Atrial Fibrillation and Novel Oral Anticoagulants

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Background

Atrial fibrillation

Risk assessmentfor stroke andthromboembolism

Novelanticoagulants

Factor Xainhibitors

New agents vswarfarin

inside

DR STEFAN BUCHHOLZconsultant cardiologist, cardiacservices, Mackay Base Hospital,Mackay, Queensland.

The authors

DR VIJAY SOLANKIhead of cardiology, Hornsby Ku-ring-gai Hospital, Hornsby;VMO, echocardiographydepartment, St Vincent’s Hospital,Darlinghurst, NSW.

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FOR many decades, warfarin hasbeen the only oral anticoagulantavailable in Australia for primaryand secondary prevention of strokein patients with valvular and non-valvular atrial fibrillation. It hasproven to be very effective, but hassignificant limitations. In April 2011,the Therapeutic Goods Administra-tion approved a new oral anticoagu-

lant — the direct thrombin inhibitordabigatran — as an alternative oralanticoagulant to reduce the risk ofstroke and systemic embolism inpatients with non-valvular AF.

History of oral anticoagulationIt has been 70 years since a USfarmer handed a dead cow to a locallaboratory, stating part of his herd

was dying from uncontrolled haem-orrhage. Further investigation foundthe animals had ingested largeamounts of the coumarin-containingsweet clover plant (Melilotus offici-nalis, figure 1, see next page), which,when mouldy, converts to the activemetabolite, vitamin K antagonistdicoumarol.

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Atrial fibrillation andnovel oral anticoagulants

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Subsequent research producedthe first branded form of warfarin,Coumadin, approved by the USFood and Drug Administration asan oral anticoagulant in 1954.Since that time, on a worldwidebasis, warfarin has consistentlybeen shown to reduce the incidenceof AF-related stroke by about two-thirds.

In Australia, there are two reg-istered warfarin formulations:Coumadin and Marevan. Thesetwo products are not interchange-able, because bioequivalence hasnot been tested.

Unfortunately, warfarin isunderutilised or often used subop-timally. Research has demon-strated that in general terms only50% of eligible patients with AFreceive warfarin. Of that group,

30% will discontinue the drugwithin one year for various rea-sons including the fact warfarintherapy has a high incidence ofmajor bleeding (up to 20%) in thefirst year after treatment initiation.

Warfarin has a very narrowtherapeutic window with slowonset and offset of action. Itexhibits considerable genetic vari-ability in metabolism, with some-times unpredictable INR levelsoften related to multiple food anddrug interactions. The need forfrequent monitoring often provesinconvenient for elderly patientsand despite monitoring, onlyabout 60% of INR readings arewithin the target range (2.0-3.0).

Despite its clinical effectiveness,warfarin is commonly disliked bythe patient — and is oftenreferred to as “rat poison”.

What is needed is an effective,safe and convenient oral anti-coagulant, without the limita-tions of vitamin K antagonisttherapy, including the need formonitoring.

The potential benefits of using anovel agent, the direct thrombininhibitor ximelagatran, were showna few years ago by a large trial, inwhich ximelagatran proved to benon-inferior to warfarin for AF-related stroke prevention andmajor haemorrhage (the SPORTIFIII trial).1 However, in 2006,AstraZeneca withdrew its US appli-cation even though ximelagatranwas already approved for use in adozen European countries. Theconcern for hepatic toxicity relatedto short-term therapy was the pri-mary reason for the abandonmentof the drug.

OVER the past decade, a varietyof stroke-risk schemes relating tonon-valvular AF have been pub-lished. The simplest and one ofthe most widely used risk assess-ment schemes today is theCHADS2 score. This scoringsystem has identified Cardiac fail-ure, arterial Hypertension, Age(!75 years), Diabetes mellitus, andprevious Stroke or TIA as majorrisk factors for AF-related throm-boembolism.

CHADS2 is based on a scoringsystem by which one point isassigned for each risk factor,except previous stroke or TIA,scoring two points if present. Themaximum point score is 6, andtable 1 shows adjusted annualstroke rates reported based on noprior antithrombotic therapy inpatients.

The original description of theCHADS2 score has, somewhatarbitrarily, classified patients witha CHADS2 score of 0 as low risk,1-2 as moderate risk, and >2 ashigh risk. Current treatmentguidelines, however, try to de-emphasise different risk categoriesand encourage viewing the strokerisk according to the CHADS2score as a continuum. As such, itis now accepted that in patientswith CHADS2 score !2, long-termoral anticoagulant therapy isstrongly recommended and (in thecase of warfarin) aiming for anINR target of 2.5 (range: 2-3).

Eminent professor of cardiol-ogy Valentin Fuster proclaimed atthe American College of Cardiol-ogy 59th Annual Scientific Ses-

sions in Atlanta, Georgia in 2010:“If a patient has a CHADS2 scoreof two or more, it is negligent notto commence oral anticoagulationunless a valid contraindicationexists!”

Additionally, various publishedanalyses support the view thatpatients who were previouslyclassed at moderate risk (ie, aCHADS2 score of 1) still derivesignificant benefit from oral anti-coagulant therapy over antiplatelettherapy with aspirin, with pub-lished low rates of major haemor-rhage. Patients with non-valvularAF and a CHADS2 score of 0 havea low annual risk of thromboem-bolism, and here the risk of harmwith warfarin — such as majorgastrointestinal or intracranial

bleeding — outweighs the bene-fits and therefore either no therapyat all or low-dose aspirin is cur-rently recommended.

Other ‘clinically relevant non-major’ risk factors have beenincorporated into the morerecently developed CHA2DS2-VASc score, which features heavilyin the European Society of Cardi-ology guidelines for the manage-ment of AF.5 This score, in addi-tion to the recognised major riskfactors featured in the CHADS2score, includes a history of Vas-cular disease (MI, peripheralartery disease, and presence ofcomplex aortic plaque), Age 65-74 years (note: age !75 herescores 2 points), and Sex Category(female = 1 point).

This scoring system is slowlystarting to gain popularity in Aus-tralia, with the annual stroke ratesranging from 1.3% (CHA2DS2-VASc score = 1) to 15.2% (score =9). The recommendations for com-mencing oral anticoagulants are thesame as for the CHADS2 score.

Stroke risk modifiers, other thanthose listed in the CHADS2 and theCHA2DS2-VASc, score may thenadditionally be considered in acomprehensive stroke risk assess-ment. A pooled analysis of morethan 1000 patients from three largeAF anticoagulation trials thatincorporated echocardiographyinto their risk-stratification scheme(BAATAF, SPINAF, and SPAF I)found left ventricular systolic dys-function and left atrial enlargementto be independent high-risk predic-tors for thromboembolism.

Transoesophageal echocardiog-raphy (TOE) can be very valuablein identifying other left atrialabnormalities that are associatedwith increased stroke risk, such asspontaneous echocardiographic

contrast and left atrial appendagethrombus (figure 2). These featuresare not appreciable on routinetransthoracic imaging.

Spontaneous echocardiographiccontrast (also called ‘smoke’ or‘haze’) is caused by an increasedultrasonic backscatter from sponta-neous aggregation of erythrocytesand plasma proteins at low flowand shear rates, and has beenfound to predict thrombus forma-tion within the left atrial cavityindependently.

In addition, the left atrialappendage emptying velocity canbe reliably measured in most cases,providing a quantifiable measureof blood stasis and hence increasedrisk of thrombus formation (figure3, see page 30).

TOE is also extremely useful inproviding information about thepresence and extent of atherosclerosisof the thoracic aorta. Advancedatheroma of the aorta, such asmarked irregularity of the intimalsurface and thickening of the intimaextending !4mm into the aorticlumen, or atherosclerotic plaqueswith a mobile element, have all beenrecognised to increase stroke riskgreatly (figure 4, see page 30).

Bleeding riskGeneral considerationsIn most non-anticoagulated AFpatients, thromboembolic eventrates are markedly higher thanbleeding rates. Reported rates ofmajor bleeding among individu-als with AF taking oral vitamin Kantagonists vary widely, ranging

AF is the most common sustainedarrhythmia worldwide, estimated toaffect about 1% or 240,000 of theAustralian population. More thanhalf of those affected are over theage of 75. Studies indicate the relativerisk of stroke for people with AFvaries from 2.5-7 times that of thegeneral population. About one-quar-ter of first-ever strokes are expectedto occur in patients with AF.

It is estimated 39% of high-riskand 42% of moderate-risk patientswith non-valvular AF are untreated.About 10% of high-risk patients are

treated only with aspirin. If allpatients with non-valvular AF werediagnosed and treated as per guide-lines, 3500 first-ever strokes couldbe prevented each year.

AF is generally classified intofour categories: • Paroxysmal (usually lasting <48

hours).• Persistent (>7 days or requiring

cardioversion).• Permanent (>1 year). • Lone (ie, without evidence of

structural heart disease). The risk of cardioembolic stroke

appears to be similar in patientswith paroxysmal, persistent andpermanent AF, and can occur inpatients who have had acute AF foras little as 48 hours. In one study ofAF lasting less than 72 hours, 15%of patients had evidence of leftatrial appendage thrombus on tran-soesophageal echocardiography.2

Among patients with paroxysmalAF, about 90% have recurrentepisodes of AF and up to 90% ofthose are not detected and recog-nised by the patient.

During continuous Holter mon-

itoring, up to 17% of patientsexperience asymptomatic episodesof AF lasting as long as 48 hours.The Rate Control vs ElectricalCardioversion for Persistent AtrialFibrillation (RACE) and AtrialFibrillation Follow-up Investiga-tion of Rhythm Management(AFFIRM) trials, published in2002, demonstrated embolicevents occurred most often afteroral anticoagulant therapy hadbeen stopped or when the INRwas subtherapeutic and withequal frequency, regardless of

whether a pharmacologicallybased rate control or rhythm con-trol was in use.3,4

The strategy of rate control wasnon-inferior to rhythm control inboth these trials and permits con-sideration of rate control as pri-mary therapy. Current guidelinesrecommend patients with parox-ysmal AF receive warfarin if theyhave risk factors for stroke.Patients treated with rhythm con-trol remain at risk for cardioem-bolic stroke probably because ofundetected periods of AF.

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Atrial fibrillation and novel oral anticoagulantsHOW TO TREAT

from previous page Figure 1. Sweet clover plant(Melilotus officinalis).

Figure 2: Left atrial appendage thrombus.

What is needed is aneffective, safe andconvenient oralanticoagulant,without thelimitations of vitaminK antagonist therapy,including the need formonitoring.

Atrial fibrillation

Risk assessment for stroke and thromboembolism

Table 1: CHADS2 scoring system

CHADS2 score Annual stroke rate (%)

0 1.9

1 2.8

2 4.0

3 5.9

4 8.5

5 12.5

6 18.2

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THE latest anticoagulants in themost advanced stages of develop-ment are designed to target eitherfactor Xa (fXa) or thrombin.

Thrombin is the final effector inthe coagulation cascade and appearsa logical target for new anticoagu-lants (figure 5). Thrombin convertsfibrinogen to fibrin, but also ampli-fies its own generation by feedbackactivation of factors V, VIII and XI,as well as being a strong platelet ago-nist. As such, thrombin inhibitionleads to reduced fibrin formation,reduces thrombin generation, andinhibits platelet activation. Anotheradvantage of direct thrombininhibitors is the ability to inactivatefibrin-bound as well as free thrombinequally well because fibrin-boundthrombin is an important trigger ofthrombus expansion.

Factor Xa is also an acceptabletarget for new agents. Factor X ispositioned at the convergence of theintrinsic and extrinsic coagulationpathways, and once activated, onemolecule of fXa is able to generatemore than 1000 thrombin molecules.

Dabigatran (Pradaxa)Dabigatran etexilate mesylate(Pradaxa) is an oral, competitive,reversible, direct thrombin inhibitorapproved by the TGA in Australia inApril 2011 for the following twoindications: • Prevention of stroke and systemic

embolism in non-valvular AF andat least one additional risk factorfor stroke as defined by theCHADS2 score.

• Prevention of venous thromboem-bolic events in adult patients whohave undergone elective total hipor knee replacement. Non-valvular AF is defined as

patients without a history of rheu-matic mitral valve disease, prosthetic

valve replacement, or mitral valverepair. Dabigatran is available in75mg, 110mg and 150mg capsules.With regard to treating AF, currentguidelines suggest a dose of 150mgtwice daily or a reduced dose (110mgtwice daily) in patients with moderaterenal impairment, above 75 years ofage, or in patients at higher risk ofmajor bleeding.

Although dabigatran has beenapproved for use in Canada andEurope since 2008 for primary pre-vention of venous thromboembolicdisease in patients undergoing hip andknee replacement, the TGA approvalof dabigatran for stroke preventionin patients with non-valvular AF rep-resents a significant event. This isbecause of the sheer number ofpatients who are potentially eligiblefor the drug. Dabigatran etexilate ismetabolised to dabigatran with amaximum activity about one hourafter ingestion, is 80% renallyexcreted (hence the cautious dosing inkidney failure) and has a half-life inthe range of 12-17 hours.

It is important for healthcareproviders to keep in mind the currentindications for dabigatran use — withspecial emphasis on the fact it is notrecommended for patients with valvu-lar AF (eg, AF related to mitral steno-sis). It is also not approved forpatients with mechanical heart valves,since these patient groups were notevaluated in the Randomised Evalua-tion of Long-term AnticoagulationTherapy (RE-LY) study.6 Unfortu-nately, a number of cases havealready been reported of patients withmechanical valves who were inappro-priately switched from warfarin todabigatran, only to have theirmechanical valves clotted off, therebyrequiring urgent valve replacement(figure 6).

from 1.5-7.2% a year. A common score recommended

to calculate individual bleedingrisk is the HAS-BLED score: his-tory of uncontrolled Hypertensionwith systolic BP >160mmHg,

Abnormal liver and/or kidneyfunction, Stroke, Bleeding history,Labile INR, Elderly (age >65years), Drugs (NSAIDS,antiplatelet therapy, alcohol !8units/week), with 1 point for thepresence of each risk factor (maxi-

mum of 9 points). A score of !3indicates ‘high risk’ and regularreview is required following theinitiation of any antithrombotictherapy — oral vitamin K antago-nists, antiplatelet drugs, or thenewer agents (although the HAS-

BLED score has not been validatedfor those).

Not surprisingly, studies haveshown the expected net clinicalbenefit of oral vitamin K antago-nist therapy to be highest amongpatients with the highest

untreated risk of stroke, includ-ing the oldest age category (!85years), whereas the absoluteincrease in risk for intracranialhaemorrhage due to vitamin Kantagonist therapy across agegroups appears fairly consistent.

Figure 6: Intraoperative image during replacement of a mechanical aorticvalve. The black arrows indicate organised thrombus on the valve leaflets,which led to severe aortic regurgitation as a result of valve malfunction.

Figure 5: The role of thrombin in the coagulation cascade. (Photo courtesy of the New England Journal of Medicine.)

Figure 4. Transoesophageal echocardiogram of the proximal descending aorta.This example shows high-risk features for stroke and systemic embolism:aortic intimal thickening !4mm (long arrow), a mobile echo target of any size(short arrow), and a large irregular atheroma protruding !4mm into the aorticlumen (arrow head).

Figure 3: Transoesophageal echocardiography examples of different pulse wave velocity pattern within the left atrialappendage (LAA), measured within the proximal third of the LAA and expressed in cm/sec of red blood celldisplacement. A: Normal sinus rhythm. The LAA flow pattern in normal sinus rhythm is quadriphasic, with the LAAemptying velocity during atrial contraction exceeding 80cm/sec (asterisk). B: Atrial flutter with about 300 LAAcontractions per minute. Note the emptying velocities average 40-60 cm/sec consistent with normal LAA mechanicalfunction. C: Coarse atrial fibrillation with mildly reduced LAA mechanical function (velocities averaging 30cm/sec).D: Markedly reduced LAA emptying velocities averaging 10-15cm/sec. This is commonly associated with spontaneousechocardiographic contrast within the left atrial cavity and confers the highest risk of left atrial thrombus formation.

Novel anticoagulants

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THE new group of oral fXainhibitors are small molecules thatbind reversibly to the active site offXa. There are currently quite afew agents in this class under devel-opment, and those in the mostadvanced stages of testing arerivaroxaban, apixaban, and edoxa-ban. Figure 7 shows a comparisonof novel anticoagulants.

RivaroxabanRivaroxaban is an oral direct fXainhibitor. The main advantage ofthis drug is its once-daily dosingthat in the future might prove tobe a key advantage with regard toconvenience, drug adherence andpersistence.

Rivaroxaban has a high bioavail-ability (about 80%) with plasmaconcentration peaking 2.5-4 hoursafter dosing. The half-life is about9-12 hours, and about one-third ofthe drug is renally excreted.Another third of the drug ismetabolised by the liver viacytochrome P450 CYP3A4-dependent and independent path-ways, and then excreted via thefaeces or (as inactive metabolites)via the kidneys.

The critical trial designed todemonstrate superior efficacy overwarfarin was the RivaroxabanOnce Daily Oral Direct Factor XaInhibition Compared With VitaminK Antagonism for Prevention ofStroke and Embolism Trial inAtrial Fibrillation (ROCKET-AF).7

This trial targeted high-risk AFpatients with a CHADS2 score !2,and demonstrated a 12% relativerisk reduction in the incidence ofstroke or systemic embolismtreated with rivaroxaban, provingnon-inferiority— but not superior-ity — to warfarin. However, there

was a significant reduction inintracranial bleeding, as well asreduced bleeding-associated mor-tality when compared with warfarin.

ApixabanApixaban (Bristol-Myers Squibb,Pfizer) is a direct fXa inhibitor witha half-life of about 12 hours. It wasdeveloped for twice-daily oraladministration in preventing AF-related stroke. It is 25% renallyexcreted and utilises thecytochrome P450 pathways for itsmetabolism, resulting in the poten-tial for significant drug interactionwith strong cytochrome P450

inhibitors such as azole antifungals(eg, ketoconazole or itraconazole),macrolide antibiotics (eg, clari-thromycin) and protease inhibitors(eg, atazanavir), which should beavoided altogether in apixaban-treated patients.

To date, two large trials pub-lished in 2011 have demonstratedapixaban’s superior performance instroke prevention in AF.

The first trial published in theNew England Journal of Medicinewas the Apixaban Versus Acetyl-salicylic Acid to Prevent Strokes(AVERROES) trial, comparingapixaban 5mg twice daily withaspirin (varying doses 81-325mg

daily) in 5600 patients deemedunsuitable for vitamin K antago-nist oral anticoagulation treat-ment.8 This trial was stopped pre-maturely because of the clearstatistical superiority of apixabanover aspirin in reducing the inci-dence of stroke, with major bleed-ing rates comparable to aspirin.

The pivotal Apixaban for Reduc-tion In STroke and Other Throm-boemboLic Events in Atrial Fibril-lation (ARISTOTLE) trial waspublished shortly after, comparingapixaban with warfarin.9 Theresults of this trial were mostencouraging, showing patients withAF and at least one additional risk

factor for stroke treated with apix-aban during a median follow-up of20 months had statistically signifi-cant lower rates of stroke and sys-temic embolism (21% relative riskreduction), major bleeding (31%relative risk reduction), and overallmortality (11% relative risk reduc-tion). It was also better toleratedthan warfarin, with fewer drug dis-continuations.

Overall the ARISTOTLE trialdemonstrated that for every 1000patients treated for 1.8 years, apix-aban prevented a stroke in sixpatients (four haemorrhagic strokesand two ischaemic strokes), majorbleeding in 15 patients, and deathin eight patients.

Taking all the recently publishedstudies into account, it is interestingto note neither dabigatran norrivaroxaban could match apixa-ban’s performance in terms of effi-cacy, bleeding safety and overallmortality. However, it should bepointed out there are many differ-ences between these large trials thatmake it difficult to compare thenovels agents directly. A simplifiedoverview of these novel agents isprovided in figure 7.

EdoxabanThe efficacy of another once-dailyoral direct inhibitor of fXa, edoxa-ban, is currently being investigatedin the Effective AnticoagulationWith Factor Xa Next Generationin Atrial Fibrillation trial(ENGAGE AF-TIMI 48). This trialhas completed randomisation ofover 20,000 patients and the resultsare expected to be published thisyear. Edoxaban has a half-life of8-10 hours and about 40% is elim-inated via the kidney, with theremainder excreted in the faeces.



Factor Xa inhibitorsFigure 7: Simplified comparison of novel anticoagulants.

The RE-LY trialThe RE-LY trial was an importantPhase III, multinational trial com-paring dabigatran 110mg twicedaily, 150mg twice daily and war-farin (target INR 2-3) in over18,000 patients with AF and oneadditional risk factor for stroke(mean CHADS2 score of 2.1) for amedian of 24 months of treatment.6

The primary efficacy endpoint(a composite of time to first occur-rence of stroke or systemicembolism) showed both doses ofdabigatran were statistically eithernon-inferior (110mg twice daily)or superior (150mg twice daily)when compared with warfarin. Infact, compared with warfarin,dabigatran 110mg twice dailyreduces the risk of stroke by 10%and 150mg twice daily by 35%.The yearly event rate for stroke orsystemic embolism was lowestwith the higher dose dabigatran(1.11%), followed by the 110mgtwice-daily dosing (1.53%) andwarfarin (1.69%) — the differenceprimarily driven by the ischaemicstroke event rate. The yearly eventrates for systemic embolism, with-out including ischaemic stroke,were 0.13%, 0.11% and 0.18%,respectively.

The secondary study endpointincluded the time to first occurrenceof stroke, systemic embolism or all-

cause death. This composite endpointdemonstrated dabigatran 110mgtwice daily reduced the risk by 7%relative to warfarin and 150mg twicedaily reduced the risk by 17% rela-tive to warfarin. The major contribu-tor to the composite event endpointin the three treatment groups was

death and the most common cause ofdeath was vascular.

Bleeding risk in the RE-LY trialDespite dabigatran 150mg twicedaily being superior to warfarinin reducing the incidence of strokeand embolic embolism by 35%,there was no significant differencein major bleeding (3.36% a yearin the warfarin arm and 3.11% ayear in the dabigatran 150mggroup).6

Dabigatran 110mg twice daily,which was non-inferior to war-farin in preventing stroke and sys-temic embolism, was associatedwith a significant 20% relativerisk reduction in major bleeding,compared with warfarin (2.71% ayear with dabigatran 110mg vswarfarin). The rate of haemor-rhagic stroke was 0.38% a yearin the warfarin group, comparedwith 0.12% a year with dabiga-tran 110mg and 0.10% a yearwith dabigatran 150mg.

The addition of concomitantmedications, however, showedincreased major bleeding. Theaddition of aspirin to dabigatrannearly doubled the risk of bleed-ing, clopidogrel doubled the risk,a COX-2 inhibitor increased therisk by 60-80%, NSAIDs by50%, and verapamil by 30%,owing to significant drug interac-tion with dabigatran metabolism.6

Further evaluation of the origi-

nal RE-LY trial data has subse-quently shown that, in patientswith AF and at least one majorrisk factor for stroke, both dosesof dabigatran compared withwarfarin have lower risks of bothintracranial and extracranialbleeding in patients aged less than75 years. In those aged 75 yearsand above, intracranial bleedingrisk is lower, but extracranialbleeding risk is similar or higherwith both doses of dabigatranwhen compared with warfarin.There were no occurrences ofliver toxicity or other adverseevents with dabigatran except foran increase in dyspepsia.

Dabigatran and elective cardioversionA subgroup analysis of the originalRE-LY trial data identified 1270patients undergoing a total of 1983cardioversions during the trial period.The frequencies of stroke and sys-temic embolism rates within 30 daysof cardioversion on the 2 doses ofdabigatran were low (0.8% for thelower dose dabigatran and 0.3% forthe higher twice daily dose) and com-parable to those on warfarin (0.6%),with or without pre-cardioversionTOE guidance. Dabigatran appearsto be a reasonable alternative to war-farin in the context of elective car-dioversion with at least three weeksof oral anticoagulant cover prior andfour weeks afterwards.

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A FEW important questions needto be answered before deciding if apatient with non-valvular AF and aCHADS2 score of 1 or above canbe placed on dabigatran instead ofwarfarin.

First, the healthcare providershould determine the patient’s stablekidney function. The TGA posted asafety alert in November 2011 fol-lowing evaluation of internationalreports of bleeding with dabigatran.An update was made to the Pradaxaproduct information essentially out-lining new recommendations forassessing kidney function to minimisethe risk of bleeding — includingmeasurement of creatinine clearancebefore starting dabigatran and duringits use, particularly in elderly patientsand those with renal impairment. Astable creatinine clearance between30mL/minute and 60mL/minute isconsistent with reduced kidney func-tion and the lower dose of dabiga-tran should be used with caution. Acreatinine clearance less than30mL/minute indicates advancedkidney disease and in the RE-LY trialthese patients were excluded fromparticipating in the trial. Dabigatranshould not be used in these patientseven with the reduced dosing.

Second, will the patient complywith dabigatran in its current twice-daily preparation? Compliance andadherence with this short-acting drugis of utmost importance, and thepatient needs to understand thatmissing a few doses will invariablyincrease their risk of stroke. Further-more, issues surrounding the patient’sability to pay for the drug, as wellas any existing GI pathology willneed to be addressed.

The RE-LY trial has shown anassociation between dabigatran use

and dyspepsia and for thesepatients, stomach upset could resultin drug non-compliance. Bleedingrisk should be assessed and theHAS-BLED score as described is agood tool to be used to calculatebleeding risk.

Current status of dabigatranavailabilityDabigatran received a positive rec-ommendation from the Pharmaceu-tical Benefits Advisory Committeein March 2011. Internationally, ithas received approval for strokeprevention from over 50 regulatoryagencies globally, including majormarkets such as the US, Canada,and the UK.

To date, over half a million AFpatients around the world havebeen treated with dabigatran forstroke prevention. The PBAC notedin the minutes from its March

2011 meeting: “Dabigatran repre-sents a safe, efficacious and cost-effective therapy for ‘at risk’patients with atrial fibrillation forthe reduction of stroke and sys-temic thromboembolism. Thesereductions represent importantreductions in morbidity, and canbe expected to result in mortalityreductions.”

Despite this endorsement,approval for PBS listing is stillpending. Interventions for improv-ing warfarin need to be consideredin the way healthcare is delivered inAustralia. The Federal Governmentannounced on 30 September 2011that it will commission a review ofPradaxa and other anticoagulants,including warfarin. This review isbeing conducted by former PBACchair Emeritus Professor LloydSansom and is due in September2012.

DESPITE all the known limitationsof current vitamin K antagonisttherapy, it is undeniable that war-farin is highly effective when usedin an optimal clinical setting. Totake over as first choice, new anti-coagulants must be more ‘patientfriendly’ (ie, convenient), and mustresult in equally good or betterclinical outcomes at an acceptablecost and comparable safety profile.

One could argue that the neweragents are more patient-friendlybecause they do not require rou-tine coagulation monitoring or fre-quent dose adjustments. However,this makes patient compliance anddrug adherence an extremelyimportant issue.

Remembering that rivaroxabanand edoxaban are given once dailyand dabigatran and apixaban needto be given twice daily owing to ashorter half-life, one can easilyimagine that in case of reducedcompliance, the potential for moresustained periods of subtherapeuticanticoagulation may have a seriousimpact on drug efficacy and there-fore may infer an increased risk ofstroke or systemic embolism. It hasbeen shown in previous studies thatabout 50% of patients across vary-ing genders and ages fail to followtheir prescribed medication regi-mens, with a further drop of about10% for medications that are taken

twice daily instead of once daily. Furthermore, out-of-pocket

expense for the new anticoagulantswill be significantly higher than forwarfarin ($35.40 for 20 capsules[10 days] dabigatran etexilate cap-sules versus $19.16 for 50 warfarintablets at 5mg each), which mayalso affect drug adherence.

There is considerable ongoingdebate regarding the government’sdecision to delay the PBS listing ofdabigratran for the prevention ofAF-related stroke — although dabi-gatran is currently prescribable to asmall number of patients free ofcharge through a time-limitedproduct familiarisation program,initiated by Boehringer Ingelheim.

A major disadvantage of thesenewer agents is the fact that at thecurrent time, no coagulation assayis easily available to precisely meas-ure their anticoagulation effect.This makes it difficult to assess thecause for failure of therapy (in caseof a stroke or systemic embolism)or determine if the patient is exces-sively anticoagulated at the time ofa major bleeding episode.

In addition, there is currently noantidote or well-established proce-dure available for reversing antico-agulation in emergency situations.Whereas warfarin can be easilyreversed with vitamin K antagonistsor, in urgent or life-threatening situa-

tions, with fresh frozen plasma or 3-or 4-factor prothrombin complexconcentrates, no equivalent measuresexist for the new agents.

Haemodialysis is presently rec-ommended to (partially) reduce theconcentration of dabigatran, butthis may prove difficult to achievein some emergencies such as intrac-erebral haemorrhage.

Clinicians must appreciate thatthe INR is relatively insensitive todabigatran. The activated partialthromboplastin time may approxi-mate anticoagulant activity andhelp to estimate bleeding risk asso-ciated with the current level ofdrug. These important disadvan-tages of novel oral anticoagulanttherapeutics are summarised in thebox, left.

These issues aside, all three newanticoagulants are at least as goodas warfarin at preventing strokeand systemic embolism and havebeen shown to provide a consistentreduction in the rate of haemor-rhagic stroke by about 40-70%and intracranial haemorrhage byabout 50%. Both lower-dose dabi-gatran and apixaban have resultedin important reductions in majorhaemorrhage and all three newagents have shown about a 10%reduction in mortality (althoughthis reached statistical significanceonly in case of apixaban).

References1. Olsson SB, et al. Stroke

prevention with the oral directthrombin inhibitor ximelagatrancompared with warfarin inpatients with non-valvular atrialfibrillation (SPORTIF III):randomised controlled trial.Lancet 2003, 362:1691-98.

2. Al-Saady NM, et al. Left atrialappendage: structure, function,and role in thromboembolism.Heart 1999; 82:547-54.

3. Van Gelder IC, et al. Acomparison of rate control andrhythm control in patients withrecurrent persistent atrialfibrillation (RACE). NewEngland Journal of Medicine2002; 347:1834-40.

4. Wyse DG, et al. A comparison ofrate control and rhythm controlin patients with atrial fibrillation(AFFIRM). New EnglandJournal of Medicine 2002;347:1825-33.

5. Camm AJ, et al. Guidelines forthe management of atrialfibrillation. The Task Force forthe Management of AtrialFibrillation of the EuropeanSociety of Cardiology (ESC).European Heart Journal 2010;31:2369-429.

6. Connolly SJ, et al. Dabigatranversus warfarin in patients withatrial fibrillation (RE-LY). NewEngland Journal of Medicine2009; 361:1139-51.

7. Patel MR, et al. Rivaroxabanversus warfarin in nonvalvularatrial fibrillation (ROCKET-AF).New England Journal ofMedicine 2011; 365:883-91.

8. Connolly SJ, et al. Apixaban inpatients with atrial fibrillation(AVERROES). New EnglandJournal of Medicine 2011;364:806-17.

9. Granger CB, et al. Apixabanversus warfarin in patients withatrial fibrillation (ARISTOTLE).New England Journal ofMedicine 2011; 365:981-92.

Online resourcesFor GPs:• Therapeutic Goods

Administration — Australianpublic assessment report fordabigatran etexilate mesilate:www.tga.gov.au/pdf/auspar/auspar-pradaxa.pdf

• Department of Health and Ageing— Dabigatran public summarydocument www.health.gov.au/internet/main/publishing.nsf/Content/pbac-psd-dabigatran-march11

• SA Health — Dabigatran clinicalguidelines update: tiny.cc/r4ocdw

For patients:• Medline Plus — dabigatran:

1.usa.gov/IKdTHt• University of Utah, Healthcare —

Pradaxa patient information:healthcare.utah.edu/thrombosis/newagents/TS.Dabi_Patient.Info.pdf

• American Heart Association — A patient’s guide to takingdabigatran etexilate:bit.ly/JWxlQH

Deciding when to use dabigatran

New agents vs warfarin

cont’d next page

Principal disadvantages ofnovel anticoagulant

therapeutics

• Short half-life — potential forincreased stroke risk with poordrug compliance

• No routine coagulation assay easilyavailable — unable to titrate dose,difficulties in assessing cause forfailure of therapy (stroke whileanticoagulated vs major bleed)

• No antidote for anticoagulationreversal available

• High cost

The patient needs tounderstand thatmissing a few dosesof this drug willinvariably increasetheir risk of stroke.

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NEXT WEEK Dizziness is mostly a harmless and self-limiting condition, amenable to diagnosis and treatment. One of the difficulties in treating dizziness is that there is more vertigo mythology than vertigofact. Next week, we will specifically tackle some of the vertigo myths in this article, as well as providing a framework to manage dizzy patients. The authors are Dr Phillip Cremer, clinical director of NorthShore Vertigo and Neurology Clinic, neurologist, Royal North Shore Hospital, St Leonards, and clinical associate professor, University of Sydney; and Dr G Michael Halmagyi, neurologist, Royal Prince AlfredHospital, Camperdown, and clinical professor, University of Sydney, NSW.

Atrial fibrillation and novel oral anticoagulants — 1 June 2012

INSTRUCTIONSComplete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer acceptquizzes by post or fax.The minimum mark required to obtain points is 80%.

ONLINE ONLY

1. With respect to warfarin which TWOstatements are correct?

a) Warfarin has consistently been shown toreduce the incidence of atrial fibrillation-related stroke by about two-thirds

b) In Australia, there are two registeredwarfarin formulations: Coumadin andMarevan

c) Coumadin and Marevan are interchangeablebecause bioequivalence has beenestablished

d) Warfarin is under-utilised with only 20% ofeligible patients with AF receiving warfarin

2. Which TWO statements are correct withrespect to the use of warfarin in clinicalpractice?

a) Warfarin exhibits little genetic variability inmetabolism

b) Despite monitoring, only about 20% of INRreadings are within the target range (2.0-3.0).

c) The need for frequent monitoring oftenproves inconvenient for elderly patients

d) Warfarin therapy has a high incidence ofmajor bleeding (up to 20%) in the first yearafter treatment initiation

3. Which THREE statements are correct withrespect to AF?

a) More than half of AF patients are over theage of 75

b) The risk of thromboembolic stroke appears to be similar in patients withparoxysmal, persistent and permanent AF

c) The relative risk of stroke for people with AFvaries from 5-15 times that of the generalpopulation

d) With respect to risk of thromboembolicstroke, 39% of high-risk and 42% ofmoderate-risk patients with non-valvular AFare untreated

4. Which THREE statements are correctwith respect to risk assessment forstroke and thromboembolism associatedwith non-valvular AF?

a) The CHADS2 score has identified Cardiacfailure, arterial Hypertension, Age (!75years), Diabetes mellitus and previousStroke or TIA as major risk factors for AF-related thromboembolism

b) Using the CHADS2 score, one point isassigned for each risk factor exceptprevious stroke or TIA, which scores twopoints if present

c) With a CHADS2 score !2 chronic oralanticoagulant therapy is stronglyrecommended

d) Patients with a CHADS2 score of 1 have alow annual risk of thromboembolism andthe risk of causing harm with warfarin —such as a major gastrointestinal orintracranial bleed — outweighs the benefits

5. Which THREE responses are clinicallyrelevant risk factors that have beenincluded in the CHA2DS2 VASc score?

a) Vascular disease (MI, peripheral arterydisease and presence of complex aorticplaque)

b) Male sexc) Age 65-74 yearsd) Left ventricular systolic dysfunction and left

atrial enlargement

6. Which THREE statements are correct with respect to bleeding risk associated with oral anticoagulation?

a) In most non-anticoagulated AF patients,thromboembolic event rates are lower thanbleeding rates

b) Bleeding history and stroke are two riskfactors that can be used to calculate the

HAS-BLED score c) The net benefit of oral anticoagulation

therapy is highest among patients with the highest untreated risk of stroke(including the oldest age category !85years) whereas the absolute increase in riskfor intracranial haemorrhage due to oralanticoagulation therapy across age groupsappears fairly constant

d) Using the HAS-BLED score, a score of !3 indicates ‘high risk’ with regular reviewrequired following the initiation of anyantithrombotic therapy

7. Which THREE statements are correctwith respect to dabigatran?

a) Dabigatran was approved by the TGA inAustralia for the following two indications: i) Prevention of stroke and systemicembolism in non-valvular AF and at leastone additional risk factor for stroke asdefined by the CHADS2 score, and ii) Prevention of venous thromboembolicevents in adult patients who haveundergone elective total hip or kneereplacement

b) In treating AF with dabigatran, currentguidelines suggest a dose of 150mg twicedaily or a reduced dose (110mg twice daily) in patients with moderate renalimpairment, above 75 years of age or inpatients at higher risk of major bleeding

c) Non-valvular AF is defined as patientswithout a history of rheumatic mitral valvedisease, prosthetic valve replacement ormitral valve repair

d) Dabigatran will soon be approved forpatients with valvular AF (eg, AF relatedto mitral stenosis) and patients with

mechanical heart valves as these patients were included in the RE-LY trial

8. With respect to dabigatran and the RE-LY trial which THREE statements arecorrect?

a) In patients aged under 75 with AF and atleast one major risk factor for stroke, bothdoses of dabigatran have lower risks ofintra- and extracranial bleeding thanwarfarin

b) Compared with warfarin, dabigatran 110mgtwice daily reduces the risk of stroke by10% and 150mg twice daily by 35%

c) Dabigatran 150mg resulted in a significantlyhigher rate of major bleeding than warfarin

d) The yearly event rate for stroke or systemicembolism was lowest with the higher dosedabigatran (1.11%), followed by the 110mgtwice daily dosing (1.53%) and warfarin(1.69%)

9. In making the decision to use a newer oral anticoagulant which THREEstatements are correct?

a) The newer agent must be more convenientb) Cost will not be a factor as newer oral

anticoagulants are covered by the PBSc) The newer agent must have a comparable

safety profiled) The newer agent must have equal or better

clinical outcomes

10. With respect to possible disadvantagesof newer oral anticoagulants, whichTHREE statements are correct?

a) A twice-daily regimen is harder to complywith than a once-daily regimen

b) At the current time no coagulation assay iseasily available to measure theiranticoagulation effect precisely

c) Dabigatran cannot be used in patients witheGFR less than 30 mL/minute

d) The antidote to reverse dabigatran isprohibitively expensive

www.australiandoctor.com.au/cpd/ for immediate feedback

How to Treat Quiz

CPD QUIZ UPDATEThe RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2011-13 triennium. You cancomplete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post orfax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.

HOW TO TREAT Editor: Dr Martine WalkerCo-ordinator: Agilene De Villa Quiz: Dr Martine Walker

WARFARIN has been in use fordecades and thus far has consistentlybeen shown to be the most effectiveoral anticoagulant therapy in reduc-ing stroke and systemic embolismrelated to AF. Both physicians andpatients have come to accept war-farin, despite its limitations, andhave engaged in a love–hate rela-tionship with this ‘rat poison’. Neworal anticoagulants have beenpushed into clinical developmentand have shown clinical superiorityor non-inferiority to warfarin inareas of critical clinical outcomessuch as stroke reduction, reducedmajor bleeding and lower mortality.

However, there are presently sev-eral unknowns to caution healthcareproviders against the general use ofnewer agents as first-line therapy forpatients with AF. Are we able to pre-dict which patient will do best onthese new drugs? What are the

patient characteristics that provide anoptimal start or transition to a neworal anticoagulant? If a patient onwarfarin has achieved optimal long-term INR control with no significant

bleeding episodes, should they thenbe changed to a new agent justbecause the patient wishes to comeoff warfarin? What is the impact onmajor bleeding rates if a novel agent

is taken concomitantly with single ordual antiplatelet therapy (aspirin,clopidogrel, prasugrel, ticagrelor)?

More research is clearly needed toimprove understanding of the impactof drug non-adherence on clinicaloutcome, the development of appro-priate assays to measure anticoagu-lant effect, the means to treat majorhaemorrhage or drug overdose, andthe appropriate patient characteris-tics for the use of these newer agents.

Until these important clinical issuesare addressed and resolved, in ouropinion, these new agents should notautomatically replace warfarin inpatients with AF. The decision-making process should be highly indi-vidualised in order to provide the bestpossible outcome for that patient.

Despite these unknowns, given thelatest development of numerous novelagents, it appears likely the days ofthe ‘rat poison’ are numbered.

ConclusionMore research isclearly needed toimprove understandingof the impact of drugnon-adherence onclinical outcome.

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Atrial Fibrillation and Novel Oral Anticoagulants