrentDVT and pulmonary embolism(PE) following an acute DVT inadults.

The National Institute forHealth and Clinical Excellence(NICE) has recommended the useof rivaroxaban in the prevention ofstroke and systemic embolism inpeople with AF.1

The recommended dose for pre-vention of stroke or systemicembolism is 20mg once daily. Thedose for initial treatment of acute

14 Prescriber 5 September 2012 www.prescriber.co.uk

New products

Rivaroxaban (Xarelto) in the

management of stroke and DVTSteve Chaplin MSc, MRPharmS, Victoria Haunton BM, DGM, MRCP, Thompson Robinson BMedSci, MD,

FRCP and Catherine Bagot MD, FRCPath

Rivaroxaban is now licensed

for the prevention of stroke

and the treatment and pre-

vention of DVT. In our New

products review, Steve

Chaplin presents the clinical

data for its efficacy and

adverse events related to

these new indications, and

specialists comment on its

likely place in therapy.

KEY POINTS

• rivaroxaban is an oral direct factor Xa

inhibitor newly licensed for the prevention

of stroke and systemic embolism in adults

with nonvalvular AF and one or more risk

factors, and as treatment of DVT and prevention of recurrent DVT and

PE following an acute DVT

• the dose for prevention of stroke or systemic embolism is 20mg once daily

• the dose for initial treatment of acute DVT is 15mg twice daily for the

first three weeks, then 20mg once daily for continued treatment and

prevention of recurrent DVT and PE

• available as 15mg and 20mg tablets; 15mg, 28=£58.80, 42=£88.20,

100=£210.00; 20mg, 28=£58.80, 100=£210.00

• in the prevention of stroke and systemic embolism (vs warfarin) and in

the treatment of acute symptomatic DVT (vs enoxaparin, then war-

farin/acenocoumarol), it was noninferior for efficacy with a similar

overall risk of major and nonmajor clinically relevant bleeding events

• it was superior to placebo in the prevention of recurrent DVT and PE

with a small increase in the risk of major bleeding episodes

• there are few drug interactions and laboratory monitoring is not required

• there is no effective antidote or reliable laboratory assay

• the dose should be reduced in moderate to severe renal impairment

and rivaroxaban is contraindicated in hepatic disease

• in stroke prevention rivaroxaban will provide an alternative treatment in

patients who are unable to tolerate warfarin or remain in the thera -

peutic range

• until more experience is gained, rivaroxaban should only be considered

in the short-term treatment and prevention of DVT

DVT is 15mg twice daily for the firstthree weeks. If a dose is missed dur-ing this phase, it should be taken withthe next dose to ensure a daily intakeof 30mg. The dose for continuedtreatment and prevention of recur-rent DVT and PE is 20mg once daily.

Short duration of therapy (threemonths) should be based on tran-sient risk factors, eg recent surgery,trauma, immobilisation, and longerdurations should be based on per-

manent risk factors or idiopathicDVT. There is limited experience oftreatment for more than a year.

No dose adjustment is requiredfor older people. The dose shouldbe reduced in patients with moder-ate or severe renal impairment (seeSPC for details). Rivaroxaban iscontraindicated in patients withhepatic impairment.

Rivaroxaban is metabolised byhepatic CYP3A4 enzymes; clinically

significant interactions occur withdrugs that inhibit or induce this sys-tem and by drugs that affect the P-glycoprotein transporter, eg someantifungals, macrolide antibiotics(see SPC for details).

Clinical trialsThe key trials were ROCKET AF(Rivaroxaban Once daily oraldirect factor Xa inhibitorCompared with vitamin K antago-nism for prevention of stroke andEmbolism Trial in Atrial Fib ril -lation) for prevention of stroke andsystemic embolism in patients withnonvalvular AF,2 and EINSTEINDVT for initial and continued treat-ment of acute DVT and preventionof recurrent DVT and PE.3

Prevention of stroke and systemicembolismROCKET AF was a noninferioritytrial comparing rivaroxaban with war-farin in 14 264 patients with nonva-lvular AF at moderate to high risk ofstroke (90 per cent had previousthromboembolism or three or morerisk factors). They were randomisedto receive treatment with rivaroxaban20mg daily (15mg daily in those withmoderate renal impairment) or war-farin with dose adjustment to inter-national normalised ratio (INR)2.0–3.0. The primary end-point wasa composite of ischaemic or haemor-rhagic stroke and systemic embolismin the per-protocol population, iethose who received at least one doseand did not violate the protocol.

Median patient age was 73; thecommonest risk factors were hyper-tension (91 per cent), heart failure(63 per cent) and previous stroke,systemic embolism or transientischaemic attack (55 per cent). Inthose taking warfarin, 55 per centof INR values were within targetrange. About 35 per cent ofpatients also took aspirin at somestage during the trial. The medianduration of treatment exposure was

16 Prescriber 5 September 2012 www.prescriber.co.uk

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Figure 1. Cumulative rates of stroke or systemic embolism in the per-protocol

population in patients with nonvalvular AF, rivaroxaban vs warfarin; after reference 2

6

5

4

3

2

1

0

Cu

mu

lative e

ven

t ra

te (%

)warfarin rivaroxaban

0 120 240 360 480 600 720 840

Days since randomisation

Figure 2. Cumulative rates of symptomatic recurrent VTE during and after three

months’ treatment of acute symptomatic DVT, rivaroxaban vs enoxaparin/warfarin

(p<0.001 for noninferiority); after reference 3

4

3

2

1

0

Cu

mu

lative e

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e (%

)

0 30 60 90 120 150 180 210 240 270 300 330 360

Days

enoxaparin/warfarin rivaroxaban

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590 days and the median follow-upperiod was 707 days.

Stroke or systemic embolismoccurred in 188 patients takingrivaroxaban (1.7 per cent per year)and in 241 patients taking warfarin(2.2 per cent per year; hazard ratio –HR 0.79, 95% CI 0.66–0.96, p<0.001for noninferiority; see Figure 1).There were no differences betweenrivaroxaban and warfarin accordingto time within the target INR rangeor in the rates of myocardial infarc-tion or death (2.9 per cent withrivaroxaban vs 3.5 per cent).

The rates of major and clinicallyrelevant nonmajor bleeding withrivaroxaban and warfarin were sim-ilar (14.9 vs 14.5 per cent per year).Decreased haemoglobin, transfu-sions and major gastrointestinalbleeding were more common withrivaroxaban, whereas fatal bleedingand critical bleeding, eg intracra-nial, intraspinal, intraocular, wereless frequent.

Treatment of acute DVT and preventionof recurrent DVT and PEEINSTEIN DVT was a trial in 3449patients with acute symptomatic DVT.There were two phases: a three-month acute noninferiority study

compared rivaroxaban (15mg twicedaily for three weeks, then 20mgdaily) with enoxaparin (Clexane)1mg per kg twice daily initially fol-lowed by warfarin or acenocoumarol(Sinthrome). Enoxaparin was discon-tinued when INR ≥2.0 (median duration eight days) and the anti co -ag ulant dose was adjusted to maintainINR in the range 2.0–3.0 (achievedfor 58 per cent of the time).

A continued-treatment superi-ority study compared rivaroxaban20mg daily with placebo in 1197patients; of these, about two-thirdsdid not participate in the acute-phase DVT study.

The primary end-point in bothphases was symptomatic recurrentVTE, defined as the composite ofDVT or nonfatal or fatal PE.

Mean patient age was 56 for theacute study and 58 for the contin-ued-treatment study. Most (61–74per cent) of DVTs or PEs were con-sidered unprovoked; identifiedcauses included surgery, trauma,immobilisation and oestrogen ther-apy. Previous VTE was known in 14–19 per cent of patients.

In the acute phase, the primaryend-point occurred in 36 (2.1 percent) of patients treated with rivarox-

aban and in 51 (3.0 per cent) ofthose taking enoxaparin/warfarin(HR 0.68, 95% CI 0.44–1.04, p<0.001for noninferiority, p=0.08 for superi-ority; see Figure 2). The first majoror clinically relevant nonmajorbleeding event occurred in 8.1 percent of patients in both treatmentgroups. Significantly fewer patientstaking rivaroxaban had either arecurrent VTE or a major bleedingevent (2.9 vs 4.2 per cent with war-farin). There were no differences inefficacy or safety outcomes by treat-ment duration of 3, 6 or 12 months.

In the continued-treatment study,the primary end-point occurred ineight patients (1.3 per cent) withrivaroxaban and 42 patients (7.1 percent) in the placebo group (HR 0.18,95% 1CI 0.09–0.39, p<0.001; seeFigure 3). Major bleeding occurredin 0.7 per cent of patients in therivaroxaban group and in none ofthose assigned to placebo. Signif -icantly fewer patients taking rivarox-aban had a recurrent VTE or a majorbleeding episode (2.0 vs 7.1 per centwith placebo).

There were no differences inthe balance of risk and benefit invarious subgroups and no differ-ences in liver function testsbetween rivaroxaban and warfarinor placebo in either study.

References1. NICE. Rivaroxaban for the preventionof stroke and systemic embolism in peoplewith atrial fibrillation. Technologyappraisal TA256. May 2012.2. Patel MR, et al. N Engl J Med2011;365:883–91.3. EINSTEIN Investigators. N Engl J Med2010;363:2499–510.

Declaration of interestsSteve Chaplin has undertaken paidwriting work for several pharma-ceutical companies.

Steve Chaplin is a pharmacist whospecialises in writing on therapeutics

Figure 3. Cumulative rates of symptomatic recurrent VTE during and after 12 months’

prevention of DVT, rivaroxaban vs placebo (p<0.001 for superiority); after reference 3

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Days

placebo

rivaroxaban

Place in therapy –

stroke prevention

The last two decades have seen sig-nificant and exciting developmentsin the field of stroke medicine.Nonetheless, stroke remains a dev-astating condition with high ratesof mortality and morbidity. Indeed,stroke is currently the third largestcause of death and the singlelargest cause of adult disability inEngland.1

Each year, approximately110 000 people in England willhave a first or recurrent stroke andmore than 900 000 people are cur-rently living with the effects ofstroke, with half of these beingdependent on others for help witheveryday activities.2

The financial implications ofstroke are substantial, with an esti-mated cost to the economy of £7billion per year.1

WarfarinAF, which is all too frequentlyasymptomatic, is associated withup to 15 per cent of ischaemicstrokes in all ages and 30 per centin persons over the age of 80.3

When AF is detected, it is there-fore vital that the opportunity toprotect patients is not missed.Individual risk stratification, usingthe CHA2DS2-VASc score,

4 andopen and informed discussionswith patients will guide anticoagu-lation decisions.

When anticoagulation is indi-cated, warfarin offers excellentcost-effective stroke preventionwith a relative risk reduction of 62per cent (95% CI, 48–72 per cent)5

and surprisingly low rates of signif-icant bleeding.

However, fears regardingbleeding, multiple interactionsand the need for frequent bloodtests and dose adjustments lead tohigh rates of discontinuation.

Indeed, it is estimated that onlyhalf of warfarin-eligible patientswith AF actually receive anticoag-ulation.6 Furthermore, warfarin’sefficacy is powerfully dependenton the time spent in the therapeu-tic range and there are a signifi-cant number of patients who donot achieve this.7

A number of alternatives towarfarin are becoming availablefor some patients where anticoag-ulation is clinically indicated andsafe.

RivaroxabanFollowing on from the RE-LY(Randomized Evaluation of Longterm anticoagulant therapY)study,8 which demonstrated thesuperiority (150mg twice-dailydose) and noninferiority (110mgtwice-daily dose) of the directthrombin inhibitor dabigatran(Pradaxa), the ROCKET-AFstudy9 has demonstrated the non-inferiority of the factor Xainhibitor rivaroxaban to warfarinin the prevention of stroke andsystemic embolism in patientswith AF, with similar rates ofbleeding.

Rivaroxaban has few inter -actions and needs no laboratorymonitoring. However, there aresome important considerations.Although bleeding rates are simi-lar to warfarin, the study did showan increase in haemoglobinreduction, transfusion require-ments and major GI bleeding in the rivaroxaban group.Furthermore, in keeping with the other warfarin alternatives,rivaroxaban has no establishedantidote and no reliable labora-tory assay. It also requires cautionin renal failure and is absolutelycontraindicated in hepatic failure.

While warfarin is likely toremain the mainstay of treatmentfor most patients with AF, direct

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www.prescriber.co.uk Prescriber 5 September 2012 23

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Place in therapy –

DVT treatment and

prevention

Rivaroxaban appears to be anattractive alternative to warfarin inthe treatment of acute DVT and thesecondary prevention of DVT andPE for a number of reasons: no rou-tine monitoring of anticoagulationis required; there is minimal risk oferroneous anticoagulation; there islimited interaction with diet andmedication; and the repeatedadministration of low-molecular-weight heparin (LMWH) injectionsat the commencement of warfarintherapy is unnecessary – rivaroxa-ban is effective immediately.

ConcernsHowever, caution is required whenconsidering these benefits. Firstly,patient education must not be neg-lected: it will still be essential thatpatients are informed of the risk ofbleeding and the action that needsto be taken should it occur.

Furthermore, the omission ofeven a single dose of rivaroxabancould lead to a more significant

period of underanticoagulationcompared to warfarin due to itsshorter half-life. Patients will there-fore need to understand theimportance of regular, sustainedcompliance with rivaroxaban.

Perhaps of greatest concern tothose involved in anticoagulationmanagement is the lack of an effec-tive antidote to rivaroxaban, a com-plete contrast to warfarin. Animalmodels provide only limited datathat replacement with either pro-thrombin complex concentrates(in the active or inactive form) orrecombinant VIIa might be effec-tive. Therefore, if a patientrequires urgent surgery or is admit-ted with major haemorrhage, thereis currently no reliable reversalstrategy.

This is not helped by the inabil-ity of current laboratory techniquesto give little more than a qualitativeindication of the presence orabsence of the drug.

ConclusionOverall, rivaroxaban has the poten-tial to enhance the management ofacute DVT and secondary preven-tion of venous thrombosis as it hasbeen shown to be as effective as

warfarin for these indications.However, there is limited evidenceon the use of rivaroxaban beyond12 months. It might therefore beprudent that, until further experi-ence is accrued, rivaroxaban is onlyused in patients who are antici-pated to require short-term anti -coagulation for three to six monthsand not in those who require long-term treatment for secondary pre-vention.

In the meantime, there must bestrict data collection of the real-world experience with rivaroxabanto monitor the frequency, manage-ment and outcome of bleedingepisodes in patients using this drug.Ongoing development of labora-tory methods for accurately detect-ing drug plasma concentrations iscrucial. Finally, hospitals will needto formulate protocols to managebleeding episodes, and the educa-tion of patients in drug complianceand reporting of bleeding will beessential.

Declaration of interestsNone to declare.

Dr Bagot is a consultant haematolo-gist at Glasgow Royal Infirmary

thrombin and factor Xa inhib -itors are a significant and excitingdevelopment in the field of strokemedicine. It is likely that they willbe initially reserved for patientswho cannot tolerate warfarin,who struggle to remain in thetherapeutic range or where thereare concerns regarding compli-ance and drug interactions inpatients with multiple co-morbidities, but in whom strokerisk outweighs the risk of majorbleeding.

References1. Mant J, et al. Health care needsassessment: stroke. In: Stevens A, et al,

eds. Health care needs assessment: the epi-demiologically based needs assessmentreviews. First series, 2nd ed. Oxford:Radcliffe Medical Press, 2004;141–244.2. National Audit Office. Reducing braindamage: faster access to better stroke care.(HC 452 Session 2005–2006). London:The Stationery Office, 2005.3. Wolf PA, et al. Arch Intern Med 1987;147:1561–4.4. Camm AJ, et al. Europace 2010;12:1360–420.5. Fuster V, et al. Circulation 2006;114:e257–e354.6. Glazer NL, et al. Arch Intern Med 2007;167:246–52.7. Samsa GP, et al. Arch Intern Med 2000;160(7):967–73.8. Conolly SY, et al. New Eng J Med 2009;

361(12):1139–51.9. Patel MR, et al. New Eng J Med2011;365(10):883–91.

Declaration of interestsDr Haunton, none to declare;Professor Robinson has receivededucational grants and honorariain respect of advisory boards fromBoehringer Ingelheim.

Dr Haunton is clinical research fellowand honorary specialist registrar, andThompson Robinson is professor ofstroke medicine, Ageing and StrokeMedicine, Department ofCardiovascular Sciences, University ofLeicester