Ximelagatran--promises and concerns.

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EDITORIALS
Editorials represent the opinions
of the authors and THE JOURNAL and not those of
the American Medical Association.
Ximelagatran—Promises and Concerns
V
ing in cattle. Originally developed as a rat poison, vitamin
Kantagonistssuchaswarfarinareusedsuccessfullyforthe
prevention of venous and arterial thromboembolism for a
wide range of clinical indications, including atrial fibrilla-
tion (AF), venous thromboembolism (VTE), coronary ar-
tery disease, some orthopedic procedures, and congenital
or acquired thrombophilia. Since both age and obesity in-
crease the risk of atrial fibrillation2and VTE, the need for
anticoagulants is increasing.
Warfarin treatment is complicated by several inherent
problems that have limited its use. These include delayed
onset of its antithrombotic action, narrow therapeutic in-
dex,unpredictableandvariablepharmacologicalresponse,
and the mandatory regular laboratory monitoring to con-
trolitsanticoagulanteffectandminimizeriskofseriousbleed-
ing. In addition, numerous drugs, certain dietary supple-
ments, alcohol, and even some foods markedly influence
warfarin dose response.3As a consequence, a higher level
of patient diligence and reliability is required than with al-
mostanyotherdrug;furthermore,warfarinmanagementis
labor intensive for the physician and is not reimbursed. In
addition,thereisthediscomfortingrealizationthatwhereas
thehemorrhagiceffectsofwarfarinarevisibleandoftendra-
matic (usually dose-related), the benefits are impercep-
tible to the individual patient.
Theoverallannualincidenceofmajorhemorrhagedueto
oralanticoagulantshasrangedfrom1.2%to7.0%,4butislower
(0.5%-4.2%) in clinical trials with rigorous management of
selected patient populations.5In general practice, vitamin K
antagonistsremainaleadingiatrogeniccauseofhospitaliza-
tion. For instance, in France, among an estimated 500000
patientstreatedeachyearwithanticoagulants,17000arehos-
pitalized annually for hemorrhagic events.6
Unquestionably,lesscomplicatedanticoagulantsareneeded.
Ideally,theseagentsshouldbeavailableinbothparentaland
oral formulations, have prompt onset of action, have a pre-
Victor Gurewich, MD
ITAMIN K (“KOAGULATION”) ANTAGONISTS HAVE
been the sole oral anticoagulants available for 60
years, ever since Link1identified the compo-
nentsinspoiledsweetcloverresponsibleforbleed-
dictable dose response not requiring laboratory monitoring,
andshouldnotinteractwithotherdrugs.Theprofileofximela-
gatran, the oral form of the antithrombin agent melagatran,
fulfillstheserequirements,sotrialsofitsclinicaleffectshave
been followed with keen interest for some time.
Thrombinistheenzymegeneratedbythecoagulationcas-
cade and is directly responsible for clotting fibrinogen and
aggregating platelets. Inhibitors of thrombin or antithrom-
bins are effective natural anticoagulants. For instance, hiru-
din(fromthemedicinalleechHirudomedicinalis)anditsana-
loguessuchashirulog,argatroban,andmelagatranarehighly
specific thrombin inhibitors that have been developed only
for short-term clinical use, since they must be administered
parenterally.7Melagatranisasmalldipeptideanaloguewhich,
unlikehirudin,bindsonlytotheactivesiteofthrombinand
binds reversibly. This property is relevant since melagatran
hasbeenassociatedwithlessbleedingthanisseenwithtighter-
bindinginhibitors.8Liketheotherdirectantithrombins,mela-
gatran inhibits not only free thrombin but also clot-bound
thrombin, whereas heparin inhibits only the former. Mela-
gatran also has a more predictable anticoagulant effect than
heparin, since it is not protein cofactor–dependent.
Ximelagatranisaprodrugformofmelagatran,whichen-
ables it to be rapidly absorbed in the small intestine. After
absorption,ximelagatranisbioconvertedtoitsactiveform,
melagatran, which has about 20% bioavailability.9After in-
gestionofximelagatran,peakbloodlevelsofmelagatranare
reached in 2 to 3 hours; its antithrombotic activity is im-
mediate, and it is cleared entirely by renal excretion within
12 hours.
At therapeutic doses, melagatran induces prolongation of
prothrombin time, partial thromboplastin time, and throm-
bin time, but since the effect is predictable at a fixed dose,
monitoring these parameters is unnecessary. A specific an-
tidote is not available, but when renal function is unim-
paired,therapidclearanceofmelagatranlimitsitseffect.How-
ever,intravenousactivatedprothrombincomplexoractivated
factor VII preparations could be used to more promptly at-
tenuate the anticoagulant effect of melagatran.10No specific
food or drug interactions have been reported.
See also pp 681, 690, and 699.
Author Affiliation: Vascular Research Laboratory, Beth Israel Deaconess Hospital
Medical Center, Boston, Mass.
Corresponding Author: Victor Gurewich, MD, Vascular Research Laboratory, Beth
Israel Deaconess Hospital Medical Center, 21-27 Burlington Ave, PO Box 15709,
Boston, MA 02215 (vgurewic@bidmc.harvard.edu).
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©2005 American Medical Association. All rights reserved.

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Morethanadozenstudiesin4clinicalindications(ortho-
pedicsurgery,VTE,postmyocardialinfarction,AF)havebeen
published, in which a combined total of almost 14000 pa-
tients were randomly assigned to receive a fixed-dose of
ximelagatrancomparedwithpatientsreceivinglow-molecular-
weight heparin, warfarin, or both. Seven trials were for the
primary prevention of VTE in patients undergoing total hip
or total knee replacement surgery, and the drugs were ad-
ministered for about 12 days.11-17The efficacy of ximelaga-
traninpreventingpostoperativeVTEwascomparabletostan-
dard therapy in 4 studies11,12,15,17and was significantly more
effectivein3.13,14,16In1study,14inwhichximelagatrantreat-
ment was initiated with subcutaneous melagatran adminis-
teredbeforesurgery,severebleedingwasmorefrequentthan
withlow-molecular-weightheparin,butintheremainderof
trialsnodifferencesintheincidenceofbleedingwerefound.
As of October 2004, ximelagatran had been marketed in 7
countriesinEuropeforVTEprophylaxisinhospitalizedpa-
tients undergoing joint replacement surgery,18at a dose of
24mgtwicedailyforupto11days.19Postmarketingclinical
information is not yet available.
The secondary prevention of VTE by ximelagatran was
evaluatedinatrialinwhichpatientswererecruitedafterthey
hadcompleted6monthsofstandardtreatmentforacuteVTE.1
Thereafter, 1233 patients were randomly allocated to re-
ceive ximelagatran (24 mg) or placebo twice daily. During
18 months of follow-up, symptomatic recurrent VTE devel-
opedin71patients(11.6%)intheplacebogroup,compared
withonly12events(1.9%)receivingximelagatran.Majornon-
fatalhemorrhageoccurredin5patientsreceivingplaceboand
6receivingximelagatran.Asinothertrials,ximelagatranwas
associatedwitha6%incidenceofasymptomaticincreasesin
alanine aminotransferase (ALT) levels to more than 3 times
theupperlimitofnormal.Thisdecreasedovertimewhether
or not the drug was discontinued.20
Secondary prophylaxis initiated within 14 days after an
acute myocardial infarction was evaluated in 1883 patients
randomized to receive ximelagatran (24, 36, 48, or 60 mg)
or placebo twice daily for 6 months. All patients received
160mgaspirindaily.Ximelagatransignificantly(P?.05)re-
duced cardiovascular events during the observation pe-
riod.Majorbleedingoccurredin1.8%ofpatientsreceiving
ximelagatran compared with 0.9% in the placebo group.21
In a major clinical study reported in this issue of JAMA,
Fiessinger and colleagues,22on behalf of the THRIVE In-
vestigators, present the findings from a 279-center, multi-
national study of acute VTE. A total of 2489 patients with
deep vein thrombosis were randomized to receive either
ximelagatran alone (36 mg twice daily) or low-molecular-
weightheparin(enoxaparin)followedbywarfarin.Onethird
ofthepatientsineachgrouphadassociatedpulmonaryem-
bolism,butpatientswithpulmonaryembolismcausinghe-
modynamic instability were excluded, as were those with
deep vein thrombosis of longer than 2 weeks duration and
obesity.Patientsandphysicianswereblindedtothe6months
oftreatment,necessitatingplaceboinjectionsaswellassham
regular laboratory testing. The incidence of recurrent VTE
was comparable and remarkably low in both groups—
2.1% and 2.0% with ximelagatran and enoxaparin/
warfarin, respectively. This is about half the rate antici-
pated with conventional therapy, a finding the authors
suggestmayhavebeenrelatedtothecomplexityofthestudy
leading to selection of healthier patients. Since regular sur-
veillancewithultrasonographywasperformed,plusvenog-
raphyifdistaldeepveinthrombosiswassuspected,itisun-
likely that cases were overlooked.
Theincidenceofmajorbleedingcomplicationsduringthe
6-monthtreatmentperiodwasalsolow(ximelagatran,1.3%;
enoxaparin/warfarin, 2.2%), without any apparent differ-
encesinthesitesatwhichbleedingoccurred.Alsonotedwas
a locally reported incidence of 10 (0.8%) serious coronary
events in the ximelagatran group compared with 1 (0.08%)
intheenoxaparin/warfaringroup.Suchafindinghasnotbeen
previouslyreported.Itisnoteworthythatthisassociationwas
not found in the large AF trials, which were of longer dura-
tion, and that ximelagatran specifically prevented coronary
eventswhenthisindicationwasevaluated.21Ximelagatranwas
associated with an asymptomatic increase (?3 times the up-
perlimitofnormal)ofALTlevelsin9.6%ofpatients,slightly
higherthaninotherstudies,butthiscomparedwitha2%in-
cidence in the enoxaparin/warfarin group. The increase oc-
curred at a mean of 2.5 months after initiation of treatment
andresultedinthediscontinuationofximelagatranin76pa-
tients (6%), which was mandated by the protocol if the in-
crease exceeded 5 times the upper limit of normal.
The findings from the study by Fiessinger et al suggest
that fixed-dose ximelagatran is as effective as, and is possi-
bly safer than, the more complicated regimen of low-
molecular-weightheparin/warfarinforthestandardcourse
of treatment of acute VTE (without major pulmonary em-
bolism). At the same time, the authors caution that the
mechanism and clinical relevance of the increases in ALT
levels require further evaluation.
Atrialfibrillationisaconditionwithanestablishedlong-
term risk of potentially devastating thromboembolism and
remains notoriously undertreated using oral anticoagu-
lants.23Atrial fibrillation is one of the prime indications for
an oral anticoagulant that is more predictable and less de-
mandingofbothpatientsandphysicians.Afteraninitialdose-
ranging study in nonvalvular AF,24the European open-
label SPORTIF III study was conducted in which 3410
patients were randomized to receive fixed-dose ximelaga-
tran(36mgtwicedaily)ordose-adjustedwarfarinandthen
followed up for a mean duration of 17.4 months. The pri-
mary event rates in this study were similar (1.6% per year
for ximelagatran and 2.3% per year for warfarin), and the
combinedmajorandminorbleedingrateswereslightlylower
with ximelagatran (25.8% vs 29.8%).25
TheSPORTIFIIIstudyhasnowbeenfollowedbyaNorth
Americantrial,reportedbyHalperinandcolleagues26onbe-
EDITORIALS
©2005 American Medical Association. All rights reserved.
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half of the SPORTIF V investigators in this issue of JAMA.
The design was identical to the European study except for
theimportantdifferencethattreatmentwasdouble-blind.A
total of 3922 patients who had AF and at least 1 additional
thromboembolicriskfactor(74%hadmorethan1)werein-
cluded, making it the largest such study of stroke preven-
tion in AF with ximelegatran reported. During a mean fol-
low-up of 20 months, strokes or systemic emboli occurred
withcomparablefrequency(1.2%peryearwithwarfarinand
1.6% per year with ximelagatran), and overall mortality was
thesame.Ratesofmajorbleedingwere3.1%peryearand2.4%
per year with warfarin and ximelagatran, respectively. Rates
of minor bleeding were significantly lower with ximelaga-
tran, and the authors observed a correlation between bleed-
inganduseoflow-doseaspirininbothtreatmentgroups.In-
creases in serum levels of ALT occurred with ximelagatran
in 6% of patients (0.8% with warfarin), typically within the
first6months,andreturnedtobaselinespontaneouslyoraf-
ter stopping the drug. One patient developed hepatic necro-
sisandatautopsyshowedapatternofresolvinghepatitis(vi-
ralantibodytitersnotreported),andanotherwithamarkedly
increased ALT level (?11 times the upper limit of normal)
developed a fatal gastrointestinal hemorrhage.
Halperin et al call attention to the relevant fact that the
quality of anticoagulant control of warfarin in the study is
seldom achieved in practice. The results of this study con-
firm the findings from the open-label SPORTIF III that the
efficacies of ximelagatran and warfarin in preventing arte-
rial emboli in patients with nonvalvular AF are compa-
rableandthatmajorandminorbleedingeventsweresome-
what lower with ximelagatran.
O’BrienandGage27havetakenthedatafromthesestudies
of AF and have subjected them to a challenging cost-benefit
analysis, which is also published in this issue of JAMA. The
authors’calculationswerepredicatedontheAFstudies’find-
ings that ximelagatran and warfarin have identical rates of
stroke but with ximelagatran having a lower (0.74) hemor-
rhagic risk, a $1280 per year higher cost, and a marginally
higherqualityoflifeutilityvalue(0.989comparedwith0.987
for warfarin). Based on these principal assumptions, the re-
sults were expressed in terms of quality-adjusted life-years
and US dollars. Their analysis led the authors to the sober-
ing but inescapable conclusion, related to established crite-
ria, that ximelagatran was not likely to be cost-effective ex-
ceptinpatientswithAFandahighbleedingrisk,alowutility
value, or low quality of life with warfarin.
However, certain of the fundamental differences be-
tween these 2 drugs affect some of the assumptions under-
lying this analysis and may warrant reconsideration of this
conclusion. For example, the authors note that calculation
for the cost-effectiveness of ximelagatran was “exquisitely
sensitivetoitseffectiveness”instrokeprevention,forwhich
the 2 drugs were rated equal. However, the efficacy of war-
farinisdirectlyrelatedtothequalityofitsanticoagulantcon-
trol, which was quite exceptional in these studies of se-
lected populations under unusually strict supervision.
Comparable efficacy is unlikely to be achieved in general
practice,26wheredoublethestrokeratewithwarfarinismore
typical.28By contrast, since ximelagatran is given at a fixed
dosewithoutanymonitoringforanticoagulantcontrol,there
is little reason to believe its efficacy in these clinical trials
cannot be duplicated in general practice. The authors sug-
gest that the short half-life of ximelagatran makes it espe-
cially susceptible to lapses in adherence, but this problem
pales in comparison with that of maintaining the narrow
therapeutic range of warfarin in the face of its innumerable
food, drug, and lifestyle interactions.
Second, the utility value—to which the calculations were
alsosensitive—assignedtowarfarinissurprisinglyhigh,being
littledifferentfromthatassignedtoximelagatran.Thisvalue
wasbasedonaprevioussurveyof83patientswithAFbutin
which 16% of patients “rated the utility of warfarin so low
that their quality-adjusted life expectancy would be greater
with aspirin.”29More important, the utility value of 0.987 is
difficulttoreconcilewiththeauthors’acknowledgmentthat
warfarin is currently prescribed for only half of the patients
with AF who are candidates for anticoagulation. Even if this
poorutilizationwereattributabletosomelackofeducation,
theuniquelycomplicatednatureofwarfarinmanagementcan-
not be dismissed as a significant contributing factor. A util-
ity value for warfarin more commensurate with the well-
establishedlimitsofitsusewouldhavesignificantlyincreased
the relative cost-benefit calculation for ximelagatran.
Third, ximelagatran is a less complicated, more user-
friendlyanticoagulant,makingitapotentiallymoreaccept-
ableandlessintimidatingalternativetowarfarin.Thesequali-
ties should help overcome much of the current reluctance
associated with anticoagulant prophylaxis and encourage
its use in the treatment of a substantially higher percentage
of patients with AF, or those at risk of VTE, than is cur-
rently the case. Since 2.3 million Americans have AF and a
stroke risk of at least 0.2% to 2% per year,30,31a substan-
tiallyhighernumberofdebilitatingandcostlystrokescould
thereby be prevented. Although speculative, providing an-
ticoagulationtothislargepopulationcouldincreasetheclini-
cal effectiveness of ximelagatran even if its efficacy were
equivalent to warfarin.
The principal caveat concerns the increased ALT levels
associatedwithximelagatranandtheconcernthatsomehepa-
totoxicity may occur with longer-term use. O’Brien and
Gage27estimate 1 death from hepatic failure among 2300
patients treated, based on 3 deaths with liver failure re-
ported in the trials. A causal relationship is difficult to es-
tablish and has not been established definitively, but the
mechanism responsible for the enzyme changes remains to
be established.
Whilethereisnoevidencethatshort-termuse(≤11days),
such as for knee and hip replacement surgery, is associated
with a risk of hepatotoxicity, patients in these studies were
onlyfollowedupfor4to6weeksaftersurgery;delayedhepa-
EDITORIALS
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Page 4

totoxicitywasnotassessed.32However,analysisofdatafrom
longer-term exposure suggests that signs of liver injury as
reflected by elevations of ALT levels were typically ob-
served after 1 to 2 months in approximately 6% of patients
receivingximelagatrantherapy.32Accordingly,ifximelaga-
tran is prescribed, monitoring of liver function test results
is warranted to detect early signs of liver injury and to pos-
sibly prevent more severe hepatotoxicity.
Withrespecttothemoretroublesomepossibilityoflong-
term adverse effects from the drug, it seems unlikely that
yet another clinical trial will resolve this question. Diligent
postmarketing surveillance is essential to monitor use and
to determine the risks associated with this agent, and this
may be the best, if not the only, way to deal with this ques-
tion.Itispossiblethatsuchdatawillbecomeavailablefrom
Europe, but this is unlikely at present since for now only
short-termusehasbeenapproved.IntheUnitedStates,the
Food and Drug Administration, perhaps feeling the effects
of recently having to withdraw drugs from the market, has
deniedapprovalofximelagatranbecauseofconcernsabout
hepatotoxicity.18However, this precaution concerning the
risk of hepatotoxicity from ximelagatran must be balanced
against the serious risk of discouraging, if not foreclosing
indefinitely,anyimprovementinoralanticoagulanttherapy,
whichremainsanimportantandgrowingtherapeuticneed.
Financial Disclosure: None reported.
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EDITORIALS
©2005 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 9, 2005—Vol 293, No. 6
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