Clinical trial NCT02942576
Conditions: Atrial Fibrillation
Sponsor: Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company
Start date: 2017-03-21; Completion date: 2018-09-24
Enrollment: 632 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
There are insufficient data on the safety and efficacy of edoxaban therapy in subjects with AF following catheter ablation. This phase 3b study is designed to evaluate the safety and to explore the efficacy of an edoxaban-based antithrombotic regimen versus a VKA-based antithrombotic regimen in subjects with AF following catheter ablation. Bleeding is a central safety outcome in cardiovascular clinical trials, especially for antithrombotic strategies and invasive procedures.

Detailed description:

Arms: arm 1: Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period. arm 2: VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen)
Interventions: intervention 1: Edoxaban intervention 2: VKA-Based Regimen intervention 3: VKA-Based Regimen intervention 4: VKA-Based Regimen intervention 5: VKA-Based Regimen
Intervention descriptions: intervention 1: Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects. intervention 2: Dosed at International Normalised Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in Canada, Italy, Poland, Hungary, Czech Republic, United Kingdom (UK), Taiwan and Korea. intervention 3: Dosed at INR levels. Standard of Care treatment in Germany, Belgium, and the Netherlands. intervention 4: Dosed at INR levels. Standard of Care treatment in France. intervention 5: Dosed at INR levels. Standard of Care treatment in Spain.

Protocol documents:
Prot_SAP_000.pdf: 
C LI NI C A L S T U D Y P R O T O C O L 
A P R O S P E C TI V E, R A N D O MI Z E D, O P E N- L A B E L, 
B LI N D E D E N D P OI N T E V A L U A TI O N ( P R O B E) 
P A R A L L E L G R O U P S T U D Y C O M P A RI N G E D O X A B A N 
V S. V K A I N S U B J E C T S U N D E R G OI N G C A T H E T E R 
A B L A TI O N O F N O N- V A L V U L A R A T RI A L 
FI B RI L L A TI O N ( E LI MI N A T E- A F) 
 
 
D S E- E D O- 0 1- 1 6- E U 
E u dr a C T N U M B E R 2 0 1 6- 0 0 3 0 6 9- 2 5 
 
V E R SI O N 3. 0, 2 7 J ul y 2 0 1 7 
 
 
D AII C HI S A N K Y O E U R O P E G m b H 
ZI E L S T A T T S T R A S S E 4 8, 8 1 3 7 9 M U NI C H, G E R M A N Y 
 
 
C O N FI D E N TI A LI T Y S T A T E M E N T 
I nf or mati o n c o ntai ne d i n t his d oc u me nt pre pare d b y D AII C HI S A N K Y O E U R O P E G m b H 
Gl o bal Me dical Affairs is pr o prietar y t o Daiic hi  Sa n k y o ( D S).  T he i nf or mati o n is pr o vi de d t o 
y o u i n c o nfi de nce w hic h is re q ueste d u n der a n  a gree d u p o n a n d si g ned C o nfi de ntialit y a n d 
Discl os ure A gree me nt.  D o n ot gi ve t his d oc u m e nt or a n y c o p y of it or re veal a n y pr o prietar y 
i nf or mati o n c o ntai ne d i n it t o a n y t hir d part y ( ot her t ha n t h ose i n y o ur or ga nizati o n w h o are 
assisti n g y o u i n t his w or k a n d are b o u n d b y t h e C o nfi de ntialit y a n d Discl os ure A gree me nt) 
wit h o ut t he pri or writte n pe r missi o n of a n a ut h orize d re prese ntati ve of D S. 
 
 








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I n vesti g at or’s Si g n at ure: 
I ha ve f ull y disc usse d t he o bjecti ves of t his st u d y a n d t he c o nt e nts of t his pr ot oc ol wit h 
t he S p o ns or’s re prese ntati ve. 
I u n dersta n d t hat i nf or mati o n c ontai ne d i n or pertai ni n g t o t h is pr ot oc ol is c o nfi de ntial 
a n d s h o ul d n ot be discl ose d, ot her t ha n t o t h os e directl y i n v ol ve d i n t he e xec uti o n or t he 
et hical re vie w of t he st u d y, wit h o ut writte n a ut h orizati o n fr o m t he S p o ns or.  It is, 
h o we ver, per missi ble t o pr o vi de i nf or mati o n t o  a s u bject i n or der t o o btai n c o nse nt. 
I a gree t o c o n d uct t his st u d y acc or di n g t o t his pr ot oc ol a n d t o c o m pl y wit h its 
re q uire me nts, s u bject t o et hical a n d safet y co nsi derati o ns a n d g ui deli nes, a n d t o c o n d uct 
t he st u d y i n acc or da nce wit h t he Declaratio n of Helsi n ki, I nter nati o nal C o u ncil o n 
Har m o nizati o n g ui deli nes o n G o o d Cli nical Pr actice (I C H E 6), a n d a p plica ble re gi o nal 
re g ulat or y re q uire me nts. 
I a gree t o ma ke a vaila ble t o S p o ns or perso n nel, t heir re prese nta ti ves a n d rele va nt 
re g ulat or y a ut h orities, m y s u bjects’ st u d y rec or ds i n or der t o verif y t he data t hat I ha ve 
e ntere d i nt o t he case re p ort f or ms.  I a m a ware of m y res p o nsi bilities as a Pri nci pal 
I n vesti gat or as pro vi de d b y t he S p o ns or. 
I u n dersta n d t hat t he S p o ns or ma y deci de t o s us pe n d or pre mat urely ter mi nate t he st u d y 
at a n y ti me f or w hate ver reas o n; s uc h a deci si o n will be c o m m u nicate d t o me i n writi n g.  
C o n versel y, s h o ul d I deci de t o wit h dr a w fr o m e xec uti o n of t he st u d y, I will 
c o m m u nicate m y i nte nti o n i m me diatel y i n writi n g t o t he S p o ns or. 
  
  
 
  
D ate 
  Si g n at ure 
 
  
 
 
 
 
  
Site n o.  
  I n vesti g at or’s n a me a n d a d dress ( pri nt or st a m p)  
 


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P R O T O C O L S Y N O P SI S 
E u dra C T N u m ber:  
2 0 1 6- 0 0 3 0 6 9- 2 5 
Pr ot oc ol N u m ber:  
D S E- E D O- 0 1- 1 6- E U  
I n vesti gati o nal 
Pr o d uct: 
E d o xa ba n ( D U- 1 7 6 b) 
Acti ve I n gre die nt(s)/ 
i nter nati o nal 
n o n- pr o prietar y na me: 
N -( 5- C hl or o p yri di n- 2- yl)- N-[( 1 S, 2 R, 4 S)- 4-
( N, N- di met h ylcar ba m o yl)- 2-( 5- met h yl- 4, 5, 6, 7-
tetra h y dr o[ 1, 3]t hiaz ol o[ 5, 4-c] p yri di ne- 2-
car b o xa mi d o)c ycl o he x yl] o xa mi de m o n o ( 4- met h yl be nze nes ulf o nate) 
m o n o h y drate/ E d o xa ba n  
St u d y Title:  
A Pr os pecti ve, Ra n d o mize d, O pe n- La bel, Bli n de d E n d p oi nt 
E va luat io n ( P R O B E) Parallel Gr o u p St u d y C o m pari n g E d o xa ba n vs. 
V K A i n S u bjects U n der g oi n g Cat h eter A blati o n of N o n- val v ular 
A trial F i brillati o n ( E LI MI N A T E- A F) 
St u d y P hase:  
P hase 3 b 
I n dicati o n U n der 
I n vesti gati o n: 
N o n- val v ular atrial fi brillati o n ( A F) 
St u d y O bjecti ves: 
Pri m ar y o bjecti ves of t his st u d y: 
Pri m ar y effic ac y o bjecti ve: 
T o c o m pare descri pti vel y t he i nci de nce of t he c o m p osite of all-ca use 
deat h, str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) a n d Maj or 
Blee di n g (I nter nati o nal S ociet y o n T hr o m b osis a n d He m ostasis 
[I S T H] defi niti o n) i n t he e d o xa ba n gr o u p a gai nst t he vita mi n K 
a nta g o nist ( V K A) gr o u p i n s u bjects  u n der g oi n g cat heter a blati o n of 
atrial fi brillati o n ( A F) i n t he peri o d fr o m t he e n d of t he cat heter 
a blati o n pr oce d ure t o Da y 9 0/ e n d- of-treat me nt ( E O T). 
Pri m ar y s afet y o bjecti ve: 
T o c o m pare descri pti vel y t he i n ci de nce of Maj or Blee di n g (I S T H 
defi niti o n) i n t he e d o xa ba n gr o u p a gai nst t he V K A gr o u p i n t he peri o d 
fr o m date of first i nta ke of st u d y me dicati o n t o Da y 9 0/ E O T. 
Sec o n d ar y o bjecti ves:  
I n s u bjects u n der g oi n g cat heter a blati o n of A F, t o c o m pare 
descri pti vel y t he e d o xa ba n gr o u p a gai nst t he V K A gr o u p, wit h 


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re gar ds t o t he i nci de nce of t he f oll o wi n g effic ac y e n d p oi nts  as liste d 
bel o w: 
 C o m p osite of all-ca use deat h, st r o ke (isc he mic, he m orr ha gic, 
or u n deter mi ne d, acc or di n g t o  alter nati ve defi niti o n (1 ); see 
Secti o n 7. 4. 2 . f or details) a n d Maj or Blee di n g (I S T H 
defi niti o n) 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
s yste mic e m b olic e ve nts ( S E E), a n d car di o vasc ular ( C V) 
m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
S E E, a n d all-ca use m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
a n d tra nsie nt isc he mic attac k ( TI A) 
 Str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Str o ke (isc he mic) 
 Str o ke ( he m orr ha gic) 
 Str o ke ( u n deter mi ne d) 
 S E E 
 TI A 
 Fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n-fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Disa bli n g str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n- disa bli n g str o ke (isc he mic, he m orr ha gic, or 
u n deter mi ne d) 
 
T o c o m pare descri pti vel y t he e d o xa ba n gr o u p a gai nst t he V K A gr o u p, 
wit h re gar ds t o t he i nci de nce of t he f oll o wi n g s afet y e n d p oi nts as 
liste d bel o w: 
 Maj or Blee di n g ( defi ne d b y T h r o m b ol ysis i n M y ocar dial 
I nfarcti o n [ TI MI], Blee di n g Aca de mic Researc h C o ns orti u m 
[ B A R C] 2 or hi g her) 
 Maj or a n d Cli nicall y Rele va nt  N o n- Maj or ( C R N M) Blee di n g 
(I S T H defi niti o n) 
 C R N M Blee di n g (I S T H defi niti o n) 
 Mi n or Blee di n g (I S T H defi niti o n) 


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 A n y Blee di n g 
 I ntracra nial he m orr ha ge (I C H) 
 Life-t hreate ni n g blee di n g 
 Fatal Maj or Blee di n g (I S T H defi niti o n) 
 N o n-fatal Maj or Blee di n g (I S T H defi niti o n) 
 Fatal Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or hi g her]) 
 N o n-fatal Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or 
hi g her]) 
 Safet y para meters s uc h as a d verse e ve nts ( A Es), seri o us 
a d verse e ve nts ( S A Es), la b orat or y para meters, 
electr ocar di o gra m ( E C G) a n d vital si g ns. 
Ot her o bjecti ves:  
T o c o m pare descri pti vel y t he e d o xa ba n gr o u p a gai nst t he V K A gr o u p, 
wit h re gar ds t o t he f oll o wi n g:  
 Rele va nt Healt h Ec o n o mics O utc o me Researc h ( H E O R) 
para meters: 
o  N u m ber of s u bjects wit h ca ncellati o n of t he a blati o n 
pr oce d ure d ue t o i na d e q uate a ntic oa g ulati o n 
o  N u m ber of h os pital a d missi o ns d ue t o C V ca uses 
( be y o n d a blati o n pr oce d ure), i ncl u di n g b ut n ot li mite d 
t o o verall, f or blee di n g, S E E, ve n o us t hr o m b osis, etc. 
Re mar k: H os pital a d missi o ns d ue t o C V ca uses 
i ncl u de, b ut are n ot li mite d t o E mer ge nc y De part me nt 
( E D), I nte nsi ve Care U nit (I C U), C V war d. 
o  Mea n le n gt h of sta y ass ociat e d wit h t he differe nt t y pe 
of h os pital a d missi o ns, s uc h as E D, I C U a n d C V war ds
o  A d diti o nal o ut patie nt p h ysicia n or n urse visits t hat are 
C V e ve nt relate d o utsi de sc he d ule d visits as defi ne d b y 
st u d y pr ot oc ol 
 Sile nt cere bral lesi o ns ( S C L) as defi ne d b y Diff usi o n 
Wei g hte d Ma g netic Res o na nce I ma gi n g ( D W- M RI) p ost 
a blati o n pr oce d ure (at preselecte d ce nters) 
 Car diac mar kers 
St u d y Desi g n:  
T his is a m ulti nati o nal pr os pecti ve, ra n d o mize d, o pe n-la bel, bli n de d 
e n d p oi nt e val uati o n ( P R O B E) parallel gr o u p p hase 3 b st u d y 
c o m pari n g e d o xa ba n vs. V K A i n  s u bjects u n der g oi n g cat heter 
a blati o n of n o n- val v ular A F.  Af ter Scree ni n g a n d ra n d o mizati o n, 


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eli gi ble s u bjects recei ve 2 1 da ys ( + 7) a ntic oa g ulati o n bef ore bei n g 
assesse d f or s uita bilit y f or t he cat het er a blati o n pr oce d ure.  S u bjects 
will recei ve 9 0 da ys a ntic oa g ulati o n p ost- pr oce d ure a n d are t he n 
f oll o we d- u p after a n a d diti o nal 3 0 da ys.  I n all s u bjects, ke y 
de m o gra p hic a n d ris k c haracteristic s of b ot h str o ke a n d blee di n g (f or 
e xa m ple, C H A 2D S 2- V A Sc sc ore, H A S- B L E D, t y pe of A F, prese nce 
of c or o nar y arter y disease ( C A D), heart fail ure ( H F), dia betes mellit us 
( D M), a n d h y perte nsi o n) will be c ollecte d. S u bjects will be 
ra n d o mize d i n a 2: 1 rati o t o e d o xa ba n vs. V K A i nt o o ne of t he t w o 
st u d y ar ms as descri be d bel o w. 
E d o x a b a n st u d y ar m 
S u bjects will be re q uire d t o c o m ple te at least 2 1 ( u p t o + 7) da ys of 
a ntic oa g ulati o n wit h e d o xa ba n. S u bj ects recei vi n g a ntic oa g ula nts at 
t he ti me of e nr oll me nt will be s witc he d t o e d o xa ba n (t he s witc hi n g 
p r oce d ure will f oll o w t he e d o xa ba n label a n d is descri be d i n Secti o n 
5. 2. 1. 3 ). It is ma n dat or y t hat i n t he pre-a blati o n peri o d, t he o nce- dail y 
d ose of e d o xa ba n is ta ke n e ver y da y i n t he e ve ni n g. E d o xa ba n ca n be 
ta ke n wit h or wit h o ut f o o d. 
If a s u bject has ta ke n t he st u d y dr u g i n t he e ve ni n g, t he pr oce d ure ca n 
be perf or me d i n t he m or ni n g of t he ne xt da y. T he i nter val bet wee n t he 
last i nta ke of e d o xa ba n a n d t he pr oce d ure m ust n ot e xcee d 1 8 h o urs. 
After t he a blati o n, st u d y me dicati o n m u st be re-starte d o n t he da y of 
p r oce d ure b ut n o earlier t ha n 6 h o urs p ost-s heat h re m o val a n d o nl y 
o nce a de q uate he m ostasis has bee n ac hie ve d. 
Ti mi n g of t he last d ose of e d o xa ba n pri or t o t he cat heter a blati o n 
p r oce d ure a n d t he first d ose after t he pr oce d ure will be rec or de d i n t he 
electr o nic case re p ort f or m (e C R F). 
V K A st u d y ar m 
S u bjects e nr olle d i n t he V K A st u d y ar m will be re q uire d t o c o m plete 
at least 2 1 da ys ( u p t o + 7 da ys) of a ntic oa g ulati o n treat me nt wit h 
V K A. S u bjects will ta ke t he V K A acc o r di n g t o t he directi o n of t he 
I n vesti gat or. E ver y atte m pt will be ma de t o bri n g s u bjects i nt o t he 
t hera pe utic tar get ra n ge (I N R [Inter nati o nal N or malize d Rati o] 
2. 0- 3. 0) as fast as p ossi ble a n d t o mai ntai n t he tar get I N R ra n ge 
c o nsiste ntl y.  
I N R will nee d t o be meas ure d fre q ue ntl y at t he start of t he st u d y 
( u nless a s u bject is recei vi n g a n u n var yi n g V K A d ose at t he ti me of 
ra n d o mizati o n) t o rec or d t he ti me w he n I N R reac hes a le vel of ≥2. 0.  
Bef ore a blati o n, eac h s u bject m ust be i n t he I N R ra n ge of 2. 0- 3. 0 f or 
t he last 1 0 da ys pri or t o t he cat heter a blati o n. T his will nee d t o be 
d oc u me nte d b y fre q ue nt I N R meas ure m e nts, at least o nce per wee k i n 
t he pre-a blati o n peri o d. O n t he day of, or t he da y pri or t o, t he 


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sc he d ule d a blati o n pr oce d ure, s u bjects I N R s h o ul d be wit hi n t he ra n ge 
2. 0- 3. 0. If I N R is ≥1. 5 a n d < 2. 0 or if I N R is > 3. 0 a n d ≤3. 5 t he 
p r oce d ure ma y be perf or me d at t he I n vesti gat or’s discreti o n. 
Ot her wise, t he s u bject is n ot eli g i ble f or perf or mi n g t he cat heter 
a blati o n (t he s u bject will be s witc he d fr o m st u d y me dicati o n t o 
sta n dar d of care a n d will e nter t he 3 0- da y f oll o w- u p peri o d).  
D uri n g t he cat heter a blati o n pr oce d ure, V K A will be use d wit h o ut 
i nterr u pti o n a n d bri d gi n g wit h l o w m olec ular wei g ht he pari n 
( L M W H) will n ot be all o we d at t his ti me. 
Tr a nses o p h a ge al ec h oc ar di o gr a m  bef ore c at heter a bl ati o n 
Tra nses o p ha geal ec h ocar di o gra m ( T E E)  or alter nati vel y i ntra-car diac 
ec h ocar di o gra m will be perf or me d bef ore cat heter a blati o n d uri n g t he 
h os pital sta y relate d t o t he pr oce d ure or t he da y bef ore t o i de ntif y 
p ote ntial cl ots. If T E E or t he i ntr a-car diac ec h ocar di o gra m is p ositi ve, 
i.e., s h o ws cl ots, t he a blati o n pr oce d ure will be ca ncele d a n d t he 
s u bject will be s witc he d fr o m st u d y me dicati o n t o sta n dar d of care 
a n d will e nter t he 3 0- da y f oll o w- u p peri o d. 
A ntic o a g ul ati o n d uri n g c at heter a bl ati o n 
Acc or di n g t o sta n dar d of care a n d as rec o m me n de d i n c urre nt 
treat me nt g ui deli nes (1 5 ) he pari n s h o ul d be a d mi nistere d ( 1 0 0 U/ k g 
b ol us) pri or t o or i m me diatel y f o ll o wi n g tra ns-se ptal p u nct ure d uri n g 
A F a blati o n pr oce d ures a n d a dj ust e d t o ac hie ve a n d mai ntai n a n 
acti vate d cl otti n g ti me ( A C T) of 3 0 0- 4 0 0 sec o n ds. A C T le vels s h o ul d 
be c hec ke d at 1 5- 2 0- mi n ute i nter val s u ntil t hera pe utic a ntic oa g ulati o n 
is ac hie ve d a n d t he n at 3 0- mi n ute i nter vals f or t he d urati o n of t he 
p r oce d ure. He pari n a ntic oa g ulati o n will be partiall y re verse d wit h 
p r ota mi ne a n d s heat hs re m o ve d at a n A C T < 2 5 0 sec o n ds. 
A ntic o a g ul ati o n p ost c at heter a bl ati o n 
F oll o wi n g c o m pleti o n of t he cat heter a blati o n pr oce d ure, all s u bjects 
will c o nti n ue recei vi n g treat me nt wit hi n t heir st u d y ar m u ntil Da y 9 0 
p ost- pr oce d ure.  
At t he E n d of Tre at me nt 
At Da y 9 0 p ost- pr oce d ure, t he s u bject will disc o nti n ue t he st u d y 
treat me nt c o m pletel y a n d will be c o nti n ue d o n a n y of t he a p pr o ve d 
oral a nti-c oa g ulati o n ( O A C) dr u gs or a ntic oa g ulati o n st o p pe d 
acc or di n g t o sta n dar d of care per p h ysicia n's discreti o n. Detaile d 
s witc hi n g pr ot oc ols acc or di n g t o me dicati o n la bel will be pr o vi de d.  
All s u bjects re gar dless of t heir p ost-st u d y treat me nt will ha ve a n 
a d diti o nal 3 0- da y safet y f oll o w- u p peri o d after w hic h t heir 
p artici pati o n i n t he st u d y will be c o m plete d. 


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St u d y D urati o n:  
T otal f or eac h s u bject 5- 6 m o nt hs. Pre-a blati o n treat me nt peri o d of at 
least 2 1 da ys ( u p t o + 7 da ys). P ost-a blati o n treat me nt peri o d of 9 0 
da ys ( ± 7 da ys) pl us 3 0- da y f oll o w- u p peri o d ( u p t o + 5 da ys).  
Pr ojecte d 1 6 m o nt hs e nr oll me nt 
St u d y Sites a n d 
L ocati o n: 
It is pla n ne d t o e nr oll a p pr o x. 5 6 0 s u bjects wit h 2: 1 ra n d o mizati o n 
rati o (e d o xa ba n: V K A) b y a p pr o xi matel y 7 5 st u d y sites l ocate d i n 
Ca na da, E ur o pe ( Bel gi u m, Czec h Re p u blic, Fra nce, Ger ma n y, 
H u n gar y, Ital y, Net herla n ds, P ola n d, S pai n, U nite d Ki n g d o m), K orea, 
a n d Tai wa n t o ac hie ve a p pr o x. 4 5 0 s u bjects u n der g oi n g t he cat heter 
a blati o n pr oce d ure a n d c o m pleti n g t he st u d y.  
S u bject Eli gi bilit y 
Criteria: 
I ncl usi o n criteria: 
1.  Male or fe male at least 1 8 years of a ge wit h d oc u me nte d 
hist or y of par o x ys mal (lasti n g ≤7 da ys), persiste nt (lasti n g 
> 7 da ys b ut ≤1 2 m o nt hs) or l o n g-sta n di n g [l o n g-lasti n g] 
persiste nt ( > 1 2 m o nt hs) n o n- val v ular A F. D urati o n of A F ca n 
be c o nfir me d b y a n y electrical traci n g or a rec or di n g i n t he 
s u bject’s me dical rec or ds (e. g., me dical c hart, h os pital 
disc har ge s u m mar y). 
2.  S u bject is eli gi ble a n d is sc he d ule d f or eit her ra di o fre q ue nc y 
( R F) or cr y o ball o o n cat heter a blati o n ( b ot h first a n d re peate d 
pr oce d ure i ncl u de d).  
3.  Si g ne d i nf or me d c o nse nt f or m (I C F). 
E xcl usi o n criteria: 
1.  A F c o nsi dere d t o be of a tra nsie n t or re versi ble nat ure (s uc h as 
i n m y ocar ditis, p ost-s ur ger y, i o nic dist ur ba nces, 
t h yr ot o xic osis, p ne u m o nia, se vere a ne mia etc.). 
2.  S u bject p ost str o ke, or wit h a s yste mic t hr o m b oe m b olic e ve nt 
wit hi n t he past 6 m o nt hs pri or t o ra n d o mizati o n.  
3.  S u bject has a t hr o m b us i n t he le ft atrial a p pe n da ge ( L A A), left 
atri u m ( L A), left ve ntricle ( L V), or a orta, or a n i ntracar dial 
mass. 
4.  S u bject ha d a m y ocar dial i nfarc ti o n ( MI) wit hi n t he 2 m o nt hs 
pri or t o ra n d o mizati o n or c or o nar y arter y b y pass graft ( C A B G) 
s ur ger y wit hi n 3 m o nt hs pri or t o t he ra n d o mizati o n. 
5.  S u bject has si g ns of blee di n g, hi st or y of cli nicall y-rele va nt 
blee di n g acc or di n g t o I S T H, or c o n diti o ns ass ociate d wit h 
hi g h ris k of blee di n g s uc h as past hist or y of i ntracra nial 
(s p o nta ne o us or tra u matic), or sp o nta ne o us i ntra o c ular, s pi nal, 
retr o perit o neal, or i ntra-artic ular blee di n g; o vert 


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gastr oi ntesti nal ( GI) blee di n g or acti ve ulcer wit hi n t he 
pre vi o us year; rece nt se vere tra u ma, maj or s ur ger y, or dee p 
or ga n bi o ps y; acti ve i nfecti v e e n d ocar ditis; u nc o ntr olle d 
h y perte nsi o n ( bl o o d press ure [ B P] a b o ve 1 7 0/ 1 0 0 m m H g); or 
he m orr ha gic dis or der i ncl u di n g k n o w n or s us pecte d here ditar y 
or ac q uire d blee di n g or c oa g ul ati o n dis or der i n t he last 
1 2 m o nt hs pri or t o ra n d o mizati o n.  
6.  S u bjects wit h mec ha nical heart va l ves, s u bjects wit h m o derate 
t o se vere mitral ste n osis a n d s u bjects w h o ha ve ne w 
i m pla ntati o n ( wit hi n 3 m o nt hs pri or t o ra n d o mizati o n) of a 
bi o pr ost hetic heart val ve, wit h or wit h o ut A F.  
7.  S u bjects wit h a hist or y of L A A occl usi o n/e xcl usi o n (eit her b y 
s ur ger y or b y a pr oce d ure). 
8.  S u bjects wit h a n y c o ntrai n dicati o n f or e d o xa ba n, V K A, 
L M W H, he pari n t hera p y i ncl u di n g k n o w n aller gies, 
h y perse nsiti vit y, or i nt olera nce t o a n y c o m p o ne nt of t hese 
dr u gs or its e xci pie nts. 
9.  S u bjects recei vi n g d ual a nti platelet t hera p y ( D A P T, i.e., 
as piri n a n d P 2 Y 1 2 a nta g o nist) or pla n ne d t o recei ve D A P T 
d uri n g t he st u d y. 
1 0.  U nfracti o nate d he pari n ( U F H), l o w m olec ular wei g ht he pari ns 
( L M W H; e n o xa pari n, dalte pari n, etc.), he pari n deri vati ves 
(f o n da pari n u x, etc.), a n d oral a ntic oa g ula nts ( warfari n, 
da bi gatra n ete xilate, ri var o xa ba n, a pi xa ba n etc.) ca n n ot be 
use d c o nc o mita ntl y t o st u d y me dicati o n. A n y bri d gi n g wit h 
L M W H ar o u n d t he C A pr oce d ure is pr o hi bite d. D uri n g t he C A 
pr oce d ure, U F H will be use d acc o r di n g t o sta n dar d of care t o 
ac hie ve A C T of 3 0 0 t o 4 0 0 sec. S u bjects w h o re q uire c hr o nic 
use of me dici nes affecti n g he m ost asis s uc h as hi g her d oses of 
as piri n (acet ylsalic ylic aci d [ A S A]) ( A S A u p t o 1 0 0 m g per 
da y all o we d) or c hr o nic oral or pare nteral i nta ke  of n o n-as piri n 
n o n-ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI D) o n ≥4 
da ys/ wee k ( use of N S AI Ds via ot her r o utes is n ot restricte d). 
1 1.  S u bjects wit h acti ve li ver diseas e or persiste nt (c o nfir me d b y 
re peat assess me nts at least a wee k a part) ele vati o n of li ver 
e nz y mes/ bilir u bi n: 
―  Ala ni ne tra nsa mi nase ( A L T) or as partate tra nsa mi nase 
( A S T) ≥2 ti mes t he u p per li mit of n or mal ( U L N) 
―  T otal bilir u bi n ( T B L) ≥1. 5 ti mes t he U L N (s u bjects w h ose 
ele vate d T B L is d ue t o k n o w n Gil bert’s s y n dr o me ma y be 
i ncl u de d i n t he st u d y) 


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―  He patic disease ass ociate d wit h c oa g ul o pat h y a n d 
cli nicall y rele va nt blee di n g ris k. 
1 2.  S u bjects wit h ki d ne y fail ure (c alc ulate d creati ni ne cleara nce 
[ Cr C L] < 1 5 m L/ mi n). 
1 3.  S u bjects wit h he m o gl o bi n < 1 0 g/ d L or platelet c o u nt < 1 0 0, 0 0 0 
cells/ µ L or w hite bl o o d cell ( WB C) c o u nt < 3 0 0 0 cells/ µ L. 
1 4.  S u bjects wit h pre- pla n ne d i n vasi ve dia g n ostic or t hera pe utic 
pr oce d ures/i nter ve nti o ns ( ot her  t ha n e n d osc o p y) d uri n g t he 
st u d y peri o d i n w hic h blee di n g is a ntici pate d. 
1 5.  Partici pati o n i n a n y ot her i nte r ve nti o nal trial (s u bjects w h o 
recei ve d a n y i n vesti gati o nal dr u g or de vice wit hi n 3 0 da ys 
pri or t o ra n d o mizati o n, or pla n t o recei ve s uc h i n vesti gati o nal 
t hera p y d uri n g t he st u d y peri o d). 
1 6.  Pre vi o us ra n d o mizati o n i n t his st u d y. 
1 7.  Fe male s u bjects of c hil d beari n g p ote ntial wit h o ut  usi n g hi g hl y 
effecti ve c o ntrace pti o n (fe male of c hil d beari n g p ote ntial is 
defi ne d as o ne w h o has n ot bee n p ost me n o pa usal f or at least 
o ne year, or has n ot bee n s ur gicall y sterilise d, or has n ot ha d a 
h ysterect o m y at least t hree m o nt hs  pri or t o t he start of t his 
st u d y). Fe males ta ki n g oral c o ntrace pti ves s h o ul d ha ve bee n 
o n t hera p y f or at least t hree m o nt hs. A de q uate  c o ntrace pti ves 
i ncl u de: C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) 
oral, i ntra va gi nal or tra n s der mal h or m o nal c o ntrace pti o n 
ass ociate d wit h i n hi biti o n of o v ulati o n; pr o gest o ge n- o nl y oral, 
i njecta ble or i m pla nta ble h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n; i ntra uteri ne de vice (I U D); 
i ntra uteri ne h or m o ne-releasi n g s yste m (I U S); bilateral t u bal 
occl usi o n; vasect o mize d pa rt ner; se x ual a bsti ne nce. 
1 8.  Pre g na nt or breast- fee di n g s u bjects. 
1 9.  S u bjects wit h t he f oll o wi n g dia g n oses or sit uati o ns: 
―  Acti ve ca ncer u n der g oi n g c he m ot hera p y, ra diati o n or 
maj or s ur ger y wit hi n t he ne xt 5 m o nt hs 
―  Si g nifica nt acti ve/ u nc o ntr olle d c o nc urre nt me dical ill ness 
―  Life e x pecta nc y < 6 m o nt hs. 
2 0.  S u bjects w h o are u nli kel y t o c o m pl y wit h t he pr ot oc ol (e. g., 
u nc o o perati ve attit u de, i na bilit y t o  ret ur n f or s u bse q ue nt visits, 
a n d/ or ot her wise c o nsi dere d b y t h e I n vesti gat or t o be u nli kel y 
t o c o m plete t he st u d y). 


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2 1.  S u bjects wit h a k n o w n dr u g or al c o h ol de pe n de nce wit hi n t he 
past 1 2 m o nt hs pri or t o ra n d o mizati o n as j u d ge d b y t he 
I n vesti gat or. 
2 2.  S u bjects wit h a n y c o n diti o n t hat, i n t he o pi ni o n of t he 
I n vesti gat or, w o ul d place t he s u bject at i ncrease d ris k of har m 
if he/s he partici pate d i n t he st u d y. 
2 3.  Pla n ne d pr oce d ure usi n g laser cat heter a blati o n or ot her f or ms 
of cat heter a blati o n differe nt fr o m R F or cr y o ball o o n (i.e. hi g h 
i nte nsit y f oc use d ultras o u n d [ HI F U], micr o wa ves, h ot ball o o n, 
etc). 
D osa ge F or m, D ose, 
a n d R o ute of 
A d mi nistrati o n: 
E d o xa ba n: 6 0 m g a n d 3 0 m g pr o vi de d as fil m c oate d ta blets f or oral 
use ( 3 0 m g or 1 5 m g as tra nsi ti o n me dicati o n if a p plica ble). 
T he d ose of e d o xa ba n is 6 0 m g o nce- dail y a n d will be re d uce d t o 
3 0 m g o nce- dail y, if t he s u bject has o ne of t he f oll o wi n g:   
 M o derate or se vere re nal i m pair me nt ( Cr C L ≥1 5 t o 
≤5 0 m L/ mi n as calc ulate d usi n g t he C oc kcr oft- Ga ult f or m ula 
 L o w b o d y wei g ht ( ≤6 0 k g) 
 Recei ves o ne of t he f oll o wi n g c o nc o mita nt P- g p i n hi bit ors: 
cicl os p ori n, dr o ne dar o ne, er yt hr o m yci n, ket oc o naz ole. 
Re mar k:   I n E U c o u ntries, acc or di n g t o t he S u m mar y of 
Pr o d uct C haracteristics ( S m P C) c o nc o mita nt use of e d o xa ba n 
wit h c ycl os p ori ne, dr o ne dar o ne, er yt hr o m yci n, or 
ket oc o naz ole re q uires d ose re d ucti o n t o 3 0 m g o nce- dail y. 
C o nc o mita nt use of e d o xa ba n wit h q ui ni di ne, ver a p a mil, or 
a mi o d ar o ne  d oes n ot re q uire  d ose re d ucti o n 
It is ma n dat or y t hat i n t he pre-a blati o n peri o d, t he o nce- dail y d ose of 
e d o xa ba n is ta ke n e ver y da y i n t h e e ve ni n g. E d o xa ba n ca n be ta ke n 
wit h or wit h o ut f o o d. 
V K A: Oral V K A, as pre- defi ne d pe r c o u ntr y, wit h o nce- dail y d osi n g 
f or tar get I N R bet wee n 2. 0- 3. 0, i ncl usi ve. S u bjects will ta ke t he V K A 
o nce- dail y acc or di n g t o t he di recti o n of t he I n vesti gat or. 
V K A is s u p plie d as c o m merciall y a vaila ble ta blets of t he preferre d 
V K A f or eac h selecte d c o u ntr y partic i pati n g i n t he st u d y, bei n g eit her:
―  Warfari n: 1 a n d 2. 5 m g ta blets. 
―  P he n pr oc o u m o n: 3 m g ta blets. 
―  Fl ui n di o ne: 2 0 m g ta blets (e xcl usi ve t o Fra nce). 
―  Ace n oc o u mar ol: 4 m g ta blets. 


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T he I n vesti gat or m o nit ors t he I N R a n d a dj usts t he V K A d ose t o 
mai ntai n t he I N R wit hi n tar get. It is t he I n vesti gat or’s res p o nsi bilit y t o 
c ollect I N R assess me nts a n d rec o r d t hese t hr o u g h o ut t he st u d y. 
St u d y E n d p oi nts: 
Pri m ar y effic ac y e n d p oi nt  
C o m p osite of all-ca use deat h, str o ke (isc he mic, he m orr ha gic, or 
u n deter mi ne d), a n d Maj or Blee di n g (I S T H), a nal yze d as ti me t o first 
occ urre nce of a n y c o m p o ne nt 
Pri m ar y s afet y e n d p oi nt  
Maj or Blee di n g (I S T H), a nal yze d as ti me t o first occ urre nce of Maj or 
Blee di n g  
Sec o n d ar y e n d p oi nts 
Effic ac y: 
 C o m p osite of all-ca use deat h, st r o ke (isc he mic, he m orr ha gic, 
or u n deter mi ne d, acc or di n g t o  alter nati ve defi niti o n (1 ); see 
Secti o n 7. 4. 2  f or details) a n d Maj or Blee di n g (I S T H 
defi niti o n) 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
S E E, a n d C V m ortalit y  
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
S E E, a n d all-ca use m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
a n d TI A 
 Str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Str o ke (isc he mic) 
 Str o ke ( he m orr ha gic) 
 Str o ke ( u n deter mi ne d) 
 S E E 
 TI A 
 Fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n-fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d)  
 Disa bli n g str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n- disa bli n g str o ke (isc he mic, he m orr ha gic, or 
u n deter mi ne d) 
 


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S afet y: 
 Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or hi g her]) 
 Maj or a n d C R N M Blee di n g (I S T H defi niti o n) 
 C R N M Blee di n g (I S T H defi niti o n) 
 Mi n or Blee di n g (I S T H defi niti o n) 
 A n y Blee di n g 
 I C H 
 Life-t hreate ni n g blee di n g 
 Fatal Maj or Blee di n g (I S T H defi niti o n) 
 N o n-fatal Maj or Blee di n g (I S T H defi niti o n) 
 Fatal Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or hi g her]) 
 N o n-fatal Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or 
hi g her]) 
 Safet y para meters s uc h as A Es, S A Es, la b orat or y para meters, 
E C G a n d vital si g ns. 
All a dj u dicate d e n d p oi nts are a nal yz e d as ti me t o first occ urre nce 
of a n y of its c o m p o ne nts. 
F or all s pecific e n d p oi nts bli n dl y a dj u dicate d b y t he Cli nical 
E n d p oi nts C o m mittee ( C E C), t he C E C’s i nter pretati o n pre vails 
a n d is use d i n t he statistical a nal yses. 
Ot her e n d p oi nts:  
 Rele va nt H E O R para meters: 
o  N u m ber of s u bjects wit h ca ncellati o n of t he a blati o n 
pr oce d ure d ue t o i na d e q uate a ntic oa g ulati o n 
o  N u m ber of h os pital a d missi o ns d ue t o C V ca uses 
( be y o n d a blati o n pr oce d ure), i ncl u di n g b ut n ot li mite d 
t o o verall, f or blee di n g, S E E, ve n o us t hr o m b osis, etc. 
Re mar k:   H os pital a d missi o ns d ue t o C V ca uses 
i ncl u de, b ut are n ot li mite d t o E D, I C U, C V war d. 
o  Mea n le n gt h of sta y ass ociat e d wit h t he differe nt t y pe 
of h os pital a d missi o ns, s uc h as E D, I C U a n d C V war ds
o  A d diti o nal o ut patie nt p h ysicia n or n urse visits t hat are 
C V e ve nt relate d o utsi de sc he d ule d visits as defi ne d b y 
st u d y pr ot oc ol 


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 S C L as defi ne d b y D W- M RI p ost a blati o n pr oce d ure (at 
preselecte d ce nters)  
 Car diac mar kers 
Pla n ne d Sa m ple Size:  T he pri mar y e n d p oi nt wi ll be t he i nci de nce of a c o m p osite of all-
ca use deat h, str o ke (isc he mic str o ke, he m orr ha gic str o ke, or 
u n deter mi ne d str o ke), a n d Maj or Blee di n g e ve nts (I S T H defi niti o n) 
d uri n g t he peri o d fr o m t he e n d of t he cat heter a blati o n pr oce d ure t o 
Da y 9 0/ E O T. A rate of u p t o 3 % of t he c o m bi ne d pri mar y e n d p oi nt 
ca n be e x pecte d i n t he V K A ar m as o bser ve d fr o m p u blis he d st u dies 
a n d retr os pecti ve a nal yses (f or m ore  details, please refer t o Secti o n 
1 0. 7 ).  
Base d u p o n t his l o w pre dicte d rate, a f or mal sa m ple size 
deter mi nati o n base d o n n o n-i nferi or it y or s u peri orit y of e d o xa ba n 
vers us V K A is n ot feasi ble. T he sa m ple size is pla n ne d base d u p o n 
t he pri mar y c o m p osite e n d p oi nt t o i ncl u de a n a de q uate n u m ber of 
s u bjects t hat will pr o vi de t he e x pecte d i nci de nce rates o n t he pri mar y 
e n d p oi nt. T heref ore, t he pla n is t o i ncl u de 4 5 0 s u bjects i n t he Per 
Pr ot oc ol ( P P) a nal ysis set, i.e.  s u bjects w h o ha ve u n der g o ne a n 
a blati o n pr oce d ure a n d wit h o ut a n y maj or pr ot oc ol vi olati o n.  
I n or der t o ac hie ve t his, a p pr o xi matel y 5 6 0 s u bjects will nee d t o be 
e nr olle d i n t he st u d y. T he st u d y wi ll be st o p pe d o nce t he n u m ber of 
4 5 0 s u bjects bel o n gi n g t o t he P P a nal ysis set is reac he d. 
Statistical A nal yses:  T he f oll o wi n g a nal ysis sets are defi ne d: 
T he I nte nti o n-t o-tre at (I T T) a n alysis set c o nsists of all ra n d o mize d 
s u bjects irres pecti ve w het her t he y recei ve d a si n gle d ose of st u d y 
me dicati o n or n ot. 
T he m o difie d I nte nti o n-t o-tre at ( mI T T) a n alysis set  c o nsists of all 
ra n d o mize d s u bjects w h o recei ve d at least o ne d ose of st u d y 
me dicati o n. 
T he Per Pr ot oc ol ( P P) a n alysis set  c o nsists of all ra n d o mize d s u bjects 
w h o recei ve d at least o ne d ose of st u d y me dicati o n a n d d o n ot ha ve 
a n y of t he f oll o wi n g maj o r pr ot oc ol vi olati o ns: 
 N ot u n der g oi n g a cat heter a blati o n 
 N o A F 
 K n o w n c o ntrai n dicati o n f or O A C 
 A maj or vi olati o n of t he i ncl usi o n criteria 
 A maj or vi olati o n of t he e xcl usi o n criteria 


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T he list of maj or pr ot oc ol vi olati o ns will be descri be d i n t he statistical 
a nal ysis pla n ( S A P) a n d fi nali ze d bef ore data base l oc k.  
T he S afety ( S A F) a n alysis set  c o nsists of all ra n do mize d s u bjects w h o 
recei ve d at least o ne d ose of st u d y me dicati o n.  
Defi niti o n of ter ms: 
‘Over all St u dy Peri o d ’:   T his peri o d is define d as t he ti me fr o m t he 
refere nce date ( date a n d ti me of ran d o mizati o n or date a n d ti me of 
first d ose of st u d y me dicati o n) t o Da y 9 0/ E O T. 
‘Over all St u dy Peri o d + 3 0 d ays ’:   T his peri o d is defi ne d as t he ti me 
fr o m t he refere nce date ( date a n d ti me of ra n d o mizati o n or date a n d 
ti me of first d ose of st u d y me dicati o n) t o Da y 9 0/ E O T + 3 0 da ys. 
‘P ost- a bl ati o n St u dy Peri o d ’:   T his peri o d is defi ne d as t he ti me fr o m 
t he e n d of t he cat heter a blatio n pr oce d ure t o Da y 9 0/ E O T. 
‘P ost- a bl ati o n St u dy Peri o d + 3 0 d ays ’:   T his peri o d is defi ne d as t he 
ti me fr o m t he e n d of t he cat heter a blati o n pr oce d ure t o Da y 9 0/ E O T + 
3 0 da ys.  
P l a n ne d A n alyses: 
Acc or di n g t o t he o bjecti ves of t h is st u d y, t he statistical a nal ysis 
s h o ul d be i nter prete d i n a p urel y e x pl orat or y- descri pti ve wa y. N o 
f or mal c o nfir mat or y statistical testi n g is pla n ne d. 
T he a nal ysis set a n d a nal ysis peri o d t o be use d f or t he mai n a nal ysis 
of t he vari o us a dj u dicate d e n d p oi nts is prese nte d bel o w: 
 
E n d p oi nt(s) 
pri m ar y  
a n al ysis set 
pri m ar y  
a n al ysis peri o d 
Pri mar y  
P P  
p ost-a blati o n peri o d
Pri mar y safet y  
mI T T  
o verall st u d y peri o d
Sec o n dar y efficac y  
P P  
p ost-a blati o n peri o d
Sec o n dar y safet y  
mI T T  
o verall st u d y peri o d
F or eac h of t he pri mar y a n d sec o n dar y a dj u dicate d e n d p oi nts, 
a p pr o priate s u m mar y statistics  (e. g. e ve nt rate) i ncl u di n g 9 5 % 
c o nfi de nce i nter val ( CI) will be pr o vi de d. 
F or eac h of t he e n d p oi nts, t he ti me fr o m refere nce date t o t he first 
occ urre nce of a n e ve nt ( base d o n C E C a dj u dicati o n), is a nal yze d 
usi n g a C o x pr o p orti o nal hazar d m o del wit h treat me nt re gi me n as a 
fact or, t o pr o vi de p oi nt esti mates a n d 9 5 % CI f or t he hazar d rati o 
( H R). De pe n di n g o n t he a nal ysis peri o d use d i n t he statistical a nal ysis, 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 8 of 1 0 9 
 
s u bjects wit h o ut a n occ urre nce of a n e ve nt will be ce ns ore d at t he last 
date of t he a nal ysis peri o d or at t he last date of k n o w n o utc o mes 
stat us. T he latter is deter mi ne d o n a n i n di vi d ual basis f or s u bjects wit h 
i nc o m plete f oll o w- u p. 
F or ti me t o first e ve nt a nal yses base d o n a n y of t he st u d y peri o ds 
defi ne d a b o ve, c u m ulati ve e ve nt rates o ver ti me are s u m marize d usi n g 
t he Ka pla n- Meier met h o d. 
T o e val uate t he r o b ust ness of t he ma i n a nal yses, t he a nal ysis will be 
re peate d usi n g t he mI T T, I T T a n d/ or P P a nal ysis set. I n a d diti o n, t he 
statistical res ults base d o n t he f oll o wi n g a nal ysis peri o ds: ‘ p ost-
a blati o n st u d y peri o d + 3 0 da ys’ a n d ‘ o verall st u d y peri o d + 3 0 da ys’ 
will be prese nte d. 
All details of t he statistical a nal ysis will be descri be d i n a S A P. 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 9 of 1 0 9 
 
T A B L E O F C O N T E N T S 
I N V E S TI G A T O R A G R E E M E N T ................................................................................... 2 
P R O T O C O L S Y N O P SI S ................................................................................................. 5  
T A B L E O F C O N T E N T S ................................................................................................ 1 9  
LI S T O F I N- T E X T T A B L E S ......................................................................................... 2 5  
LI S T O F I N- T E X T FI G U R E S ....................................................................................... 2 6  
LI S T O F A B B R E VI A TI O N S ......................................................................................... 2 7  
1.  
I N T R O D U C TI O N ........................................................................................ 3 0 
1. 1.  
Bac k gr o u n d .................................................................................................... 3 0  
1. 2.  
Descri pti o n of I n ves ti gati o nal Pr o d uct .......................................................... 3 0 
1. 2. 1. 1.  
N o ncli nical St u dies ........................................................................................ 3 0  
1. 2. 1. 2.  
Cli nical E x perie nce ........................................................................................ 3 0  
1. 2. 1. 3.  
D ose Rati o nale ............................................................................................... 3 2  
1. 3.  
Ris ks a n d Be nefits f or St u d y S u bjects ........................................................... 3 3  
2.  
S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S .......................................... 3 5  
2. 1.  
St u d y O bjecti ves ............................................................................................ 3 5  
2. 1. 1.  
Pri mar y O bjecti ves ......................................................................................... 3 5  
2. 1. 2.  
Sec o n dar y O bjecti ves ..................................................................................... 3 5  
2. 1. 3.  
Ot her O bjecti ves ............................................................................................ 3 6  
3.  
S T U D Y D E SI G N .......................................................................................... 3 7  
3. 1.  
O verall Pla n .................................................................................................... 3 7  
3. 2.  
Disc ussi o n of St u d y Desi g n ........................................................................... 3 8  
4.  
S T U D Y P O P U L A TI O N .............................................................................. 4 0  
4. 1.  
E nr oll me nt ......................................................................................................  4 0  
4. 1. 1.  
I ncl usi o n Criteria ............................................................................................ 4 0 
4. 1. 2.  
E xcl usi o n Criteria .......................................................................................... 4 0  
4. 2.  
Scree ni n g Fail ures .......................................................................................... 4 2  
5.  
S T U D Y T R E A T M E N T S ............................................................................. 4 3  
5. 1.  
Met h o d of Assi g ni n g S u bjects t o Treat me nt Re gi me ns ................................. 4 3  
5. 1. 1.  
Treat me nt Gr o u ps .......................................................................................... 4 3  
5. 1. 2.  
Met h o d of Treat me nt All ocati o n .................................................................... 4 3  
5. 1. 3.  
Bli n di n g ..........................................................................................................  4 4  


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C o nfi de ntial 
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5. 2.  
St u d y Dr u gs .................................................................................................... 4 4  
5. 2. 1.  
E d o xa ba n ........................................................................................................  4 4  
5. 2. 1. 1.  
Descri pti o n ..................................................................................................... 4 4  
5. 2. 1. 2.  
D ose ............................................................................................................... 4 4  
5. 2. 1. 3.  
Tra nsiti o ni n g t o E d o xa ba n at Ra n d o mizati o n ................................................ 4 5  
5. 2. 1. 4.  
Tra nsiti o n fr o m E d o xa ba n at E n d of Treat me nt ............................................ 4 6  
5. 2. 2.  
Vita mi n K A nta g o nist .................................................................................... 4 7  
5. 2. 2. 1.  
D ose ............................................................................................................... 4 7  
5. 2. 2. 2.  
Tra nsiti o ni n g t o St u d y Vita mi n K A nta g o nist at Ra n d o mizati o n .................. 4 8  
5. 2. 2. 3.  
I nter nati o nal N or malize d Rati o Ma na ge me nt ................................................ 4 8 
5. 2. 2. 4.  
Tra nsiti o n fr o m Vita mi n K A nta g o ni st at E n d of Treat me nt ......................... 4 9 
5. 2. 3.  
I nterr u pti o ns a n d Disc o nti n uati o ns of St u d y Treat me nt ................................ 4 9 
5. 3.  
La beli n g a n d Pac ka gi n g ................................................................................. 4 9  
5. 4.  
Pre parati o n ..................................................................................................... 5 0  
5. 5.  
A d mi nistrati o n ............................................................................................... 5 0  
5. 6.  
St ora ge ........................................................................................................... 5 0  
5. 7.  
Dr u g Acc o u nta bilit y ....................................................................................... 5 1  
5. 8.  
Met h o d of Assessi n g Re gi me n C o m plia nce .................................................. 5 1  
5. 9.  
Pri or a n d C o nc o mita nt Me dicati o ns .............................................................. 5 2  
5. 9. 1.  
Pr o hi bite d Me dicati o ns .................................................................................. 5 2  
5. 1 0.  
S u bject Wit h dra wal/ Disc o nti n uati o n ............................................................. 5 3  
5. 1 0. 1.  
Reas o ns f or Wit h dra wal ................................................................................. 5 3  
5. 1 0. 2.  
Wit h dra wal Pr oce d ures .................................................................................. 5 3  
6.  
S T U D Y P R O C E D U R E S .............................................................................. 5 4  
6. 1.  
Pre-scree ni n g ..................................................................................................  5 4  
6. 2.  
S u bject E nr oll me nt ( Scree ni n g/ Ra n d o mizati o n, Visit 1, Da y - 2 1 ( ma x. 
Da y - 2 8) a n d O pti o nal Visit 2 Da y - 1 4) ........................................................ 5 4  
6. 2. 1.  
E d o xa ba n St u d y Ar m ..................................................................................... 5 6  
6. 2. 2.  
V K A St u d y Ar m ............................................................................................ 5 7  
6. 3.  
Cat heter A blati o n ( Peri pr oce d ural  Visit, Visit 3, Da y 0) ............................... 5 7 
6. 3. 1.  
E d o xa ba n St u d y Ar m ..................................................................................... 5 8  
6. 3. 2.  
V K A St u d y Ar m ............................................................................................ 5 8  
6. 3. 3.  
A ntic oa g ulati o n D uri n g Cat heter A blati o n .................................................... 5 9  


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Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 1 of 1 0 9 
 
6. 3. 4.  
A ntic oa g ulati o n P ost Cat heter A blati o n ........................................................ 5 9  
6. 4.  
H os pital Disc har ge ( Visit 4; o pti o nal) ........................................................... 5 9  
6. 5.  
Diff usi o n- Wei g hte d Ma g ne tic Res o na nce I ma gi n g ( Selecte d sites o nl y) 
( Visit 5, Da y 4) ............................................................................................... 5 9 
6. 6.  
Site Visit ( Visit 6, Da y 3 0) ............................................................................. 6 0  
6. 7.  
O pti o nal Site Visit/ Tele p h o ne Asse ss me nt ( Visit 7, Da y 6 0) ........................ 6 0 
6. 8.  
E n d of Treat me nt ( Visit 8, Da y 9 0) ............................................................... 6 0  
6. 9.  
E n d of St u d y Visit, P ost-treat me nt F oll o w- u p ( Visit 9, Da y 1 2 0) ................. 6 1  
6. 1 0.  
Misse d Visits .................................................................................................. 6 1  
6. 1 1.  
M o dificati o n of I C after Ra n d o mizati o n ........................................................ 6 1  
6. 1 1. 1.  
S u bjects L ost t o F oll o w- U p ........................................................................... 6 2  
6. 1 2.  
E n d of Trial Defi niti o n ................................................................................... 6 2  
7.  
O U T C O M E A S S E S S M E N T S ..................................................................... 6 3  
7. 1.  
Pri mar y Efficac y E n d p oi nt ............................................................................. 6 3  
7. 2.  
Pri mar y Safet y E n d p oi nt ................................................................................ 6 3  
7. 3.  
Sec o n dar y E n d p oi nts ...................................................................................... 6 3  
7. 3. 1.  
Ot her E n d p oi nts ............................................................................................. 6 4  
7. 4.  
E n d p oi nt Defi niti o ns ...................................................................................... 6 4  
7. 4. 1.  
Blee di n g ......................................................................................................... 6 5  
7. 4. 2.  
Efficac y E n d p oi nt Defi niti o ns ....................................................................... 6 5  
8.  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T S. ... 6 6  
8. 1.  
P har mac o ki netic Varia ble(s) .......................................................................... 6 6  
8. 2.  
Car diac Mar kers ............................................................................................. 6 6  
9.  
S A F E T Y A S S E S S M E N T S .......................................................................... 6 7  
9. 1.  
A d verse E ve nt C ollecti o n a n d Re p orti n g ....................................................... 6 7  
9. 2.  
Defi niti o ns ......................................................................................................  6 8  
9. 2. 1.  
A d verse E ve nt ................................................................................................ 6 8  
9. 2. 2.  
U ne x pecte d A d verse E ve nt ............................................................................ 6 8  
9. 2. 3.  
E x pecte d A d verse E ve nt ................................................................................ 6 8  
9. 2. 4.  
Seri o us A d verse E ve nt ................................................................................... 6 8  
9. 2. 5.  
A d verse E ve nts of S pecial I nterest ................................................................ 6 9  
9. 2. 5. 1.  
C o m bi ne d Ele vati o ns of A mi n ot ra nsferases a n d Bilir u bi n ............................ 6 9 
9. 3.  
Classificati o n f or A E assess me nt ................................................................... 6 9  


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 2 of 1 0 9 
 
9. 3. 1.  
Se verit y Assess me nt ...................................................................................... 6 9  
9. 3. 2.  
Ca usalit y Assess me nt ..................................................................................... 6 9  
9. 3. 3.  
Acti o n Ta ke n Re gar di n g t he Assi g ne d A ntit hr o m b otic Re gi me n ................. 7 0  
9. 3. 4.  
Ot her Acti o n Ta ke n f or E ve nt ........................................................................ 7 0  
9. 3. 5.  
A d verse E ve nt O utc o me ................................................................................ 7 0  
9. 4.  
Ti mi n g of A d verse E ve nt Re p orti n g .............................................................. 7 1  
9. 5.  
Re p orti n g S A Es/ A Es ...................................................................................... 7 1  
9. 5. 1.  
D oc u me ntati o n ............................................................................................... 7 1  
9. 5. 2.  
N otif yi n g Re g ulat or y A ut h orities, I n ve sti gat ors a n d I nstit uti o nal Re vie w 
B oar d/I n de pe n de nt Et hics C o m mittee ........................................................... 7 2  
9. 6.  
Re p orti n g of Pre g na nc y/ E x p os ure i n Uter o .................................................. 7 3  
9. 7.  
Cli nical La b orat or y E val uati o ns .................................................................... 7 3  
9. 8.  
Vital Si g ns ...................................................................................................... 7 4  
9. 9.  
Electr ocar di o gra ms ........................................................................................ 7 4  
9. 1 0.  
P h ysical E xa mi nati o n Fi n di n gs ...................................................................... 7 4  
9. 1 1.  
Ma g netic Res o na nce I ma gi n g: Di ff usi o n- Wei g hte d I ma gi n g ....................... 7 5 
1 0.  
S T A TI S TI C A L M E T H O D S ....................................................................... 7 6  
1 0. 1.  
A nal ysis Sets .................................................................................................. 7 6  
1 0. 1. 1.  
I nte nt-t o- Treat A nal ysis Set ........................................................................... 7 6 
1 0. 1. 2.  
M o difie d I nte nt-t o- Tr eat A nal ysis Set ........................................................... 7 6  
1 0. 1. 3.  
Per Pr ot oc ol A nal ysis Set ............................................................................... 7 6  
1 0. 1. 4.  
Safet y A nal ysis Set ........................................................................................ 7 7  
1 0. 2.  
Ge neral Statistical C o nsi derati o ns ................................................................. 7 7  
1 0. 3.  
St u d y P o p ulati o n Data ................................................................................... 7 9  
1 0. 4.  
Statistical A nal ysis ......................................................................................... 7 9  
1 0. 4. 1.  
A nal ysis of A dj u dicate d Efficac y E n d p oi nts ................................................. 7 9  
1 0. 4. 2.  
A nal ysis of A dj u dicate d Safet y E n d p oi nts .................................................... 8 0  
1 0. 4. 3.  
A nal ysis of Ot her Para meters ........................................................................ 8 1  
1 0. 4. 4.  
Safet y A nal yses .............................................................................................. 8 1  
1 0. 4. 4. 1.  
A d verse E ve nt A nal yses ................................................................................ 8 1  
1 0. 4. 4. 2.  
Cli nical La b orat or y E val uati o n A nal yses ...................................................... 8 1  
1 0. 4. 4. 3.  
Vital Si g ns A nal yses ...................................................................................... 8 1  
1 0. 4. 4. 4.  
Electr ocar di o gra m A nal yses .......................................................................... 8 2  


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 3 of 1 0 9 
 
1 0. 4. 4. 5.  
P h ysical E xa mi nati o n A nal yses ..................................................................... 8 2  
1 0. 4. 5.  
Ot her A nal yses ............................................................................................... 8 2  
1 0. 5.  
I nteri m A nal yses ............................................................................................ 8 2 
1 0. 6.  
Data a n d Safet y M o nit ori n g B oar d ................................................................ 8 2  
1 0. 7.  
Sa m ple Size Deter mi nati o n ............................................................................ 8 2  
1 1.  
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E .............................. 8 4  
1 1. 1.  
M o nit ori n g a n d I ns pecti o ns ........................................................................... 8 4  
1 1. 2.  
Data C ollecti o n .............................................................................................. 8 4  
1 1. 3.  
Data Ma na ge me nt .......................................................................................... 8 4  
1 1. 4.  
St u d y D oc u me ntati o n a n d St ora ge ................................................................. 8 5  
1 1. 5.  
Rec or d Kee pi n g .............................................................................................. 8 6  
1 2.  
FI N A N CI N G A N D I N S U R A N C E .............................................................. 8 7  
1 2. 1.  
Fi na nces ......................................................................................................... 8 7  
1 2. 2.  
Rei m b urse me nt, I n de m nit y, a n d I ns ura nce .................................................... 8 7  
1 3.  
P U B LI C A TI O N P O LI C Y ........................................................................... 8 8  
1 4.  
E T HI C S A N D S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N ............. 8 9  
1 4. 1.  
C o m plia nce State me nt, Et hics a n d Re g ulat or y C o m plia nce ......................... 8 9  
1 4. 2.  
S u bject C o nfi de ntialit y .................................................................................. 8 9  
1 4. 3.  
I nf or me d C o nse nt Pr oce d ure ......................................................................... 8 9 
1 4. 4.  
Re g ulat or y C o m plia nce .................................................................................. 9 0  
1 4. 5.  
Pr ot oc ol De viati o ns ........................................................................................ 9 0  
1 4. 6.  
S u p pl y of Ne w I nf or mati o n Affec ti n g t he C o n d uct of t he St u d y .................. 9 0 
1 4. 7.  
Pr ot oc ol A me n d me nts .................................................................................... 9 1  
1 4. 8.  
A d dress List ................................................................................................... 9 1  
1 4. 8. 1.  
S p o ns or ...........................................................................................................  9 1  
1 4. 8. 1. 1.  
D S E Pr oject Lea der ........................................................................................ 9 1  
1 4. 8. 1. 2.  
D S E Me dical E x pert ...................................................................................... 9 1  
1 4. 8. 2.  
C R O ............................................................................................................... 9 2  
1 4. 8. 2. 1.  
C R O Me dical M o nit or ................................................................................... 9 2  
1 4. 8. 2. 2.  
C R O Pr oject Ma na ger .................................................................................... 9 2  
1 4. 8. 3.  
Dr u g Safet y .................................................................................................... 9 2  
1 4. 8. 3. 1.  
D S E ................................................................................................................ 9 2  


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 4 of 1 0 9 
 
1 4. 8. 3. 2.  
C R O ............................................................................................................... 9 2  
1 4. 8. 4.  
Bi ostatistics & Data Ma na ge me nt .................................................................. 9 2  
1 4. 8. 4. 1.  
D S E Data Ma na ge me nt .................................................................................. 9 2  
1 4. 8. 4. 2.  
D S E Bi ostatisticia n ........................................................................................ 9 3  
1 4. 8. 5.  
Bi ol o gical S peci me ns ..................................................................................... 9 3  
1 4. 8. 6.  
I nteracti ve We b V oice Res p o nse S yste m (I X R S) .......................................... 9 3 
1 4. 8. 7.  
Bi oa nal ytical La b orat or y ................................................................................ 9 3  
1 4. 8. 8.  
e C R F Pr o vi der ................................................................................................ 9 3  
1 4. 8. 9.  
Ot her ...............................................................................................................  9 3  
1 5.  
R E F E R E N C E S ............................................................................................. 9 4  
1 6.  
A P P E N DI C E S .............................................................................................. 9 7  
1 6. 1.  
St u d y Or ga nizati o n ........................................................................................ 9 7  
1 6. 1. 1.  
Data a n d Safet y M o nit ori n g B oar d ................................................................ 9 7  
1 6. 1. 2.  
Cli nical E ve nts C o m mitt ee ............................................................................ 9 7  
1 6. 1. 3.  
E xec uti ve C o m mittee ..................................................................................... 9 7  
1 6. 1. 4.  
O perati o ns C o m mittee ................................................................................... 9 8  
1 6. 2.  
S u b-st u d y ....................................................................................................... 9 8  
1 6. 3.  
Blee di n g Criteria ............................................................................................ 9 9  
1 6. 4.  
Defi niti o n of ter ms ....................................................................................... 1 0 2  
1 6. 5.  
C o m p o ne nts of t he C H A D S 2, C H A2D S 2- V A Sc Sc ore a n d H A S- B L E D Sc ore 1 0 3 
1 6. 6.  
Esti mati o n of Creati ni ne Cleara nce ( Cr C L) ................................................. 1 0 4  
1 6. 7.  
M o difie d Ra n ki n Scale ................................................................................. 1 0 5  
1 6. 8.  
Re gi o nal G ui deli ne Rec o m me n dati o ns f or I N R .......................................... 1 0 6  
1 6. 9.  
Sc he d ule of E ve nts ....................................................................................... 1 0 7  
 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 5 of 1 0 9 
 
LI S T O F I N- T E X T T A B L E S 
Ta ble 1. 1:  
S u m mar y of t he H o k usai V T E a n d E N G A G E A F- TI MI 4 8 St u dies ........ 3 1  
Ta ble 2:  
Tra nsiti o ni n g t o E d o xa ba n at Ra n d o mizati o n ........................................... 4 5  
Ta ble 3:  
Tra nsiti o ni n g fr o m E d o xa ba n  at E n d of Treat me nt .................................. 4 6 
Ta ble 1 6. 1:  
I S T H Blee di n g Criteria ............................................................................. 9 9 
Ta ble 1 6. 2:  
TI MI Blee di n g Criteria .............................................................................. 9 9  
Ta ble 1 6. 3:  
B A R C Blee di n g Criteria ......................................................................... 1 0 0  
Ta ble 1 6. 4:  
C o m p o ne nts of t he C H A D S 2 Sc ore ........................................................ 1 0 3 
Ta ble 1 6. 5:  
C o m p o ne nts of t he C H A 2D S 2- V A Sc Sc ore ............................................ 1 0 3 
Ta ble 1 6. 6:  
C o m p o ne nts of t he H A S- B L E D Sc ore .................................................... 1 0 3  
Ta ble 1 6. 7:  
M o difie d Ra n ki n Scale ............................................................................ 1 0 5  
Ta ble 1 6. 8:  
Re gi o nal G ui deli ne Rec o m me n dati o ns f or I N R ..................................... 1 0 6  
 


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LI S T O F I N- T E X T FI G U R E S 
Fi g ure 3. 1 St u d y Desi g n .................................................................................................... 3 8  
 


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LI S T O F A B B R E VI A TI O N S 
A B B R E VI A TI O N  
D E FI NI TI O N 
A C T 
Acti vate d cl otti n g ti me 
A E
 A d verse
 
e ve nt
 
A E SI 
A d verse e ve nt of s pecial i nterest 
A F
 Atrial
 
fi brillati o n
 
A L P
 Al kali ne
 
p h os p hatase
 
A L T
 Ala ni ne
 
tra nsa mi nase
 
A R C 
Aca de mic Researc h C o ns orti u m 
A S A
 Acet ylsalic ylic
 
aci d
 
A S T
 As partate
 
tra nsa mi nase
 
B A R C 
Blee di n g Aca de mic Researc h C o ns orti u m 
B P
 Bl o o d
 
press ure
 
C A B G 
C or o nar y arter y b y pass graft 
C A D
 C or o nar y
 
arter y
 
disease
 
C E C 
Cli nical E ve nts C o m mittee 
C H A D S 2 
C o n gesti ve heart fail ure, H y perte nsi o n, A ge,  Dia betes, pre vi o us Str o ke ris k sc ore 
CI
 C o nfi de nce
 
i nter val
 
C N S 
Ce ntral ner v o us s yste m 
C O X
 C y cl o o x y ge nase
 
Cr C L
 Creati ni ne
 
cleara nce
 
C R F 
Case re p ort f or m 
C R N M 
Cli nicall y rele va nt n o n- maj or 
C R O 
C o ntract Researc h Or ga nizati o n 
c T n- hs 
car diac tr o p o ni n hi g h se nsiti vit y  
C V
 Car di o vasc ular
 
D A P T 
D ual A nti platelet T hera p y (e. g., as piri n a n d P 2 Y 1 2 a nta g o nist) 
D M
 Dia betes
 
mellit us
 
D S E 
Daiic hi Sa n k y o E ur o pe 
D S M B 
Data a n d Safet y M o nit ori n g B oar d 
D V T 
Dee p vei n t hr o m b osis 
D WI 
Diff usi o n wei g hte d i ma gi n g  
D WI- F L AI R  
Diff usi o n wei g hte d i ma gi n g fl ui d atte n uate d i n versi o n rec o ver y 
D W- M RI 
Diff usi o n wei g hte d ma g netic res o na nce i ma gi n g 
E C
 Et hics
 
C o m mittee
 
E C G
 Electr ocar di o gra m
 
e C R F 
Electr o nic case re p ort f or m 
E D
 E mer ge nc y
 
de part me nt
 
E D C 
Electr o nic data ca pt ure 
E H R A 
E ur o pea n Heart R h yt h m Ass ociati o n 
E O T
 E n d- of- Treat me nt
 
E U
 E ur o pea n
 
U ni o n
 


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A B B R E VI A TI O N  
D E FI NI TI O N 
E u dra C T 
E ur o pea n u ni o n dr u g re g ulati n g a ut h orities cli nical trials 
F Xa
 Fact or
 
Xa
 
G C P 
G o o d Cli nical Practice (refers t o I C H) 
GI
 Gastr oi ntesti nal
 
G M
 Gre y
 
matter
 
H E O R 
Healt h Ec o n o mics O utc o me Researc h 
H F
 Heart
 
fail ure
 
HI F U 
Hi g h i nte nsit y f oc use d ultras o u n d 
H R
 Hazar d
 
rati o
 
I B
 I n vesti gat or
 
Br oc h ure
 
I C 
I nf or me d c o nse nt  
I C F 
I nf or me d C o nse nt F or m 
I C H
 I ntracra nial
 
he m orr ha ge
 
I C U 
I nte nsi ve Care U nit 
I D
 I de ntificati o n
 
I E C
 I n de pe n de nt
 
Et hics
 
C o m mittee
 
I N R
 I nter nati o nal
 
n or malize d
 
rati o
 
I R B
 I nstit uti o nal
 
Re vie w
 
B oar d
 
I S T H 
I nter nati o nal S ociet y o n T hr o m b osis a n d He m ostasis 
I T T 
I nte nt-t o-treat (a nal ysis set) 
I X R S 
I nteracti ve we b/ v oice res p o nse s yste m 
L A
 Left
 
atri u m
 
L A A 
Left Atrial A p pe n da ge 
L M W H 
L o w m olec ular wei g ht he pari n 
L V
 Left
 
ve ntricle
 
Me d D R A 
Me dical Dicti o nar y f or Re g ulat or y Acti vities 
MI
 M y ocar dial
 
i nfarcti o n
 
mI T T 
M o difie d I T T (a nal ysis set) 
M RI 
Ma g netic res o na nce i ma gi n g 
m R S 
m o difie d Ra n ki n Scale 
N O A C 
N o n- vita mi n K a nta g o nist oral a ntic oa g ula nt 
N S AI D
 N o n-ster oi dal
 
a nti-i nfla m mat or y
 
dr u g
 
N T- pr o B N P  
N-ter mi nal fra g me nt B-t y pe natri uretic pe pti de  
O A C
 Oral
 
a ntic oa g ula nt
 
P D
 P har mac o d y na mic
 
P E
 P ul m o nar y
 
e m b olis m
 
P- g p
 P- gl y c o pr otei n
 
P K
 P har mac o ki netic
 
P P
 Per
 
pr ot oc ol
 
P R O B E desi g n  
Pr os pecti ve, Ra n d o mize d, O pe n-la bel st u d y wit h Bl i n de d E val uati o n of e n d p oi nts 
R F
 Ra di o
 
fre q ue nc y
 


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A B B R E VI A TI O N  
D E FI NI TI O N 
S A E 
Seri o us a d verse e ve nt 
S A F 
Safet y (a nal ysis set) 
S A P 
Statistical a nal ysis pla n 
S C E 
sile nt cere bral e ve nts 
S C L 
sile nt cere bral lesi o ns 
S E E 
S yste mic e m b olic e ve nts 
S m P C 
S u m mar y of Pr o d uct C haracteristics 
S O P 
Sta n dar d o perati n g pr oce d ures 
S U S A R 
S us pecte d, u ne x pecte d, seri o us a d verse reacti o n 
T B L
 T otal
 
bilir u bi n
 
T E A E 
Treat me nt-e mer ge nt a d verse e ve nt 
T E E
 Tra nses o p ha geal
 
ec h ocar di o gra m
 
 
TI A 
Tra nsie nt isc he mic attac k 
TI MI 
T hr o m b ol ysis i n M y ocar dial I nfarcti o n  
T T R 
Ti me i n t hera pe utic ra n ge 
U L N 
U p per li mit of n or mal 
V K A 
Vita mi n K a nta g o nist 
vs
 Vers us
 
V T E
 Ve n o us
 
t hr o m b oe m b olis m
 
W B C
 W hite
 
bl o o d
 
cells
 
 
 
 


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1.  
I N T R O D U C TI O N  
1. 1.  
B ac k gr o u n d  
Atrial fi brillati o n ( A F) is t he m o st c o m m o n arr h yt h mia i n a d ults, affecti n g 0. 5 % t o 1 % of t he t otal 
p o p ulati o n a n d > 8 % of s u bjects ol der t ha n 8 0 years. S u bjects s ufferi n g fr o m A F are at a n i ncrease d 
ris k of str o ke, pr o gressi n g heart fail ure a n d s u d de n deat h. Cat heter a blati on as a met h o d of treati n g 
A F is m ore a n d m ore fr e q ue ntl y perf or me d i n cli nical practice d ue t o its effecti ve ness o n A F-
relate d s y m pt o ms a n d q ualit y of life (3 ). H o we ver, t his pr oce d ure is ass ociate d wit h a si g nifica nt 
t hr o m b oe m b olic ris k d uri n g a n d sh ortl y after t he pr oce d ure. T he ca uses of t hr o m b oe m b olic e ve nts 
d uri n g a n d after t he a blati o n are m ulti ple a n d as s u c h, t he use of oral a ntic oa g ula nts d uri n g t he 
cat heter a blati o n pr oce d ure is t heref ore warra nte d (2 ).  
Vita mi n  K  a nta g o nists  ( V K As)  ha ve  bee n  tra dit i o nall y  use d  t o  pre ve nt  pr oce d ure-relate d  
t hr o m b oe m b olis m (4 ).  T he tra diti o nal a ntic oag ulati o n a p pr oac h is t o i n terr u pt a d mi nistrati o n of 
a n oral V K A a n d use he pari n bri d gi n g.  M ore rece ntl y, st u dies ha ve i n dicat e d t hat u ni nterr u pte d 
a ntic oa g ulati o n  ma y  be  safer  a n d  m ore  effecti ve  ( 5 ).  C urre nt  A F  g ui deli nes  rec o m me n d  
c o nsi derati o n of u ni nterr u pte d oral a ntic oa g ulati o n f or patie n ts u n der g oi n g cat heter a blati o n (2 ). 
I n  a  E ur o pea n  Heart  R h yt h m  Ass ociati o n  s ur ve y,  7 1. 6 %  of  res p o n de nts  re p orte d  usi n g  t he  
u ni nterr u pte d V K A strate g y f or cat heter a blati o n ( 6 ).  
N o n- vita mi n K oral a ntic oa g ul a nts ( N O A Cs) offer i m p orta nt a d va nta ges o ver V K A be y o n d t heir 
ease of a d mi nistrati o n, s uc h as fe wer i nteracti o ns  a n d n o nee d of la b orat or y m o nit ori n g, a n d ha ve 
bec o me wi del y a vaila ble a n d re prese nt a n  attracti ve alter nati ve i n t his setti n g. 
 
1. 2.  
Descri pti o n of I n vesti g ati o n al Pr o d uct 
E d o xa ba n t os ylate ( D U- 1 7 6 b) is a n a ntit hr o m b otic a ge nt, a n orall y acti ve, se lecti ve, direct, a n d 
re versi ble  i n hi bit or  of  Fact or  Xa  ( F Xa),  ma n ufact ure d  b y  Daiic hi  Sa n k y o  C o.,  Lt d.,  Ja pa n.   
I n hi biti o n of F Xa i n t he c oa g ulati o n casca de prol o n gs cl otti n g ti me a n d p ote ntiall y re d uces t he 
ris k of s p o nta ne o us or i n d uce d t hr o m b us f or mati o n. 
I nter nati o nal n o n- pr o prietar y na me: E d o xa ba n (D U- 1 7 6) refers t o t he a n h y dr o us free base of 
e d o xa ba n t os ylate. S u bjects are gi ve n e d o xa ba n t o s ylate (a m o n o h y drate salt) b ut all d oses a n d 
plas ma c o nce ntrati o ns are e x presse d i n ter ms of e d o xa ba n, t he a n h y dr o us free base. 
F or si m plicit y, t his pr ot oc ol uses t he ter m “e d o xa ba n” t o refer t o ei t her or b ot h f or ms. 
1. 2. 1. 1.  
N o ncli nic al St u dies 
I n n o ncli nical st u dies, e d o xa ba n s h o we d e xcelle nt p ote ntial as a n a n tit hr o m b otic a ge nt.  Res ults 
of n o n-cli nical t o xic o l o g y st u dies d o n ot i n dicate a n y maj or cli nicall y c o ncer ni n g a d verse effects 
i n  st u d y  a ni mals  e x p ose d  t o  e d o xa ba n.  A d diti o nal  details  ar e  a vaila ble  i n  t he  e d o xa ba n  
I n vesti gat or’s Br oc h ure (I B) (7 ). 
1. 2. 1. 2.  
Cli nic al E x perie nce 
E d o xa ba n was i nitiall y a p pr o ve d i n Ja pa n f or t h e pre ve nti o n of ve n o us t hr o m b oe m b olis m ( V T E) 
i n patie nts u n der g oi n g a n y of t he f oll o wi n g ort h o pe dic pr oce d ures o n  t he l o wer li m b: t otal k nee 


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Pa ge 3 1 of 1 0 9 
 
re place me nt,  t otal  hi p  re place me nt,  a n d  hi p  fract ure  s ur ger y  a n d  t he n  s u bse q ue ntl y  f or  t he  
pre ve nti o n of isc he mic str o ke a n d s yste mic e m b olis m i n patie nts wit h n o n- val v ular A F; treat me nt 
a n d rec urre nce pre ve nti o n of V T E. I n 2 0 1 5, e d o xa ba n was a p pr o ve d i n t he E ur o pea n U ni o n ( E U) 
f or t he pre ve nti o n of str o ke a n d s yste mic e m b olis m i n a d ult patie nts wit h n o n val v ular A F wit h 
o ne or m ore ris k fact ors (s uc h as c o n gesti ve heart fail ure, h y perte nsi o n, a ge ≥7 5 years, dia betes 
mellit us, pri or str o ke or tra nsie nt isc hae mic attac k  ( TI A), a n d f or t he treat me nt a n d pre ve nti o n of 
rec urre nt dee p vei n t hr o m b osis ( D V T) a n d p ul m o nar y e m b olis m ( PE). Si milar i n dicati o ns were 
als o a p pr o ve d i n t he U nite d States a n d ot her c o u ntries a n d re gi o ns.   
T he efficac y a n d safet y of e d o xa ba n f or re d uci n g t h e ris k of str o ke a n d s yste mic e m b olic e ve nts 
( S E Es) i n s u bjects wit h n o n- val v ular A F was de m o nstrate d i n a lar ge pi v otal P hase 3 st u d y 
( E N G A G E A F- TI MI 4 8) (1 ). Si milarl y, t he efficac y a n d safet y of e d o xa ba n f or t he treat me nt of 
V T E, i ncl u di n g D V T a n d P E, a n d t he pre ve nti o n of  rec urre nt V T E was de m o nstrate d i n t he P hase 
3 H o k usai V T E st u d y ( 8 ). 
Feat ures of t he H o k usai V T E a n d E N G A G E A F- TI MI 4 8 st u dies are s u m marize d i n Ta ble 1. 1 . 
T a ble 1. 1:  S u m m ar y of t he H o k us ai V T E a n d E N G A G E A F- TI MI 4 8 St u dies 
St u d y 
P o p ul ati o n 
Me di a n 
D ur ati o n 
of 
Tre at me nt 
Tre at me nt Gr o u ps  N 
Pri m ar y Effic ac y O utc o me  
Pri m ar y S afet y O utc o me 
E n d p oi nt
H R ( 9 5 % CI) 
E d o x a b a n vs 
W arf ari n 
E n d p oi nt 
H R ( 9 5 % CI) 
E d o x a b a n vs 
W arf ari n 
H o k usai 
V T E (ac ute 
V T E) 
0. 7 y ears 
E d o xa ba n 6 0 m g  
4 1 1 8 
Rec urre nt 
V T E 
0. 8 9 ( 0. 7 0, 1. 1 3) 
mI T T, o verall st u d y 
peri o d 
Maj or + 
C R N M 
Blee di n g 
0. 8 1 ( 0. 7 0 5, 0. 9 3 6) 
mI T T, o n-treat me nt 
peri o d 
Warfari n
 4 1 2 2
 
E N G A G E 
A F- TI MI 
4 8 ( n o n-
val v ular 
A F) 
2. 5 y ears 
E d o xa ba n  
Hi g h D ose 
Re gi me n *  
7 0 1 2 
Str o ke 
a n d S E E 
0. 7 9 ( 0. 6 3, 0. 9 9) 
mI T T, o n-treat me nt 
peri o d 
Maj or 
Blee di n g 
0. 8 0 ( 0. 7 1, 0. 9 1) 
mI T T, o n-treat me nt 
peri o d 
E d o xa ba n  
L o w D ose 
Re gi me n * * 
7 0 0 2 
1. 0 7 ( 0. 8 7, 1. 3 1) 
mI T T, o n-treat me nt 
peri o d 
0. 4 7 ( 0. 4 1, 0. 5 5) 
mI T T o n-treat me nt 
peri o d 
Warfari n
 7 0 1 2
  
-
 
-
 
A b bre viati o ns: A F = atrial fi brillati o n; CI = c o nfi de nce i nter val; C R N M = cli nicall y rele va nt n o n- maj or; H R = 
Hazar d Rati o; S E E = s yste mic e m b olic e ve nt; vs = vers us; V T E = ve n o us t hr o m b oe m b olis m; mI T T = m o difie d 
i nte nti o n-t o-treat; N = n u m ber of treate d s u bjects 
* Hi g h D ose Re gi me n = 6 0 m g e d o xa ba n o nce- dail y wit h re d ucti o n t o 3 0 m g o nce- dail y i n s u bjects wit h l o w b o d y 
wei g ht, m o derate re nal i m pair me nt, or s pecifie d c o nc o mita nt me dicati o ns; 
* * L o w D ose Re gi me n = 3 0 m g e d o xa ba n o nce- dail y wit h re d ucti o n t o 1 5 m g o nce- dail y i n s u bjects wit h l o w b o d y 
wei g ht, m o derate re nal i m pair me nt, or s pecifie d c o nc o mita nt me dicati o ns. 
 
Ot her c o m plete d st u dies i ncl u d e P hase 1 cli nical p har mac ol o g y st u dies, P hase 2 d ose-ra n gi n g 
st u dies i n s u bjects wit h n o n- val v ular A F a n d s u bjects u n der g oi n g l o wer-e xtre mit y ort h o pe dic 
s ur ger y, a n d P hase 3 st u dies i n s u bjects u n der g oi n g l o wer-e xtre mit y ort h o pe dic s ur ger y. 
I n t he c o urse of t he e d o xa ba n cli nical de vel o p me nt pr o gra m, o ver 2 3, 5 0 0 s u bjects have bee n gi ve n 
e d o xa ba n  e nc o m passi n g  o ver  3 4, 1 0 0  s u bject- years  of  e x p os ure.  T he  safet y  a n d  efficac y  of  
e d o xa ba n has bee n e val uate d i n t he f oll o wi n g pr o gra ms: 
 P hase 1 st u dies (i ncl u di n g 1 6 2 7 s u bjects fr o m p har mac o ki netic ( P K)- p har mac o d y na mic 
( P D) st u dies, P K i n s u bjects wit h re nal i m pair me nt, a n d dr u g- dr u g i nteracti o n st u dies):  
Res ults of t hese st u dies ha ve s h o w n t hat e d o xa ba n is ra pi dl y a bs or be d wit h ra pi d o nset of 


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acti o n a n d t he d ose c o nce ntrati o n relati o ns hi p is ge nerall y li near. T he mea n ter mi nal 
half-life is bet wee n 1 0- 1 4 h o urs.  T he P D effect as meas ure d b y a nti- Xa acti vit y or 
i n hi biti o n of F Xa acti vit y lasts f or 2 4 h o urs.  D ose-relate d i ncreases i n P K c o nce ntrati o ns 
a n d a nti-t hr o m b otic acti vit y were o bser ve d, as meas ure d b y a nti- Xa acti vit y.  T he 
bi oa vaila bilit y is ~ 6 0 % a n d 5 0 % of t he a bs or b e d dr u g is e xcrete d b y re nal cleara nce.  T he 
a bs or pti o n, distri b uti o n, meta b olis m, a n d e x creti o n are als o me diate d t hr o u g h t he P 
gl yc o pr otei n ( P- g p) tra ns p ort s yste m a n d dr u gs wit h P- g p i n hi bit or y effects ma y alter 
e d o xa ba n e x p os ure. 
 P hase 2 st u dies i n A F s u bjects (i ncl u di n g 1, 9 7 3 s u bjects):  T hese st u dies pri maril y 
e val uate d safet y of differ e nt d ose re gi me ns of e d o xa ba n wit h a p pr o xi matel y 1 2 wee ks of 
treat me nt.  Res ults of t hese st u dies s h o we d t hat t he t wice a da y re gi me n ha d hi g her 
blee di n g t ha n o nce- dail y re gi me n of e d o xa ba n.  C o nse q ue ntl y, t he o nce- dail y re gi me n of 
e d o xa ba n was teste d i n t he s u bse q ue nt P hase 3 trials. 
 P hase 3 A F pi v otal trial ( E N G A G E A F- TI MI 4 8) i n v ol vi n g 2 1, 0 2 6 treate d s u bjects wit h 
a me dia n f oll o w- u p of 2. 8 years ( me dia n tr eat me nt 2. 5 years). T w o o nce- dail y re gi me ns 
of e d o xa ba n were c o m pare d wit h warfari n f o r t he pre ve nti o n of str o ke a n d s yste mic 
e m b olis m i n patie nts wit h n o n- val v ular A F. B ot h  re gi me ns were n o n-i nferi or t o warfari n 
f or t he pre ve nti o n of str o ke a n d s yste mic e m b olis m a n d were ass ociate d wit h 
si g nifica ntl y l o wer rates of blee di n g a n d deat h fr o m cardi o vasc ular ( C V) ca uses. 
E d o xa ba n has bee n a p pr o ve d f or mar keti n g i n t he U nite d States a n d E U f or t his 
i n dicati o n. 
 P hase 2/ 3 V T E pr o p h yla xis st u dies i n s u bjec ts u n der g oi n g ort h o pe dic s ur ger y (i ncl u di n g 
3, 6 7 8 s u bjects).  E d o xa ba n has bee n a p pr o ve d f o r mar keti n g i n Ja pa n f or t his i n dicati o n. 
 P hase 3 V T E pi v otal trial ( H o k usai- V T E) i n v ol vi n g 8, 2 4 0 treate d s u bjects.  E d o xa ba n 
a d mi nistere d o nce- dail y after i n itial treat me nt wit h he pari n was n o n-i nferi or t o sta n dar d 
t hera p y a n d ca use d si g nifica ntl y less blee di n g i n patie nts wit h V T E. E d o xa ba n has bee n 
a p pr o ve d f or mar keti n g i n t he U S  a n d E U f or t his i n dicati o n. 
1. 2. 1. 3.  
D ose R ati o n ale 
Base d o n t he res ults of t he E N G A G E A F- TI MI 4 8 a n d H o k usai- V T E st u dies, a n e d o xa ba n d ose 
t hat is c o nsi dere d as safe a n d effecti ve f or patie nts wit h A F or V T E a n d is i ncl u de d i n t he la bel 
( prescri bi n g i nf or mati o n) has bee n selecte d f or t his trial.  E d o xa ba n has n ot bee n e val uate d i n 
patie nts wit h A F u n der g oi n g cat heter  a blati o n of n o n- val v ular A F b ut n o e vi de nce e xists s u g gesti n g 
f urt her t hat d ose a da ptati o n is re q uire d. 
 
 


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1. 3.  
Ris ks a n d Be nefits f or St u d y S u bjects 
Atrial fi brillati o n ( A F) is t he m o st fre q ue nt s ustai ne d arr h yt h mia i n cli nical practice. Cat heter 
a blati o n of A F has bee n esta blis he d as a n effecti v e t hera p y f or t he treat me nt of s y m pt o ms i n t hese 
patie nts ( 3 ). H o we ver, t his pr oce d ure is ass ociate d wit h a si g nifica nt t hr o m b oe m b olic ris k. I n a 
rece nt w orl d- wi de s ur ve y (9 ), t he o verall i nci de nce of maj or c o m plicati o ns of car diac a blati o n 
was 4. 5 % a n d t he deat h rate was 0. 1 5 %. Ta m p o na de was t he m ost fre q ue nt c o m plicati o n ( 1. 3 1 %), 
f oll o we d b y t otal fe m oral pse u d oa ne ur ys m ( 0. 9 3 %), TI As ( 0. 7 1 %), t otal arter o- ve n o us fist ulae 
( 0. 5 4 %), p ul m o nar y vei n ste n osis re q uiri n g i nter ve nti o n ( 0. 2 9 %) a n d str oke ( 0. 2 3 %). T he ca uses 
of t hr o m b oe m b olic e ve nts d uri n g a n d after t he a blati o n are m ulti ple a n d i ncl u de (I) c har f or mati o n 
at t he cat heter ti p, (II) m o bilizati o n of pre-e xisti n g left atrial t hr o m bi, (III) t hr o m b us f or mati o n i n 
left atrial s heat hs, (I V) t he t hr o m b o ge nic p ote ntial of left atrial e n d ocar dial lesi o ns, a n d ( V) 
electrical car di o versi o n d uri n g t he pr oce d ure. 
A ntic oa g ulati o n t hera p y is t heref ore re q uire d bef ore, d uri n g, a n d f o r a peri o d after t he pr oce d ure 
(as defi ne d b y g ui deli nes), a n d ma y be c o nti n ue d i n defi nitel y i n pa tie nts wit h o n g oi n g ris k fact ors 
f or str o ke ( C o n gesti ve heart fail ure, H y perte nsi o n, A ge, Dia betes, pre vi o us Str o ke ris k sc ore 
[ C H A D S2]  ≥1 or C H A 2D S 2- V A Sc ≥2).  
Tra diti o nall y, V K As (e g, c o u mari ns a n d i n da ne di o nes) are use d as a ntic oa g ula nt me dicati o ns 
(s o meti mes wit h e n o xa pari n a d mi nistere d as a ‘ brid ge’ d uri n g t he pr oce d ure)  t o re d uce t he ris k 
of str o ke a n d t hr o m b oe m b olic c o m plicati o ns i n s u bjects wit h A F u n der g oi n g cat heter a blati o n. 
G ui deli nes rec o m me n d u ni nterr u pte d V K A t hera p y, f or e xa m ple wit h warfari n, d ose d t o a n 
I nter nati o nal N or malize d Rati o (I N R of 2. 0 – 2. 5). H o we ver, t hese V K As (a ntic oa g ula nt a ge nts) 
are i n direct t hr o m bi n i n hi bit ors w hic h act b y bl oc ki n g t he vita mi n K- de pe n de nt li ver pr o d ucti o n 
of plas ma cl otti n g fact ors, pr ot hr o m bi n ( Fact or II), a n d Fact ors VII,  I X, a n d X. T he use of warfari n 
is c o m plicate d b y se veral i n here nt pr o ble ms, i ncl u di n g a dela ye d o nset of a ntit hr o m b otic acti o n, 
narr o w  t hera pe utic  i n de x  t hat  re q uires  cl os e  a ntic oa g ulati o n  m o nit ori n g  usi n g  t he  I N R,  
u n pre dicta ble  a n d  varia ble  p ha r mac ol o gical  res p o nse,  a n d  man dat or y  re g ular  la b orat or y  
m o nit ori n g  t o  c o ntr ol  its  a ntic oa g ula nt  effect  a n d  mi ni mize  t he  ris k  of  seri o us  blee di n g.  
F urt her m ore, n u mer o us dr u gs, certai n dietar y s u p ple me nts, alc o h ol, a n d s o me f o o ds mar ke dl y 
affect warfari n d ose res p o nse. T his is i n a d diti o n t o t he fi n di n g t hat warfari n use i ncreases b ot h 
t he ris k of de vel o pi n g i ntra cere bral he m orr ha ge a n d m ortalit y. 
H o we ver, as V K As ma y be diffic ult t o ma na ge , t he fi xe d- d ose N O A Cs are i ncreasi n gl y use d 
i nstea d of V K As a n d t heir use i n patie nts u n der goi n g a blati o n is t heref or e of i nterest als o. 
T he N O A Cs offer t he be nefits of pre dicta ble e ffect wit h o ut nee d f or m o nit ori n g, fe wer f o o d a n d 
dr u g i nteracti o ns, s h orter plas ma half-life, a n d a n i m pr o ve d effic ac y/safet y rati o. Se veral s mall, 
n o n-ra n d o mize d, o bser vati o nal st u di es a n d meta-a nal yses (e. g. 1 0, 1 1, 1 2, 1 3, 1 4 ) ha ve s u g geste d 
a si milar safet y a n d efficac y pr ofile f or t he dire ct F Xa i n hi bit ors ri var o xa ba n a n d a pi xa ba n, a n d 
t he direct t hr o m bi n i n hi bit or da bigatra n, c o m pare d t o warfari n.  
I n a s u b-a nal ysis of t he lar ge, ra n d o mize d R O C K E T A F st u d y, a relati vel y s mall gr o u p of patie nts 
u n der g oi n g  cat heter  a blati o n  or  car di o versi o n  ha d  si milar  o ut c o mes  w he n  recei vi n g  eit her  
ri var o xa ba n or warfari n (1 6 ). T he use of ri var o xa ba n was i n vesti gate d i n patie nts u n der g oi n g 
cat heter a blati o n f or n o n- val v ular  A F i n t he V E N T U R E A F st u d y, w hic h s h o we d si milar safet y 


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o utc o mes wit h u ni nterr u pte d oral ri var o xa ba n a n d u ni nterr u pte d st a n dar d V K A t hera p y. T he 
i nci de nce  of  Maj or  Blee di n g  e ve nts  was  ver y l o w  i n  b ot h  treat me nt  gr o u ps,  a n d  re mai ne d  
c o nsiste nt t hr o u g h o ut t he st u d y peri o d (3 ). 
T heref ore, t here e xists a nee d f or a safer, m ore ef fecti ve, a n d easil y ma na gea ble oral a ntic oa g ula nt 
( O A C) a ge nt f or t he pre ve nti o n of ac ute str o ke i n s u bjects wit h A F w h o are sc he d ule d f or cat heter 
a blati o n. It is e x pecte d t hat e d o xa ba n will pr o vi de  c o m para ble efficac y t o warfari n, b ut wit h a 
pre dicta ble a n d faster a ntit hr o m b otic res p o ns e a n d wit h n o nee d f or la b orat or y m o nit ori n g. 
E d o xa ba n is a selecti ve F Xa i n hi bit or wit h ra pi d o nset of acti o n a n d pre dicta ble a n d e xcelle nt 
a ntit hr o m b otic pr o perties. I n m o re t ha n 3 5, 0 0 0 s u bjects treate d t o date, e d o xa ba n a p pears t o be 
well t olerate d u p t o a d ose of 9 0 m g dail y, wit h  e x pecte d tra nsie nt a n d ma na gea ble blee di n g 
a d verse e ve nts ( A Es) a n d tra nsie nt a n d re versi b le li ver e nz y me a n d bilir u bi n ele vati o ns.   
 
 


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2.  
S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S 
2. 1.  
St u d y O bjecti ves 
2. 1. 1.  
Pri m ar y O bjecti ves 
Pri m ar y Effic ac y O bjecti ve: 
T o c o m pare descri pti vel y t he i nci de nce of t he c o m p osite of all-ca use deat h, str o ke (isc he mic, 
he m orr ha gic, or u n deter mi ne d) a n d Maj or Blee di n g (I nter nati o nal S ociet y o n T hr o m b osis a n d 
He m ostasis  [I S T H]  defi niti o n)  i n  t he  e d o xa ba n  gr o u p  a gai nst  t he  V K A  gr o u p  i n  s u bjects  
u n der g oi n g cat heter a blati o n of A F, i n t he peri o d fr o m t he e n d of t he cat heter a blati o n pr oce d ure 
t o Da y 9 0/ E n d- of- Treat me nt ( E O T). 
Pri m ar y S afet y O bjecti ve: 
T o c o m pare descri pti vel y t he i nci de nce of Ma j or Blee di n g (I S T H defi niti o n) i n t he e d o xa ba n 
gr o u p a gai nst t he V K A gr o u p i n t he peri o d fr o m t he date of first i nta ke of st u d y me dicati o n t o 
Da y 9 0/ E O T. 
2. 1. 2.  
Sec o n d ar y O bjecti ves 
I n s u bjects u n der g oi n g cat heter a blati o n of A F, t o c o m pare descri pti vel y t he e d o xa ba n gr o u p 
a gai nst t he V K A gr o u p, wit h re gar ds t o t he i nci de nce of t he f oll o wi n g effic ac y e n d p oi nts  as liste d 
bel o w: 
 C o m p osite of all-ca use deat h, str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d, acc or di n g 
t o alter nati ve defi niti o n (1 ); see Secti o n 7. 4. 2 . f or details) a n d Maj or Blee di n g [I S T H 
defi niti o n] 
 C o m p osite of str o ke (isc he mic, he m orr ha gic , or u n deter mi ne d), S E E, a n d C V m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha g ic, or u n deter mi ne d) S E E, a n d all-ca use 
m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) a n d TI A 
 Str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Str o ke (isc he mic) 
 Str o ke ( he m orr ha gic) 
 Str o ke ( u n deter mi ne d) 
 S E E 
 TI A 
 Fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n-fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Disa bli n g str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n- disa bli n g str o ke (isc he mic,  he m orr ha gic, or u n deter mi ne d) 


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T o c o m pare descri pti vel y t he e d o xa ba n gr o u p a gai nst t he V K A gr o u p, wit h re gar ds t o t he i nci de nce 
of t he f oll o wi n g s afet y e n d p oi nts as liste d bel o w: 
 Maj or Blee di n g ( defi ne d b y T hr o m b ol ysis i n  M y ocar dial I nfarcti o n [ TI MI], Blee di n g 
Aca de mic Researc h C o ns orti u m [ B A R C] ( 2 or hi g her)) 
 Maj or a n d Cli nicall y Rele va nt N o n- Ma j or ( C R N M) Blee di n g (I S T H defi niti o n) 
 C R N M Blee di n g (I S T H defi niti o n) 
 Mi n or Blee di n g (I S T H defi niti o n) 
 A n y Blee di n g 
 I ntracra nial he m orr ha ge (I C H) 
 Life-t hreate ni n g blee di n g 
 Fatal Maj or Blee di n g (I S T H defi niti o n) 
 N o n-fatal Maj or Blee di n g (I S T H defi niti o n) 
 Fatal Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or hi g her]) 
 N o n-fatal Maj or Blee di n g ( defi ne d  b y TI MI, B A R C [ 2 or hi g her]) 
 Safet y para meters s uc h as A Es, seri o us a d verse e ve nts ( S A Es), la b orat or y para meters, 
electr ocar di o gra m ( E C G) a n d vital si g ns. 
2. 1. 3.  
Ot her O bjecti ves  
T o  c o m pare  descri pti vel y  t he  e d o xa ba n  gr o u p  a gai nst  t he  V K A  gr o u p,  wit h  re gar ds  t o  t he  
f oll o wi n g:  
 Rele va nt Healt h Ec o n o mics O utc o me Researc h ( H E O R) para meters: 
o  N u m ber of s u bjects wit h ca n cellati o n of t he a blati o n pr o ce d ure d ue t o i na de q uate 
a ntic oa g ulati o n 
o  N u m ber of h os pital a d missi o ns d ue t o C V ca uses ( be y o n d a blati o n pr oce d ure), 
i ncl u di n g b ut n ot li mite d t o o verall, f or blee di n g, S E E, ve n o us t hr o m b osis, etc. 
( Re mar k:   H os pital a d missi o ns d ue t o C V ca uses i ncl u de, b ut are n ot li mite d t o 
E mer ge nc y De part me nt ( E D), I nte nsi ve Care U nit (I C U), C V war d.) 
o  Mea n le n gt h of sta y ass ociate d wit h t he differe nt t y pe of h os pital a d missi o ns, s uc h 
as E D, I C U a n d C V war ds 
o  A d diti o nal o ut patie nt p h ysicia n or n urse visits t hat are C V e ve nt relate d o utsi de 
sc he d ule d visits as defi ne d b y st u d y pr ot oc ol 
 Sile nt cere bral lesi o ns as defi ne d b y diff usi o n wei g hte d ma g netic res o na nce i ma gi n g 
( D W- M RI) p ost a blati o n pr oce d ure (at preselecte d ce nters) 
 Car diac mar kers. 


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3.  
S T U D Y D E SI G N 
3. 1.  
O ver all Pl a n 
T his  is  a  m ulti nati o nal,  pr os pecti ve,  ra n d o m ize d,  o pe n-la bel,  bli n de d  e n d p oi nt  e val uati o n  
( P R O B E) parallel gr o u p p hase 3 b st u d y c o m pari n g e d o xa ba n vs. V K A i n s u bjects u n der g oi n g 
cat heter a blati o n of n o n- val v ular A F. I n all s u bjec ts ke y de m o gra p hic a n d ris k c haracteristics of 
b ot h str o ke a n d blee di n g (f or e xa m ple, C H A 2D S 2- V A Sc sc ore, H A S- B L E D, t y pe of A F, prese nce 
of c or o nar y arter y disease ( C A D), heart fail ure ( H F), dia betes mellit us ( D M), a n d h y perte nsi o n) 
will be c ollecte d.  
It is pla n ne d t o e nr oll a p pr o x. 5 6 0 s u bjects at 7 5 st u d y sites l ocate d i n Ca na da, E ur o pe ( Bel gi u m, 
Czec h Re p u blic, Fra nce, Ger ma n y, H u n gar y, Ital y,  Net herla n ds, P ola n d, S pai n, U nite d Ki n g d o m), 
K orea, a n d Tai wa n t o ac hie ve a p pr o x. 4 5 0 s u bjects u n der g oi n g t he cat heter a blati o n pr oce d ure 
a n d c o m pleti n g t he st u d y. E nr oll me nt is a ntici pate d t o occ ur o ver a peri o d of a p pr o xi matel y 1 6 
m o nt hs. 
S u bjects eli gi ble t o partici pate m ust pr o vi de wr itte n i nf or me d c o nse nt (I C) bef ore ra n d o mizati o n 
or a n y st u d y-s pecific pr oce d ures  are perf or me d. O nce t he i nf or me d c o nse nt f or m (I C F) has bee n 
si g ne d, eli gi ble s u bjects are ra n d o mize d wit h o ut dela y t o o ne of t he t w o st u d y ar ms ( 2: 1 e d o xa ba n 
vs. V K A)  
E nr oll me nt of s u bjects will occ ur bet wee n 2 1 t o 2 8 da ys bef ore t he car diac a blati o n pr oce d ure. 
T he baseli ne visit ma y be s plit i nt o t w o ste ps as  per l ocal re q uire me nts.  I n t he pre-a blati o n 
treat me nt peri o d, a n o pti o nal visit ma y occ ur f or th ose patie nts w h o d o n ot ha ve t he o pti o n of I N R 
meas ure me nt i n a n a m b ulat or y setti n g.   
S u bjects will be re q uire d t o ha ve  c o m plete d at least 2 1 ( u p t o + 7) da ys of a ntic oa g ulati o n wit h 
st u d y treat me nt (e d o xa ba n or V K A) pri or t o t he cat heter a blati o n visit / peri pr oce d ural visit ( Da y 
0). S u bjects ra n d o mize d t o V K A m ust be i n t he I N R ra n ge of 2. 0- 3. 0 f or t he last 1 0 da ys pri or t o 
t he cat heter a blati o n visit / peri pr oce d ural visit ( Da y 0). T his will nee d t o be d oc u me nte d b y 
fre q ue nt I N R meas ure me nts, at least o nce per wee k i n t he pre-a blati o n peri o d. O n t he da y of, or 
t he da y pri or t o, t he sc he d ule d a blati o n pr oce d ure, s u bjects I N R s h o ul d be wit hi n t he ra n ge 2. 0-
3. 0. If I N R is ≥1. 5 a n d < 2. 0 or if I N R is > 3. 0 a n d ≤3. 5 t he pr oce d ure ma y be perf or me d at t he 
I n vesti gat or’s discreti o n. Ot her wise, t he s u bject is n ot eli gi ble f or perf or mi n g t he cat heter a blati o n 
(t he s u bject will be s witc he d fr o m st u d y me dicatio n t o sta n dar d of care a n d will e nter t he 3 0- da y 
f oll o w- u p peri o d).  
Tra nses o p ha geal ec h ocar di o gra m ( T E E) or alter nati vel y i ntra-car diac ec h ocar di o gra m will be 
perf or me d bef ore cat heter a blati o n d uri n g t he h os pital sta y relate d t o t he pr oce d ure or t he da y 
bef ore t o i de ntif y p ote ntial cl ots. If T E E or t h e i ntra-car diac ec h ocar di o gra m is p ositi ve, i.e., 
s h o ws cl ots, t he a blati o n pr oce d ure will be ca ncele d a n d t he s u bject will be s witc he d fr o m st u d y 
me dicati o n t o sta n dar d of care a n d will e nter t he 3 0- da y f oll o w- u p peri o d.  
T he ra n d o mize d treat me nt re gi me ns are c o nti n ue d f or 9 0 da ys, w he n t he sc he d ule d E O T is 
reac he d. I n s u bjects ra n d o mize d t o V K A, w he n after a blati o n, t he s u bject s’ a ntic oa g ulati o n is 
m ore c o nsta nt, t he fre q ue nc y of I N R meas ure me nts  ma y be l o wer t ha n i n t he pre-a blati o n peri o d. 
H o we ver, i n t he p ost-a blati o n pe ri o d, at least m o nt hl y I N R c o ntr ols are re q uire d. S u bject cli nical 
visits are pla n ne d at 3 0, a n d 9 0 da ys after ca r diac a blati o n.  A tele p h o ne assess me nt ( pers o nal 
visit as a n alter nati ve o pti o n) will be ma de at Da y 6 0. All ra n d o mize d s u bjects w h o are o n st u d y 


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me dicati o n (st u d y e d o xa ba n or V K A) at 9 0 da ys, will ha ve a p ost-treat me nt c o ntact at 2 5- 3 5 da ys 
after t he E O T visit t o c ollect data o n c o nc o mita nt me dicati o ns, S A Es, a n d ot her safet y e ve nts of 
i nterest.  T he  o verall  d urati o n  of  s u bject  partici pati o n  fr o m  scree ni n g  t hr o u g h  f oll o w- u p  is  
t heref ore a p pr o x. 4 ½- 5 m o nt hs. 
A sc he matic prese ntati o n of t h e st u d y desi g n is pr o vi de d i n Fi g ure 3. 1.  
At Da y 9 0, t he s u bject will eit her disc o nti n ue t he treat me nt c o m pletel y or will be tra nsiti o ne d t o 
a n a vaila ble mar kete d O A C of t he I n vesti gat or’s c h oice. T he I n vesti gat or will f oll o w t he tra nsiti o n 
strate g y i n t he a p pr o ve d pr o d uct la bel.  
All i nf or mati o n m ust be ca pt ure d i n t he electr o nic case re p ort f or m (e C R F) a n d st u d y assess me nts 
are  perf or me d  acc or di n g  t o  t he  vi sit  sc he d ule  pr o vi de d  u n der  Secti o n1 6. 9 .  S u bjects  w h o  
pre mat urel y disc o nti n ue st u d y O A C ar e re q ueste d t o c o nti n ue cli nic al f oll o w- u p wit h st u d y visits 
acc or di n g t o t his sc he d ule. 
T he  st u d y  or ga nizati o n,  i ncl u di n g  t he  Cli nical  E ve nts  C o m m ittee  ( C E C),  Data  a n d  Safet y  
M o nit ori n g B oar d ( D S M B), E xec uti ve C o m mitt ee a n d Steeri n g C o m mittee are descri be d i n 
a p pe n di x Secti o n  1 6. 1. A n i n de pe n de nt D S M B re vie ws perti ne nt st u d y data t o pr otect t he safet y 
of t he s u bjects partici pati n g i n t he st u d y. 
 
Fi g ure 3. 1 St u d y Desi g n 
 
N ote: F or patie nts t o u n der g o a blati o n, I N R wa s t o be bet wee n 2. 0 t o 3. 0. If I N R was ≥1. 5 a n d 
< 2. 0 or > 3. 0 a n d ≤3. 5, a blati o n c o ul d be perf or me d at  t he I n vesti gat or’s discreti o n o nl y 
3. 2.  
Disc ussi o n of St u d y Desi g n 
T his st u d y is desi g ne d t o e val uate descri pti vel y t he safet y a n d t o e x pl ore t he efficac y of a n 
e d o xa ba n- base d a ntit hr o m b otic re gi me n vers us a V K A- base d a ntit hr o m b otic re gi me n i n s u bjects 
u n der g oi n g cat heter a blati o n of n o n - val v ular A F. A parallel gro u p desi g n wit h V K A ser vi n g as 
t he c o ntr ol ar m has bee n selecte d t o pr o vi de c o m parati ve data. 


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C o nfi de ntial 
Pa ge 3 9 of 1 0 9 
 
T he d urati o n of a ntic oa g ula nt treat me nt pri or t o cat heter a blati o n of  2 1 ( u p t o + 7) da ys is i n 
acc or da nce wit h t he E ur o pea n Heart R h yt h m Ass ociati o n ( E H R A) p ositi o n pa per ( 1 7 ), w hic h 
states ‘ All patie nts u n der g oi n g A F a blati o n w h o prese nt i n A F f or t he pr oce d ure s h o ul d be 
a ntic oa g ulate d f or at least 3 wee ks pri or t o A F a bla ti o n. If t he y ha ve n ot bee n a ntic oa g ulate d pri or 
t o  a blati o n,  a  T E E  s h o ul d  be  perf or me d.   I n  a d diti o n  t o  a d heri n g  t o  t hese  well-esta blis he d  
a ntic oa g ulati o n g ui deli nes t hat  a p pl y t o car di o versi o n, t he 2 0 1 2 H R S/ E H R A/ E C A S c o nse ns us 
d oc u me nt rec o m me n ds t hat all patie nts bei n g a ntic oa g ulate d d uri n g A F a bla ti o n wit h he pari n t o 
ac hie ve a n acti vate d cl otti n g ti me ( A C T) of at least 3 0 0 s. T his writi n g gr o u p f ull y s u p p orts t hese 
pri or mi ni m u m rec o m me n dati o ns f or a ntic oa g ula ti o n.’ Li ke wise, t he re q uire me nt f or patie nts 
treate d wit h a V K A or a N O A C t o have at least 3 wee ks of effec ti ve sta ble I N R at t hera pe utic 
le vels ( bet wee n 2 a n d 3 f or V K A) is als o i n-li ne wit h t hese rec o m me n dati o ns. T he treat me nt 
d urati o n after t he a blati o n pr oce d ure is i n-li ne wit h t he rece nt E S C g ui deli nes t hat rec o m me n d 
t hat a ntic oa g ulati o n s h o ul d be mai ntai ne d f or at least 8 wee ks after a blati o n f or all patie nts (2 ). 
T his st u d y re q uires T E E or alter n ati vel y i ntracar diac ec h ocar di o gra m  i n all patie nts t o e ns ure 
a p pr o priate a ntic oa g ulati o n i n t he 3 wee ks bef ore t he i nter ve nti o n i n b ot h ar ms. 
T he  e n d p oi nts  selecte d  are  rele va nt  f or  t he  st u d y.  Blee di n g  is  a  ce ntra l  safet y  o utc o me  i n  
car di o vasc ular cli nical trials, es peciall y f or a nti t hr o m b otic strate gies a n d i n vasi ve pr oce d ures (1 8, 
1 9, 2 0 ).  
 


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4.  
S T U D Y P O P U L A TI O N 
4. 1.  
E nr oll me nt 
I n vesti gat ors will mai ntai n a c o nfi de ntial pre-scree ni n g l o g of all p ote ntial st u d y ca n di dates t hat 
i ncl u des li mite d i nf or mati o n of t he s u bjects (a ge, se x), date a n d o utc o me of scree ni n g pr ocess 
(e. g., e nr oll i n t he st u d y, reaso n f or n ot partici pati n g). 
I n vesti gat ors will be e x pecte d t o mai ntai n a n E nr oll me nt L o g of all s u bjects e nr olle d i n t he st u d y 
i n dicati n g t heir assi g ne d st u d y n u m ber. 
I n vesti gat ors will mai ntai n a c o nfi de ntial s u bject i de ntificati o n (I D) c o de list.  T his c o nfi de ntial 
list of na mes of all s u bjects all ocate d t o st u d y n u m bers o n e nr olli n g i n t he st u d y, all o ws t he 
I n vesti gat or t o re veal t he i de ntit y of a n y s u bject w he n necessar y. 
A s u bject is c o nsi dere d t o be e nr olle d after t he I C F has bee n si g ne d. A u ni q ue st u d y I D n u m ber 
is  pr o vi de d  t hr o u g h  t he  i nteracti ve  we b/ v oice  res p o nse  s yste m  (I X R S)  t o get her  wit h  t he  
ra n d o mize d treat me nt assi g n me nt. 
4. 1. 1.  
I ncl usi o n Criteri a 
S u bjects m ust satisf y all of t he f oll o wi n g cr iteria t o be i ncl u de d i n t he st u d y: 
1.  Male or fe male at least 1 8 years of a ge wit h d oc u me nte d hist or y of par o x ys mal (lasti n g 
≤7 da ys), persiste nt (lasti n g > 7 da ys b ut ≤1 2 m o nt hs) or l o n g-sta n di n g [l o n g-lasti n g] 
persiste nt ( > 1 2 m o nt hs) n o n- val v ular A F. D urati o n of A F ca n be c o nfir me d b y a n y 
electrical traci n g or a rec o r di n g i n t he s u bject’s me dical rec or ds (e. g., me dical c hart, 
h os pital disc har ge s u m mar y). 
2.  S u bject is eli gi ble a n d is sc he d ule d f or eit h er ra di ofre q ue nc y ( R F) or cr y o ball o o n cat heter 
a blati o n ( b ot h first a n d re peate d pr oce d ure i ncl u de d).  
3.  Si g ne d I C F. 
4. 1. 2.  
E xcl usi o n Criteri a 
S u bjects w h o meet a n y of t he f oll o wi n g criteria  will be dis q ualifie d fr o m e nteri n g t he st u d y: 
1.  A F c o nsi dere d t o be of a tra nsie nt or re ve rsi ble nat ure (s uc h as i n m y ocar ditis, p ost-
s ur ger y, i o nic dist ur ba nces, t h yr ot o xic osis, p ne u m o nia, se vere a ne mia etc.). 
2.  S u bject p ost str o ke, or wit h a s yste mic t hr o m b oe m b olic e ve nt wit hi n t he past 6 m o nt hs 
pri or t o ra n d o mizati o n.  
3.  S u bject has a t hr o m b us i n t he left atrial a p pe n da ge ( L A A), left atri u m ( L A), left ve ntricle 
( L V), or a orta, or a n i ntracar dial mass. 
4.  S u bject ha d a m y ocar dial i nfarcti o n ( MI) wit hi n  t he 2 m o nt hs pri or t o ra n d o mizati o n or 
c or o nar y arter y b y pass graft ( C A B G) s u r ger y wit hi n 3 m o nt hs pri or t o t he 
ra n d o mizati o n. 
5.  S u bject has si g ns of blee di n g, hist or y of cli nicall y-rele va nt blee di n g acc or di n g t o I S T H, 
or c o n diti o ns ass ociate d wit h hi g h ris k of bl ee di n g s uc h as past hi st or y of i ntracra nial 
(s p o nta ne o us or tra u matic), or s p o nta ne o us i ntra oc ular, s pi nal, retro perit o neal, or i ntra-


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artic ular blee di n g; o vert gastr o i ntesti nal ( GI) blee di n g or acti ve ulcer wit hi n t he pre vi o us 
year; rece nt se vere tra u ma, maj or s ur ger y, or dee p or ga n bi o ps y; acti ve i nfecti ve 
e n d ocar ditis; u nc o ntr olle d h y perte nsi o n ( bl o o d press ure [ B P] a b o ve 1 7 0/ 1 0 0 m m H g); or 
he m orr ha gic dis or der i ncl u di n g k n o w n or s us p ecte d here ditar y or ac q uire d blee di n g or 
c oa g ulati o n dis or der i n t he last 1 2 m o nt hs pri or t o ra n d o mizati o n.  
6.  S u bjects wit h mec ha nical heart val ves, s u bjects  wit h m o derate t o se vere mitral ste n osis 
a n d s u bjects w h o ha ve ne w i m pla ntati o n ( wit hi n 3 m o nt hs pri or t o ra n d o mizati o n) of a 
bi o pr ost hetic heart val ve, wit h or wit h o ut A F.  
7.  S u bjects wit h a hist or y of L A A occl usi o n/ e xcl usi o n (eit her b y s ur ger y or b y a 
pr oce d ure). 
8.  S u bjects wit h a n y c o ntrai n dicati o n f or e d o xa ba n, V K A, l o w m olec ular wei g ht he pari n 
( L M W H), he pari n t hera p y i ncl u di n g k n o w n aller gies, h y perse nsiti vit y, or i nt olera nce t o 
a n y c o m p o ne nt of t hese dr u gs or its e xci pie nts. 
9.  S u bjects recei vi n g d ual a nti platelet t h era p y ( D A P T, i.e., as piri n a n d P 2 Y 1 2 a nta g o nist) or 
pla n ne d t o recei ve D A P T d uri n g t he st u d y 
1 0.  U nfracti o nate d he pari n ( U F H), l o w m olec ula r wei g ht he pari ns ( L M W H; e n o xa pari n, 
dalte pari n, etc.), he pari n deri vati ves (f o n da pari n u x, etc.), a n d oral a ntic oa g ula nts 
( warfari n, da bi gatra n ete xilate, ri var o xa ba n, a pi xa ba n etc.) ca n n ot be use d c o nc o mita ntl y 
t o st u d y me dicati o n. A n y bri d gi n g wit h L M W H ar o u n d t he C A pr oce d ure is pr o hi bite d. 
D uri n g t he C A pr oce d ure, U F H will be use d acc or di n g t o sta n dar d of care t o ac hie ve 
A C T of 3 0 0 t o 4 0 0 sec. S u bjects w h o re q uire  c hr o nic use of me dici nes affecti n g 
he m ostasis s uc h as hi g her d oses of as piri n (acet ylsalic ylic aci d [ A S A]) ( A S A u p t o 1 0 0 
m g per da y all o we d) or c hr o ni c oral or pare nteral i nta ke of n o n-as piri n n o n-ster oi dal 
a nti-i nfla m mat or y dr u gs ( N S AI D) o n ≥4 da ys/ wee k ( use of N S AI Ds via ot her r o utes is 
n ot restricte d) 
1 1.  S u bjects wit h acti ve li ver diseas e or persiste nt (c o nfir me d b y re peat assess me nts at least 
a wee k a part) ele vati o n of li ver e nz y mes/ bilir u bi n: 
―  Ala ni ne tra nsa mi nase ( A L T) or as partate tra nsa mi nase ( A S T) ≥2 ti mes t he u p per li mit 
of n or mal ( U L N) 
―  T otal bilir u bi n ( T B L) ≥1. 5 ti mes t he U L N (s u bjects w h ose ele vate d T B L is d ue t o 
k n o w n Gil bert’s s y n dr o me ma y be i ncl u de d i n t he st u d y) 
―  He patic disease ass ociate d wit h c oa g ul o pat h y a n d cli nicall y rele va nt blee di n g ris k.  
1 2.  S u bjects wit h ki d ne y fail ure (calc ulate d cr eati ni ne cleara nce [ Cr C L] < 1 5 m L/ mi n). 
1 3.  S u bjects wit h he m o gl o bi n < 1 0 g/ d L or platelet c o u nt < 1 0 0, 0 0 0 cells/ µ L or w hite bl o o d 
cell ( W B C) c o u nt < 3 0 0 0 cells/ µ L. 
1 4.  S u bjects wit h pre- pla n ne d i n vasi ve dia g n osti c or t hera pe utic pr oce d ures/i nter ve nti o ns 
( ot her t ha n e n d osc o p y) d uri n g t he st u d y peri o d i n w hic h blee di n g is a ntici pate d. 
1 5.  Partici pati o n i n a n y ot her i nter ve nti o nal trial (s u bjects w h o recei ve d a n y i n vesti gati o nal 
dr u g or de vice wit hi n 3 0 da ys pri or t o ra n d o mizati o n, or pla n t o recei ve s uc h 
i n vesti gati o nal t hera p y d uri n g t he st u d y peri o d). 


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1 6.  Pre vi o us ra n d o mizati o n i n t his st u d y. 
1 7.  Fe male s u bjects of c hil d beari n g p ote ntial w it h o ut usi n g hi g hl y effecti ve c o ntrace pti o n 
(fe male of c hil d beari n g p ote ntial is defi ne d as o ne w h o ha s n ot bee n p ost me n o pa usal f or 
at least o ne year, or has n ot bee n s ur gicall y  sterilise d, or has n ot ha d a h ysterect o m y at 
least t hree m o nt hs pri or t o t he start of t his st u d y). Fe males ta ki n g oral c o ntrace pti ves 
s h o ul d ha ve bee n o n t hera p y f or at least t hree m o nt hs. A de q uate  c o ntrace pti ves i ncl u de: 
C o m bi ne d (estr o ge n a n d pr o ge st o ge n c o ntai ni n g) oral, i ntra va gi nal or tra ns der mal 
h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n; pr o gest o ge n- o nl y oral, 
i njecta ble or i m pla nta ble h or m o nal c o ntrace pti o n ass ociate d wit h in hi biti o n of o v ulati o n; 
i ntra uteri ne de vice (I U D); i ntra uteri ne h or m o ne-releasi n g s yste m (I U S); bilateral t u bal 
occl usi o n; vasect o mize d part ner; se x ual a bsti ne nce. 
1 8.  Pre g na nt or breast- fee di n g s u bjects. 
1 9.  S u bjects wit h t he f oll o wi n g dia g n oses or sit uati o ns: 
- 
Acti ve ca ncer u n der g oi n g c he m ot hera p y, ra diati o n or maj or s ur ger y wit hi n t he ne xt 5 
m o nt hs 
- 
Si g nifica nt acti ve/ u nc o ntr olle d c o nc urre nt me dical ill ness 
- 
Life e x pecta nc y < 6 m o nt hs. 
2 0.  S u bjects w h o are u nli kel y t o c o m pl y wit h t he pr ot oc ol (e. g., u nc o o perati ve attit u de, 
i na bilit y t o ret ur n f or s u bse q ue nt visits, an d/ or ot her wise c o nsi dere d b y t he I n vesti gat or 
t o be u nli kel y t o c o m plete t he st u d y). 
2 1.  S u bjects wit h a k n o w n dr u g or alc o h ol de pe n de nce wit hi n t he past 1 2 m o nt hs pri or t o 
ra n d o mizati o n as j u d ge d b y t he I n vesti gat or. 
2 2.  S u bjects wit h a n y c o n diti o n t hat, i n t he o pi ni o n of t he I n vesti gat or, w o ul d place t he 
s u bject at i ncrease d ris k of har m if he/s he partici pate d i n t he st u d y. 
2 3.  Pla n ne d pr oce d ure usi n g laser cat heter a bla ti o n or ot her f or ms of cat heter a blati o n 
differe nt fr o m R F or cr y o ball o o n (i.e. hi g h i nte nsit y f oc use d ultras o u n d [ HI F U], 
micr o wa ves, h ot ball o o n, etc). 
4. 2.  
Scree ni n g F ail ures 
S u bjects are scree ne d base d o n t he i nf or mati o n a v aila ble fr o m t he sta n dar d care. F or s u bjects 
f ulfilli n g t he eli gi bilit y criteria, si g nat ure of t he I C F m ust ta ke place bef ore a n y st u d y-s pecific 
scree ni n g pr oce d ures occ ur. A s u bject w h o with dra ws I C bef ore ra n d o mizati o n or w h o fails t he 
i ncl usi o n/e xcl usi o n criteria bef ore ra n d o mizati o n is defi ne d as a scree ni n g fail ure. N o f urt her 
cli nical f oll o w- u p is perf or me d f or t hese s u bjects. 
If s u bjects fail t he scree ni n g pr oced ure, i n vesti gat ors ca n disc uss w it h t he me dical m o nit or if t he y 
feel a s u bject mi g ht be s uita ble f or rescree ni n g.  


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5.  
S T U D Y T R E A T M E N T S 
5. 1.  
Met h o d of Assi g ni n g S u bjects t o Tre at me nt Re gi me ns 
5. 1. 1.  
Tre at me nt Gr o u ps  
 E d o xa ba n 6 0 m g o nce- dail y or 3 0 m g o nce- da il y i n selecte d s u bjects (see Secti o n 
5. 2. 1. 2 ). 
 Oral V K A, as pre- defi ne d pe r c o u ntr y, wit h o nce- dail y d osi n g f or tar get I N R bet wee n 
2. 0- 3. 0, i ncl usi ve. 
 
T he V K A pr e- defi ne d f or t he vari o us  c o u ntries are s h o w n bel o w: 
C o u ntr y 
Pre- defi ne d V K A 
Bel gi u m 
P he n pr oc o u m o n & Warfari n 
Ca na da
 Warfari n
 
Czec h Re p u blic 
Warfari n 
Fra nce
 Fl ui n di o ne
 
( Pre visca n ®)
Ger ma n y
 P he n pr oc o u m o n
 
H u n gar y
 Warfari n
 
Ital y
 Warfari n
 
K orea
 Warfari n
 
Net herla n ds
 P he n pr oc o u m o n
 
P ola n d
 Warfari n
 
S pai n
 Ace n oc o u mar ol
 
( Si ntr o m ®)
Tai wa n
 Warfari n
 
U nite d Ki n g d o m 
Warfari n 
 
5. 1. 2.  
Met h o d of Tre at me nt All oc ati o n 
After t he I C has bee n si g ne d a n d eli gi bilit y c o nfir me d, t he I n vesti gat or c o ntacts t he I X R S t o 
re gister a ne w s u bject a n d assig n a n i n di vi d ual st u d y I D n u m ber. 


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T he I n vesti gat or s h o ul d be pre pare d t o pr o vi de  s u bject i nf or mati o n, i ncl u di n g, b ut n ot li mite d t o: 
date of I C, s u bject’s ye ar of birt h, a n d ge n der. 
T he n t he I n vesti gat or c o ntacts I X R S t o ra n d o mize s u bject i nt o t he st u d y. T he i n vesti gat or s h o ul d 
be pre pare d t o c o nfir m t he s u bj ect’s eli gi bilit y criteria a n d i nf or mati o n a b o ut b o d y wei g ht, a n d 
Cr C L usi n g C oc kcr oft- Ga ult (i n t h e c o urse of t he st u d y, ot her f or m ula will als o be use d, e. g., 
C K D- E PI E q uati o n; see Secti o n 1 6. 6 ). Als o t he i n vesti gat or will be as ke d t o pr o vi de i nf or mati o n 
w het her t he s u bject is ta ki n g c o nc o mita nt P- g p i n hi bit ors re q uiri n g e d o xa ba n d ose re d ucti o n ( or 
ot her d ose re d ucti o n rele va nt me di cati o n acc or di n g t o l ocal la bell i n g or I B, as a p plica ble). 
S u bjects will be assi g ne d ra n d o ml y via t he a b o ve me nti o ne d I X R S s uc h t hat t he st u d y has a 2: 1 
rati o of s u bjects i n t he e d o xa ba n: V K A treat me nt ar ms. 
T he s pecificati o ns f or ge nerati o n of t he ra n d o m izati o n sc he d ule will be pre pare d b y t he st u d y 
bi ostatisticia n a n d t he I X R S ve n d or. A n i n de pe n de nt  bi ostatisticia n, n ot ot her wise part of t he 
st u d y tea m, will ge nerate t he ra n d o mizati o n sc he d ule.  F or t his st u d y, t he ra n d o mizati o n sc he d ule 
refers  t o  a  list  t hat  i ncl u des  at  least  t he  s u bject  I D,  ra n d o mizat i o n  bl oc k  n u m ber,  a n d  
ra n d o mizati o n treat me nt.  
5. 1. 3.  
Bli n di n g 
T his is a n o pe n-la bel st u d y w it h bli n de d e n d p oi nt e val uati o n. 
 
5. 2.  
St u d y Dr u gs 
5. 2. 1.  
E d o x a b a n 
All dis pe nsati o ns m ust ta ke place t hr o u g h t he I X R S, w hic h will pr o vi de t he a p pr o priate dr u g 
s u p pl y kit n u m ber. 
5. 2. 1. 1.  
Descri pti o n 
E d o xa ba n  t os ylate  ( D U- 1 7 6 b,  tra de  na mes  Li xi a na ®,  Sa va ysa ®),  re ferre d  t hr o u g h o ut  t his  
pr ot oc ol b y t he ter m “e d o xa ba n” f or si m plicit y. Please refer t o Secti o n 5. 3 . 
I m p orta ntl y, it is ma n dat or y i n t his st u d y t hat i n t he pre-a blati o n peri o d, t he o nce- dail y d ose of 
e d o xa ba n is ta ke n e ver y da y i n t he e ve ni n g. Patie nts will be i nstr ucte d t o s wall o w t he ta blet, 
prefera bl y wit h water. E d o xa ba n ca n  be ta ke n wit h or wit h o ut f o o d (7 ). 
If a d ose of e d o xa ba n is misse d, t he d ose m ust be ta ke n as s o o n as p ossi ble as l o n g as o n t he sa me 
da y. T he d ose of e d o xa ba n m ust n ot be d o u ble d t o ma ke u p f or a misse d d ose. 
5. 2. 1. 2.  
D ose 
T he d ose of e d o xa ba n is 6 0 m g o nce- dail y b ut will be re d uce d t o 3 0 m g o nce- dail y, if t he s u bject 
has o ne of t he f oll o wi n g:   
- 
M o derate t o se vere re nal i m pair me nt ( Cr C L ≥1 5 t o ≤5 0 m L/ mi n as calc ulate d 
usi n g t he C oc kcr oft- Ga ult f or m ula 
- 
L o w b o d y wei g ht ( ≤6 0 k g) 






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Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
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5. 2. 2.  
Vit a mi n K A nt a g o nist  
All V K A m ust be dis pe nse d via t he I X R S t hat  will pr o vi de t he a p pr o priate dr u g s u p pl y kit 
n u m ber.  
5. 2. 2. 1.  
D ose 
T he I n vesti gat or m o nit ors t he I N R a n d a dj usts t he V K A d ose t o mai ntai n t he I N R wit hi n tar get. 
It is t he I n vesti gat or’s res p o nsi bilit y t o c ollect I N R assess me nts a n d rec or d t hese t hr o u g h o ut t he 
st u d y.  A preferre d V K A is selecte d f or eac h partici pati n g c o u ntr y (f or m ore  details, please refer 
t o Secti o n 5. 1. 1 ) w hic h is pr o vi de d as st u d y me dicati o n: 
―  W arf ari n  
L oa di n g d ose fr o m 2- 5 m g o nce- dail y f or 2- 4 da ys f oll o we d b y a mai nte na nce d ose of 
2- 1 0 m g o nce- dail y a dj uste d b y I N R val ues  t o mai ntai n tar get I N R bet wee n 2. 0- 3. 0 
i ncl usi ve. 
―  P he n pr oc o u m o n  
Wee kl y d ose calc ulati o n of u p t o 9 m g o n Da y 1, 6 m g o n Da y 2 a n d mai nte na nce d oses 
bet wee n 1. 5- 6. 0 m g o nce- dail y t hereafter, a dj ust e d b y I N R val ues t o mai ntai n tar get I N R 
bet wee n 2. 0- 3. 0 i ncl usi ve. 
―  Fl ui n di o ne  
T he i nitial dail y d ose of 2 0 m g is a dj uste d b y I N R val ues t o mai ntai n tar get I N R bet wee n 
2. 0- 3. 0 i ncl usi ve. I n s u bjects at partic ular ris k of blee di n g ( wei g ht < 5 0 k g, el derl y, 
he patic i m pair me nt), t he i nitial d ose is us uall y l o wer. N o l oa di n g d ose s h o ul d be use d. 
T he d ose a dj ust me nt is perf or me d i n acc or da nce t o t he pac ka ge i nsert a n d us uall y b y 
i ncre me nts of 5 m g ( 1/ 4 ta blet). 
―  Ace n oc o u m ar ol  
T he us ual starti n g d ose i n a n or mal wei g ht pers o n is bet wee n 2- 4 m g/ da y wit h o ut 
a d mi nistrati o n of a l oa di n g d ose, if t he I N R va l ue bef ore t he start of treat me nt is wit hi n 
t he n or mal ra n ge. Treat me nt ma y als o be i nitiate d wit h a l oa di n g d ose re gi me n, us uall y 
6 m g o n t he first da y f oll o we d b y 4 m g o n t he sec o n d da y. T he mai nte na nce d ose 
ge nerall y lies bet wee n 1- 8 m g o nce- dail y, a dj uste d b y I N R val ues t o mai ntai n tar get I N R 
bet wee n 2. 0- 3. 0 i ncl usi ve. 
T he d osi n g of t he af ore me nti o ne d V K As m ust be i n di vi d ualize d. T he mai nte na nce d ose varies 
fr o m s u bject t o s u bject a n d its a p pr o priate ness m ust be c hec ke d i n di vi d uall y o n basis of I N R 
val ues. 
S u bjects will ta ke t he V K A acc or di n g t o  t he directi o n of t he I n vesti gat or. 
T he I n vesti gat or or desi g nee is res p o nsi ble f o r dis pe nsi n g t he V K A a nta g o nist a n d m ust e ns ure 
t hat dr u g s u p plie d b y S p o ns or is use d i n acc or da nce wit h t he pr ot oc ol a n d t he V K A pac ka ge i nsert.  


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Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 4 8 of 1 0 9 
 
5. 2. 2. 2.  
Tr a nsiti o ni n g t o St u d y Vit a mi n K A nt a g o nist at R a n d o miz ati o n 
S u bjects are tra nsiti o ne d t o a n a vaila ble st u d y V K A (c o u ntr y s pecific as pr o vi de d b y I X R S, see 
Secti o n 5. 1. 1 . f or details). T he I n vesti gat or will f oll ow t he tra nsiti o n strate g y i n t he a p pr o ve d 
pr o d uct la bel.  
F or  s u bjects  n ot  pre vi o usl y  o n  V K A,  c o m m o nl y  i nitial  d oses  of  V K A  are  hi g her  t ha n  t he  
mai nte na nce d oses w hic h will be use d after t he I N R is sta bilize d. F or t hese s u bjects bri d gi n g wit h 
pare nteral a ntic oa g ulati o n is per missi ble.  F or i nitiati o n of V K A t hera p y an d relate d bri d gi n g wit h 
pare nteral  a ntic oa g ulati o n,  f oll o w  l ocall y  esta blis he d  g ui deli nes  a n d  l ocal  a p pr o ve d  la bel  
( prescri bi n g i nf or mati o n) fro m t he V K A ma n ufact urer. 
F or s u bjects ra n d o mize d t o  V K A: If s u bject is o n: 
 V K A, c o nti n ue wit h st u d y V K A w he n I N R ≤2. 5. 
 N O A C, disc o nti n ue t he N O A C a n d start st u d y V K A at t he ti me of t he ne xt sc he d ule d 
N O A C d ose. 
F or s u bjects ra n d o mize d t o V K A w h o re q uire s witc hi n g fr o m a n ot her a ntic oa g ula nt (a n ot her V K A, 
ot her n o n- V K A O A C dr u gs or pare nt eral a ntic oa g ula nts), f oll o w t he g ui da nce f or s witc hi n g i n t he 
l ocall y a p pr o ve d la bels of t hese pr o d ucts. Ca pt ure t he date a n d ti mi n g of first st u d y d ose i n e C R F. 
5. 2. 2. 3.  
I nter n ati o n al N or m alize d R ati o M a n a ge me nt 
E ver y atte m pt will be ma de t o bri n g s u bjects i nt o  t he t hera pe utic tar get ra n ge (I N R 2. 0- 3. 0) as 
fast as p ossi ble a n d t o mai ntai n t he tar get I NR ra n ge c o nsiste ntl y. Cl ose atte nti o n t o t he I N R 
ma na ge me nt pla n a n d fre q ue nt m o nit ori n g of I N R val ues is str o n gl y r ec o m me n de d t o o pti mize 
t he  V K A  treat me nt  a n d  mai ntai n  t he  s u bject’s  I N R  val ues  bet wee n  2. 0- 3. 0  i ncl usi ve.   T he  
I n vesti gat or  will  e ns ure  t he  V K A  is  use d  acc or di n g  t o  t he  a p pr o ve d  la bel  ( prescri bi n g  
i nf or mati o n). 
Fre q ue nt I N R deter mi nati o ns u p o n i nitiati o n s h o ul d  be o btai ne d u ntil s u bject’s I N R is sta ble i n 
t he t hera pe utic ra n ge. It is e x pecte d t hat m ore fre q ue nt visits will be pla n ne d f or ‘ de n o v o’ s u bjects 
o n V K A t o a dj ust t he d ose wit h t he g oal of reac h i n g I N R 2. 0- 3. 0 wit hi n 6- 8 da ys after e nr ol me nt. 
O btai n s u bse q ue nt I N R deter mi nati o ns as per rec o m me n dati o ns a n d g ui deli nes pr o vi de d i n t he 
l ocal a p pr o ve d la bel fr o m t he res pecti ve V K A ma n ufact urer. 
Bef ore a blati o n, eac h s u bject m ust be i n t he I N R ra n ge of 2. 0- 3. 0 f or t he last  1 0 da ys pri or t o t he 
cat heter a blati o n. T his will nee d t o be d oc u me nte d b y fre q ue nt I N R meas ure me nts, at least o nce 
per wee k i n t he pre-a blati o n peri o d. O n t he da y of, or t he da y pri or t o, t he sc he d ule d a blati o n 
pr oce d ure, s u bjects I N R s h o ul d be wit hi n t he ra n ge 2. 0- 3. 0. If I N R is ≥1. 5 a n d < 2. 0 or if I N R is 
> 3. 0 a n d ≤3. 5 t he pr oce d ure ma y be perf or me d at t he I n vesti gat or’s discreti o n.  
After  a blati o n,  w he n  t he  s u bjects’  a ntic oa g ula ti o n  is  m ore  c o nsta nt,  t he  fre q ue nc y  of  I N R  
meas ure me nts ma y be l o wer t ha n i n t he pre-a bla ti o n peri o d. H o we ver, i n t he p ost-a blati o n peri o d, 
at least m o nt hl y I N R c o ntr ols are re q uire d. 
I N R val ues a n d V K A d ose are c ollecte d eit her d uri n g t he o n-site vi sits or b y l ocal la b orat or y 
deter mi nati o n. I N R val ues a n d V K A d oses c ollecte d  t hr o u g h t he ge neral practiti o ner or l ocal 
a ntic oa g ulati o n cli nic m ust als o be c o nsi dere d a n d c ollecte d b ut t his d oes n ot c o nstit ute a wai ver 
f or s u bjects’ pla n ne d I N R deter mi nati o n d uri n g o n-site visits. I n a n y case t he st u d y p h ysicia n is 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 4 9 of 1 0 9 
 
res p o nsi ble f or c hec ki n g t he I N R val ue, a da ptin g t he V K A d ose acc or di n gl y, a n d f or e nteri n g all 
t he data i nt o t he e C R F. 
5. 2. 2. 4.  
Tr a nsiti o n fr o m Vit a mi n K A nt a g o nist at E n d of Tre at me nt 
S u bjects  are  tra nsiti o ne d  t o  a n  a vaila ble  mar k ete d  O A C  of  t he  I n vesti gat or’s  c h oice.  T he  
I n vesti gat or  will  f oll o w  t he  tra nsiti o n  strate g y i n  t he  a p pr o ve d  pr o d uct  la bel.  S u bjects  w h o  
pre mat urel y disc o nti n ue st u d y O A C ar e re q ueste d t o c o nti n ue cli nic al f oll o w- u p wit h st u d y visits 
acc or di n g t o t his sc he d ule. 
 
5. 2. 3.  
I nterr u pti o ns a n d Disc o nti n u ati o ns of St u d y Tre at me nt 
T he i nte n de d d urati o n of t he t w o st u d y treat me nts after a blati o n is 9 0 da ys. S u bjects sta y o n t he 
assi g ne d re gi me n as m uc h as p ossi ble. 
Per ma ne nt  disc o nti n uati o n  of  t he  assi g ne d  re gi me n  is  ma n dat or y  if  t he  Cr C L  falls  bel o w  
1 5 m L/ mi n o n t w o c o nsec uti ve occasi o ns  or if s u bject is place d o n dial ysis. If t he I n vesti gat or 
d o u bts t he acc urac y of t he Cr C L val ue calc ulate d wit h t he C oc kcr oft- Ga ult f or m ula, he/s he ma y 
c o nsi der calc ulati n g Cr C L usi n g a 2 4- h o ur uri n e c ollecti o n, f or c o nfir mat or y p ur p oses. If a 
s u bject’s Cr C L, calc ulate d wit h eit her t he C oc kcr oft- Ga ult f or m ula or 2 4- h o ur uri ne c ollecti o n, 
rec o vers t o ≥1 5 m L/ mi n, t he s u bject s h o ul d res u me st u d y re gi me n i n li ne wit h t he a p plica ble 
la bels. 
F or s u bjects wit h a s us pecte d tra nsie nt decreas e i n Cr C L < 1 5 m L/ mi n it is rec o m me n de d t hat 
re peat testi n g of Cr C L occ ur after c orrecti ve acti o n is ta ke n or w he n t he me dical c o n diti o n t hat 
ca use d t he w orse ni n g re nal f u ncti o n  res ol ves. T he ti mi n g of t he re peat testi n g is at t he discreti o n 
of t he I n vesti gat or a n d will var y de pe n di n g o n t he nat ure of t he me dical c o n diti o n (e. g., 1- 2 wee ks 
f or uri nar y tract i nfecti o n or o ver di uresis vs. se veral wee ks t o m o nt hs f or gl o mer ul o ne p hritis). 
If ot her cli nical c o ntrai n dicati o ns f or a n y st u d y me dicati o n de vel o p (acc or di n g t o t he la bel of t he 
res pecti ve dr u g), t he st u d y me dicatio n m ust be disc o nti n ue d ( or d ose decrease d if a p plica ble). If 
t he  c o ntrai n dicati o n  res ol ves,  t he  res pecti ve  st u d y  me dicati o n  is  restarte d.  D uri n g  eac h  
i nterr u pti o n of a ntic oa g ula nt t hera p y, s u bjects are e val uate d t o deter mi ne w het her t he s u bject ca n 
safel y res u me t he st u d y dr u g. A p ost-ra n d o mizati o n c ha n ge i n healt h stat us  t hat res ults i n t he 
s u bject  meeti n g  o ne  or  m ore  of  t he  e xcl usi o n  criteria  s h o ul d  o nl y  lea d  t o  i nterr u pti o n  or  
disc o nti n uati o n  of  t he  assi g ne d  me dicati o ns  if  t he  c ha n ge  i n  healt h  stat us  i m plies  a  
c o ntrai n dicati o n acc or di n g t o t he dr u g la bels. 
St u d y  me dicati o ns  are  per ma ne ntl y  disc o nti n ue d  if  t he  s u bject  ref uses  c o nti n uati o n  of  a n y  
me dicati o n i n t he assi g ne d st u d y re gi me ns.  
All st u d y me dicati o n start a n d st o p  dates are ca pt ure d i n e C R F t o get her wit h t he reas o n f or 
i nterr u pti o n or disc o nti n uati o n. 
 
5. 3.  
L a beli n g a n d P ac k a gi n g 
T he I n vesti gat ors/st u d y c o or di nat ors m ust e ns ure  t hat t he a p pr o priate fiel ds o n t he la bel are 
c o m plete d, i ncl u di n g u ni q ue s u bject I D a n d i nitials. 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 5 0 of 1 0 9 
 
T he I n vesti gat or pr o vi des t he s u bjects wit h s ufficie nt st u d y me dicati o ns t o last u ntil t he ne xt 
sc he d ule d dis pe nsi n g visit. 
E d o xa ba n is s u p plie d as 3 0 or 6 0 m g  fil m c oate d ta blets ( 3 0 m g or 1 5 m g as tra nsiti o n me dicati o n 
if a p plica ble) f or oral use a n d will be pr o vi de d t o all sites via I X R S. Materials are s u p plie d a n d 
la belle d wit h a si n gle pa nel m ultili n g ual b o o klet. 
V K A me dicati o n f or oral use a n d will be pr o vi de d t o all sites via I X R S. Materials are s u p plie d 
a n d la belle d wit h a si n gle pa nel m ultili n g ual b o o kl et. T he S p o ns or will pr o vi de a n oral preferre d 
V K A as pre-selecte d b y c o u ntr y, bei n g eit her: 
- 
W arf ari n  s u p plie d as c o m merciall y a vaila ble ta blets of 1 m g, a n d 2. 5 m g i n wallets wit h 
blisters. 
- 
P he n pr oc o u m o n  s u p plie d as c o m merciall y a vaila ble ta blets of 3 m g stre n gt h i n wallets wit h 
blisters. 
- 
Fl ui n di o ne  s u p plie d as c o m merciall y a vaila ble ta blets of 2 0 m g stre n gt h i n wallets wit h 
blisters. Fl ui n di o ne s u p pl y is e xcl usi ve t o Fra nce a n d will n ot be a vaila ble i n ot her 
partici pati n g c o u ntries. Fl ui n di o n e is o nl y la belle d i n Fre nc h. 
- 
Ace n oc o u m ar ol  s u p plie d as c o m merciall y a vaila ble ta blets of 4 m g stre n gt h i n wallets wit h 
blisters. 
 
5. 4.  
Pre p ar ati o n 
All i n vesti gati o nal pr o d ucts will be s u p plie d as ta blets t hat nee d n o f urt her pre parati o n at t he sites. 
 
5. 5.  
A d mi nistr ati o n 
E d o xa ba n will be a d mi nistere d i n acc or da nce wit h t he l ocal la bel or I B, a n d V K A will be 
a d mi nistere d i n acc or da nce wit h t he a p pr o ve d l ocal la bel. 
 
5. 6.  
St or a ge 
W he n a dr u g s hi p me nt is recei ve d, t he I n vesti gat or or desi g nee will d o t he f oll o wi n g wit hi n 
4 8 h o urs of recei pt: c hec k t he a m o u nt a n d c o n diti o n of t he dr u g, c hec k f or a p pr o priate l ocal 
la n g ua ge o n t he la bel, c hec k t he dr u g e x pirati o n date, a n d si g n t he Recei pt of S hi p me nt F or m 
pr o vi de d.  T he site will ac k n o wle d ge recei pt of t he s hi p me nt i n t he I X R S.  All i nstr ucti o ns o n t he 
Recei pt of S hi p me nt F or m will be f oll o we d, a n d t he f o r m will be fille d i n at t he site.  I n a d diti o n, 
t he I n vesti gat or or desi g nee will c o ntact t he site m o nit or as so o n as p ossi ble b ut wit hi n 4 8 h o urs, 
if t here is a pr o ble m wit h t he s hi p me nt. 
Dr u g s u p plies m ust be st ore d i n a sec ure, li mite d access st ora ge area u n der t he rec o m me n de d 
st ora ge  c o n diti o ns  as  meas ure d  b y  a  mi nim u m/ ma xi m u m  t her m o meter.  Te m perat ure  
meas ure me nt will be rec or de d dail y o n a te m perat ure l o g, e xcl u di n g wee ke n ds a n d h oli da ys.  T he 
s p o ns or a n d site m o nit or m ust be c o ntacte d i n t he e ve nt of a te m perat ure e xc ursi o n o utsi de of t he 
rec o m me n de d st ora ge c o n diti o ns. 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 5 1 of 1 0 9 
 
 
5. 7.  
Dr u g Acc o u nt a bilit y 
T he e C R F c o ntai ns a dr u g acc o u nta bilit y m o d ule f o r me dicati o ns s u p plie d b y t he s p o ns or.  T he 
I n vesti gat or or desi g nee e nters t he re q uire d i nf or mati o n i n t his m o d ule. 
At t he e n d of t he st u d y, or as di recte d, all me dicati o ns s u p plie d b y t he s p o ns or, i ncl u di n g u n use d, 
partiall y use d, or e m pt y c o ntai ners, will be ret ur n e d t o a desi g nee as i nstr ucte d b y Daiic hi Sa n k y o 
E ur o pe ( D S E) or destr o ye d at t he site.  I n vest i gati o nal Pr o d uct will be ret ur ne d o nl y after t he 
st u d y m o nit or has c o m plete d a fi nal in ve nt or y t o verif y t he q ua ntit y t o  be ret ur ne d.  T he ret ur n of 
all st u d y me dicati o ns m ust be d oc u me nte d a n d t he d oc u me ntati o n i ncl u de d i n t he s hi p me nt.  At 
t he e n d of t he st u d y, a fi nal st u d y me dicati o n rec o nciliati o n state me nt m ust be c o m plete d b y t he 
I n vesti gat or or desi g nee a n d pr o vi de d t o t he s p o ns or.  Dr u g s u p plies ma y be destr o ye d b y t he 
I n vesti gat or w he n a p pr o ve d i n writi n g b y D S E a n d D S E has recei ve d c o pies of t he site’s dr u g 
ha n dli n g a n d dis p ositi o n sta n dar d o perati n g pr oce d ures ( S O Ps).  
All i n ve nt or y f or ms m ust be ma de a vaila ble f or a u dits b y a s p o ns or a ut h or ize d re prese ntati ve or 
desi g nee a n d / or i ns pecti o ns b y re g u lat or y a ge nc y i ns pect ors.  T he I n vesti gat or is res p o nsi ble f or 
t he acc o u nta bilit y of all use d a n d u n use d me dicati o ns pr o vi de d  b y t he s p o ns or at t he site. 
 
5. 8.  
Met h o d of Assessi n g Re gi me n C o m pli a nce 
Eac h  s u bject  s h o ul d  d oc u me nt  misse d  d oses  i n  t he  s u bject  b o o klet.  T he  s u bject  s h o ul d  be  
i nstr ucte d b y t he I n vesti gat or t o bri n g t his b o o klet t o a n y visit s o t hat t he rele va nt i nf or mati o n ca n 
be ca pt ure d i n t he e C R F. 
At eac h visit, t he I n vesti gat or or desi g nee asse sses t he s u bject’s c o m plia nce wit h t he assi g ne d 
re gi me n b y as ki n g t he s u bject a b o ut misse d d oses a n d vis uall y i ns pecti n g t he dr u g s u p pl y t he 
s u bject br o u g ht t o t he visit. T he I n vesti gat or or desi g nee assesses t he c o m plia nce of e d o xa ba n, b y 
ta blet c o u nts, a n d ca pt ures i nf or mati o n i n t he e C R F. If zer o ta blets are ret ur ne d w hile a n o vera ge 
is e x pecte d, t he s u bject s h o ul d be as ke d w het her a n y were dis p ose d/t hr o w n a wa y, rat her t ha n 
ta ke n orall y. 
M ore o ver, t he I n vesti gat or ca pt ures t he e x p os ure t o e d o xa ba n a n d V K A i n t he e C R F: 
- 
T he i nf or mati o n pr o vi de d b y t he s u bject o n t heir me dicati o n l o g. 
- 
I nf or mati o n pr o vi de d b y s u bject d uri n g site visits or site tele p h o ne assess me nts c o ncer ni n g 
misse d d oses ( date, dr u g a n d reas o n). 
- 
F or V K A, t he I n vesti gat or assesses t he I N R at l ocal la b orat or y at eac h o n site visit a n d uses 
t he deter mi ne d I N R val ue i n t he assess me nt of V K A e x p os ure a n d tar get I N R bet wee n 
2. 0- 3. 0. It is t he I n vesti g at or’s res p o nsi bilit y: 
o  t o m o nit or t he I N R a n d a dj ust t he V K A d ose t o mai ntai n t he I N R wit hi n tar get, a n d 
o  t o c ollect at least m o nt hly I N R assess me nts a n d rec or d t hese t hr o u g h o ut t he st u d y. 
- 
I n case of a s us pecte d st u d y e n d p oi nt, a n a d diti onal assess me nt f or s u bject c o m plia nce t o t he 
assi g ne d re gi me n m ust be perf or me d. 


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5. 9.  
Pri or a n d C o nc o mit a nt Me dic ati o ns 
Pri or me dicati o ns t hat t he s u bject has ta ke n wit hi n 3 0 da ys bef ore ra n d o mizati o n are rec or de d i n 
t he e C R F. T hese me dicati o ns ta ke n b y t he s u bjects pri or t o ra n d o mizati o n or at a n y ti me d uri n g 
t he st u d y are re gar de d as c o nc o mita nt me dicati ons a n d m ust be d oc u me nte d o n t he a p pr o priate 
pa ges of t he e C R F. 
If t he s u bject e x perie nces a stu d y e n d p oi nt e ve nt (see Secti o n 7. 1 a n d 7. 3 , i ncl u di n g i n di vi d ual 
c o m p o ne nts) or a n S A E, t he n i nf or mati o n o n c o nc o mita nt me dicati o ns ta ke n wit hi n t he past 
3 0 da ys m ust be d oc u me nte d i n t he a p pr o priate e C R F pa ges. 
C o nc o mita nt me dicati o n use is ca pt ure d i n t he e C R F u ntil t he p ost-treat me nt f oll o w- u p visit. 
 
Me dicati o ns liste d bel o w are all o we d wit h t he f oll o wi n g restricti o ns: 
 A S A is all o we d if d ose ≤1 0 0 m g o nce- dail y 
 I n t he e d o xa ba n- base d re gi me n, e d o xa ba n d ose re d ucti o n t o 3 0 m g o nce- dail y is re q uire d 
d uri n g c o nc o mita nt use wit h t he P- g p i n hi bit o rs c ycl os p ori ne, dr o ne dar o ne, er yt hr o m yci n, 
or ket oc o naz ole ( please refer t o l ocal la belli n g or t o t he I B, as a p plic a ble); Re mar k: I n E U 
c o u ntries, acc or di n g t o t he S m P C c o nc o mita nt use of e d o xa ba n wit h c ycl os p ori ne, 
dr o ne dar o ne, er yt hr o m yci n, or ket oc o naz ole re q uires d ose re d ucti o n t o 3 0 m g o nce- dail y. 
C o nc o mita nt use of e d o xa ba n wit h q ui ni di ne, ver a p a mil, or a mi o d ar o ne d oes n ot re q uire  
d ose re d ucti o n. 
 
5. 9. 1.  
Pr o hi bite d Me dic ati o ns 
T he f oll o wi n g dr u gs are n ot per mitte d d uri n g t he treat me nt peri o d: 
 A d diti o nal a ntic oa g ula nts, ot her t ha n t he assi g ne d e d o xa ba n or V K A, b y a n y r o ute ( wit h 
t he e xce pti o n of pare nteral a ge nts use d t o treat a ne w cli nical e ve nt, s uc h as ac ute 
c or o nar y s y n dr o me, or as a bri d ge w h e n starti n g or res u mi n g t he assi g ne d V K A); 
 D ual a nti platelet t hera p y ( D A P T, i.e., as piri n a n d P 2 Y 1 2 a nta g o nist); 
 Fi bri n ol ytic a ge nts, u nless re q uire d t o treat a ne w cli nical e ve n t, s uc h as ac ute MI, P E, or 
str o ke, i n w hic h case t he ris ks a n d be nefits of s uc h treat me n t s h o ul d be c o nsi dere d a n d, if 
gi ve n, t he assi g ne d e d o xa ba n or V K A s h o ul d be te m p oraril y disc o nti n ue d;  
 C hr o nic use of me dici nes affecti n g he m ostasis  s uc h as hi g her d oses of A S A ( A S A u p t o 
1 0 0 m g per da y all o we d) or c hr o nic oral or pare nteral i nta ke of  n o n-as piri n N S AI Ds o n 
≥4 da ys/ wee k ( use of N S AI Ds via ot her r o utes is n ot restricte d); 
 Vita mi n K s u bstit uti o n me dicati o ns; 
 I n vesti gati o nal dr u gs ( ot her t ha n t he ra n d o mize d st u d y treat me nt re gi me n). 
 


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S u bjects o n t hese dr u gs at t he ti me of ra n d o mi zati o n ca n n ot be i ncl u de d i nt o t he st u d y. After 
ra n d o mizati o n,  s h ort-ter m  c o nc o mita nt  use  of  t hese  dr u gs  ma y  re q uire  a  st u d y  me dicati o n  
i nterr u pti o n. All st u d y me dicati o n i nterr u pti o ns m ust be ca pt ure d i n t he e C R F. After c o m pleti o n of 
a s h ort c o urse of t hera p y wit h t he pr o hi bite d dr u g, t he i nterr u pte d st u d y me dicati o n ma y be 
res u me d. L o n ger-ter m c o nc o mita nt use of t hese dru gs (e. g., ne w i n dicati o n f or c hr o nic D A P T) will 
re q uire wit h dra wal of t he s u bject fr o m t he st u d y. 
5. 1 0.  
S u bject Wit h dr a w al/ Disc o nti n u ati o n 
I n acc or da nce wit h t he Declarati o n of Helsi n ki a n d ot her a p plica ble  re g ulati o ns, a s u bject has t he 
ri g ht t o wit h dra w c o nse nt f or partici pati o n i n  t he st u d y at a n y ti me a n d f or a n y reas o n wit h o ut 
prej u dice t o his or her f ut ure me dical car e b y t he p h ysicia n or at  t he i nstit uti o n. 
5. 1 0. 1.  
Re as o ns f or Wit h dr a w al 
A n y s u bject w h o is wit h dra w n fr o m  t he st u d y treat me nt f or a n y reas o n will ha ve t heir reas o ns f or 
wit h dra wal rec or de d. S u bjects ma y be wit h dra w n fr o m t he st u d y after si g ni n g t he I C F f or t he 
f oll o wi n g reas o ns: 
 A E 
 Wit h dra wal b y s u bject 
 P h ysicia n decisi o n 
 Deat h 
 Lac k of effi cac y 
 Pre g na nc y 
 Pr ot oc ol de viati o n 
 St u d y ter mi nate d b y s p o ns or 
 L ost t o f oll o w- u p 
 Ot her 
 
5. 1 0. 2.  
Wit h dr a w al Pr oce d ures 
If a s u bject is wit h dra w n fr o m t he st u d y, t he I n vesti gat or will c o m plete an d re p ort t he o bser vati o ns 
as t h or o u g hl y as p ossi ble u p t o t he date of wit h dra w al i ncl u di n g t he date of  last treat me nt a n d t he 
reas o n f or wit h dra wal. 
If t he s u bject is wit h dra w n d ue t o a n A E, t he I n vesti gat or will f oll o w t he s u bject u ntil t he A E has 
res ol ve d or sta bilize d. 
All s u bjects w h o are wit h dra w n fr o m t he st u d y s h o ul d c o m plete prot oc ol-s pecifie d wit h dra wal 
pr oce d ures. S u bjects will be f oll o we d i n t he trial (f or all pr ot oc ol s pecifie d e val uati o ns of efficac y 
or safet y e ve nts, c o nc o mita nt t hera pies, etc) u nless t here is writte n d oc u me ntati o n of wit h dra w n 
c o nse nt ( b y t he s u bject a n d/ or  b y t he I n vesti gat or).   


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6.  
S T U D Y P R O C E D U R E S 
A ta b ular s u m mar y of t he visit sc he d ule f or t he st u d y is pr o vi de d i n Secti o n 1 6. 9 . T he me dicati o ns 
use d i n t he st u d y re gi me ns are pr o vi de d b y t h e S p o ns or a n d details o n dr u g acc o u nta bilit y are 
pr o vi de d i n Secti o n 5. 7 . 
S u bjects eli gi ble t o part ici pate i n t he st u d y m ust ha ve si g ne d t he I C F bef ore ra n d o mizati o n or a n y 
st u d y-s pecific pr oce d ures are perf or me d. After t he I C F is si g ne d, s u bjects are ra n d o mize d wit h o ut 
dela y t o o ne of t he t w o st u d y ar ms ( 2: 1 e d o xa ba n vs. V K A).  
 
6. 1.  
Pre-scree ni n g  
T he pre-scree ni n g will be d o ne o ut si de t he pr ot oc ol at t he site’s discreti o n t h o u g h i nf or mati o n 
re q uire d b y t he pr ot oc ol will nee d t o be rec or de d i n t he e C R F a n d s u bject n otes.   
 
6. 2.  
S u bject  E nr oll me nt  ( Scree ni n g/ R a n d o miz ati o n,  Visit  1,  D a y  - 2 1  ( m a x.  D a y - 2 8) 
a n d O pti o n al Visit 2 D a y - 1 4) 
T he scree ni n g peri o d will be 1- 3 da ys. Visits f or Scree ni n g a n d Ra n d o mizati o n ma y be c o m bi ne d 
if t he I ncl usi o n/ E xcl usi o n criteria ca n be c hec ke d o n t he basis of t h e patie nt's healt h rec or d a n d 
act ual la b orat or y res ults w it h s ufficie nt acc urac y a n d if t he s u bject has bee n ha n de d o ut t he I C F 
at least 1 da y bef ore ra n d o mizati o n a n d prec o n diti o ne d t hat all of t he s u bject's q uesti o ns c o ul d be 
a ns were d.  
E nr oll me nt of s u bjects will occ ur bet wee n 2 1 t o 2 8 da ys bef ore t he pr oce d ure. S u bjects will 
u n der g o st u d y s pecific pr oce d ures o nl y after t he I C F is si g ne d. T his  visit ma y be s plit i nt o t w o 
ste ps at baseli ne as per l ocal re q uire me nts. I n t he pre-a blati o n treat me nt peri o d, a n o pti o nal visit 
ma y occ ur f or t h ose patie nts w h o d o n ot ha ve t he o pti o n of I N R meas ure me nt i n a n a m b ulat or y 
setti n g ( o pti o nal Visit 2, Da y - 1 4).  
T he  f oll o wi n g  acti vities  a n d/ or  assess me nts  ar e  perf or me d  pri or  t o  ra n d o mizati o n  a n d  t he  
o utc o mes rec or de d i n t he e C R F: 
 I C F si g ne d; 
 C hec k t hat t he s u bject meets all of t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria 
(see Secti o n 4. 1 ); i n case t hat Ra n d o mizati o n is n ot at t he sa me da y as Scree ni n g, 
i ncl usi o n a n d e xcl usi o n criteria will be re-assesse d at Ra n d o mizati o n;   
 C ollect de m o gra p h y i nf or mati o n (a ge, b o d y wei g ht a n d ge n der)  
 Re vie w me dical hist or y i n cl u di n g blee di n g hist or y a n d hist or y of car di o versi o ns; 
 Rec or d pri or me dicati o n wit hi n t he 3 0 da ys pr i or t o ra n d o mizati o n; 
 P h ysical e xa mi nati o n; 
 Bl o o d dra w f or ce ntral la b at Scree ni n g:  
―  Creati ni ne, esti mate d Cr C L acc or di n g t o t he C oc kcr oft- Ga ult f or m ula (see Secti o n 
1 6. 6 ), 


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―  Re d Bl o o d Cell c o u nt a n d stat us  (e. g., he m o gl o bi n, he mat ocrit), platelet c o u nt, W B C 
( wit h differe ntial if ele vate d), T B L (if ele vate d, deter mi ne c o nj u gate d/ u nc o nj u gate d 
bilir u bi n fracti o n), A L T, A S T, al kali ne p h os p hatase, I N R i n all s u bjects;  
―  T otal c h olester ol a n d tri gl yceri d es o nl y d o ne at scree ni n g;  
―  Bl o o d dra w f or ce ntral la b orat or y a nal ysis of car diac mar kers. 
If a vaila ble rece nt l ocal la b orator y res ults are of s ufficie nt acc urac y t o verif y t he patie nt’s 
eli gi bilit y a n d s u p p ort ra n d o mizati o n i n t he j u d g me nt of t he i n vesti gat or t he patie nt ca n be 
ra n d o mize d o n t he sa me da y as scree ni n g. 
 W o me n of c hil d beari n g p ote nti al m ust ha ve a ne gati ve uri ne test f or pre g na nc y at 
scree ni n g (a fe male of c hild beari n g p ote ntial is defi ne d as o ne w h o has n ot bee n 
p ost me n o pa usal f or at least o ne year, or has n ot bee n s ur gicall y sterilise d, or has n ot ha d a 
h ysterect o m y at least 3 m o nt hs pri or t o t he start of t his st u d y). T hese s u bjects m ust be 
willi n g a n d a ble t o use a de q uate c o ntrace pti o n a n d a d here t o t he f oll o wi n g pr o hi biti o ns 
a n d restricti o ns:  Fe males ta ki n g oral c o ntra ce pti ves s h o ul d ha ve bee n o n t hera p y f or at 
least t hree m o nt hs. A de q uate  c o ntrace pti ves i ncl u de: C o m bi ne d (estr o ge n a n d 
pr o gest o ge n c o ntai ni n g) oral, i ntra va gi nal  or tra ns der mal h or m o nal c o ntrace pti o n 
ass ociate d wit h i n hi biti o n of o v ulati o n; pr o ge st o ge n- o nl y oral, i njecta ble or i m pla nta ble 
h or m o nal c o ntrace pti o n ass ociate d wit h i n hi bi ti o n of o v ulati o n; i ntra uteri ne de vice (I U D); 
i ntra uteri ne h or m o ne-releasi n g s yste m (I U S); bilateral t u bal occl usi o n; vasect o mize d 
part ner; se x ual a bsti ne nce. T his test will be c o nfir me d at Visit 3 ( Baseli ne / Da y 0 / 
cat heter a blati o n da y) a n d Visit 6 ( Site Visi t Da y 3 0). F urt her m ore, pre g na nc y tests are 
carrie d o ut w he ne ver t here are cli nical i n di cati o ns f or t he e xiste nce of a pre g na nc y. 
Eli gi ble s u bjects s h o ul d be ra n d o mi ze d wit h o ut dela y. T he I n vesti gat or will c o ntact t he I X R S a n d 
pr o vi de t he f oll o wi n g i nf or mati o n: 
 C o nfir mati o n t hat I C F has bee n si g ne d a n d date; 
 De m o gra p h y ( year of birt h, b o d y wei g ht a n d ge n der); 
 C o nfir m if Cr C L is less or e q ual 5 0 m L/ mi n. or > 5 0 m L/ mi n.; 
 Usa ge of a P- g p i n hi bit or t hat re q uires a n e d o xa ba n d ose re d ucti o n (acc or di n g t o l ocal 
e d o xa ba n la belli n g or I B as a p plica ble); 
 C o nfir mati o n s u bject f ulfills all i ncl usi o n a n d n o ne of t he e xcl usi o n criteria. 
S u bject I D n u m ber will be assi g ne d t hr o u g h I X R S a n d t he f oll o wi n g if t he s u bject is 
ra n d o mize d: 
―  t he ra n d o mize d treat me nt re gi me n;  
―  prese nce of e d o xa ba n d ose re d ucti o n re q uire me nt; 
―  kit n u m bers of t he me dicati o ns t o be use d. 
After ra n d o mizati o n,  
 T he assi g ne d st u d y me dicati o n a n d t he pr o per dail y  d osi n g is e x plai ne d t o t he s u bject. It 
is als o e x plai ne d h o w t he dr u g acc o u ntabilit y is d oc u me nte d i n t he st u d y.  


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F or s u bjects ra n d o mize d t o e d o xa ba n (see Secti o n 5. 2. 1 . f or m ore details): If s u bject is 
o n: 
     (a) V K A, disc o nti n ue t he V K A a n d start e d o xa ba n w he n I N R is ≤2. 5. 
     ( b) N O A C, disc o nti n ue N O A C a n d start e do xa ba n at t he ti me of  t he ne xt sc he d ule d 
     
N O A C d ose.  
I n t he pre-a blati o n peri o d, it is ma n dat or y t hat t he o nce- dail y d ose of e d o xa ba n is ta ke n 
i n t he e ve ni n g. 
 
F or s u bjects ra n d o mize d t o V K A (see Secti o n 5. 2. 2 . f or m ore details): If s u bject is o n: 
     (a) V K A, c o nti n ue wit h me dicati o n as pr o vi de d b y I X R S w he n I N R ≤2. 5. 
     ( b) N O A C, disc o nti n ue t he N O A C a n d start V K A at t he ti me of t he ne xt sc he d ule d 
           N O A C d ose. 
 I nstr ucti o n is pr o vi de d t o t he s u bject t o brin g all st u d y me dicati o n t o eac h visit, i ncl u di n g 
e d o xa ba n. Eac h s u bject s h o ul d d oc u me nt mi sse d d oses i n t he s u bject b o o klet. T he 
s u bject s h o ul d be i nstr ucte d b y t he I n vesti gat or t o bri n g t his b o o klet t o  a n y visit s o t hat 
t he rele va nt i nf or mati o n ca n be ca pt ure d a n d I n vesti gat or ca pt ures i nf or mati o n i n t he 
e C R F. 
 O nl y f or V K A s u bjects:   o btai n I N R a n d V K A d ose i nf or mati o n.  Fre q ue nt I N R 
deter mi nati o ns u p o n i nitiati o n s h o ul d be o btai ne d u ntil s u bject’s I N R is sta ble i n t he 
t hera pe utic ra n ge. It is e x pecte d t hat m ore fre q ue nt visits  will be pla n ne d f or ‘ de n o v o’ 
s u bjects o n V K A t o a dj ust t he d ose wit h t he g oal of reac hi n g I N R 2. 0- 3. 0 wit hi n 6-
8 da ys after e nr ol me nt. O btai n s u bse q ue nt I N R deter mi nati o ns as per rec o m me n dati o ns 
a n d g ui deli nes pr o vi de d i n t he l ocal a p pr o ve d la bel fr o m t he res pecti ve V K A 
ma n ufact urer. 
 Vital si g ns ( heart rate, sitti n g bl o o d press u re, hei g ht [at ra n d o mizati o n o nl y], a n d b o d y 
wei g ht); 
 1 2-lea d E C G; 
 C o nc o mita nt me dicati o n; 
 A E a n d s us pecte d cli nic al e ve nts re p orti n g. 
T he S p o ns or will s u p pl y st u d y s u bj ects wit h e d o xa ba n a n d V K A f or t he pre-a blati o n st u d y peri o d 
acc or di n g t o assi g ne d re gi me n at ra n d o mizati o n. Me dicati o n kits are assi g ne d t hr o u g h t he I X R S. 
Acc o u nta bilit y f or me dicati o ns pr o vi de d b y D S E is perf or me d at dis pe nsi n g visits a n d t he E O T 
visit. 
All s u bjects will be re q uire d t o c o m plete at least 2 1 ( u p t o + 7) da ys of a ntic oa g ulati o n pri or t o t he 
car diac a blati o n. 
6. 2. 1.  
E d o x a b a n St u d y Ar m 
S u bjects recei vi n g a ntic oa g ula nts at t he ti me of  e nr oll me nt will be s witc he d t o e d o xa ba n (t he 
s witc hi n g pr oce d ure will f oll o w t he e d o xa ban la bel a n d is descri be d i n Secti o n 5. 2. 1. 3 ). It is 


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ma n dat or y t hat i n t he pre-a blati o n peri o d, t he o nce- dail y d ose of e d o xa ba n is ta ke n i n t he 
e ve ni n g. 
6. 2. 2.  
V K A St u d y Ar m 
S u bjects e nr olle d i n t he V K A st u d y ar m will be re q uire d t o c o m plete at least 2 1 da ys ( + 7 da ys) 
of a ntic oa g ulati o n treat me nt wit h V K A. S u bject s will ta ke t he V K A acc or di n g t o t he directi o n 
of t he I n vesti gat or. E ver y atte m pt will be ma de t o  bri n g s u bjects i nt o t he t hera pe utic tar get ra n ge 
(I N R 2. 0- 3. 0) as fast as p ossi ble a n d t o mai ntai n t he tar get I N R ra n ge c o nsiste ntl y.  
I N R will nee d t o be meas ure d fre q ue ntl y at t he start of t he st u d y ( u nless a s u bject is recei vi n g a n 
u n var yi n g V K A d ose at t he ti me of ra n d o mizati o n) t o rec or d t he ti me w he n I N R reac hes a le vel 
of ≥2. 0.  
Bef ore a blati o n, eac h s u bject m ust be i n t he I N R ra n ge of 2. 0- 3. 0 f or t he last 1 0 da ys pri or t o t he 
cat heter a blati o n. T his will nee d t o be d oc u me nte d b y fre q ue nt I N R meas ure me nts, at least o nce 
per wee k i n t he pre-a blati o n peri o d. I N R m ust be meas ure d o n t he da y of or t he da y pri or t o t he 
sc he d ule d a blati o n pr oce d ure. If I N R is ≥1. 5 a n d < 2. 0 or if I N R is > 3. 0 a n d ≤3. 5 o n t he da y of 
or t he da y pri or t o t he sc he d ul e d a blati o n pr oce d ure, t he pr oc e d ure ma y be perf or me d at t he 
I n vesti gat or’s discreti o n. Ot her wise, t he s u bject is n ot eli gi ble f or perf or mi n g t he cat heter 
a blati o n (t he s u bject will be s witc he d fr o m st u d y me dicati o n t o sta n dar d of care a n d will e nter 
t he 3 0- da y f oll o w- u p peri o d).  
D uri n g t he cat heter a blati o n pr oce d ure, V K A w ill be use d wit h o ut i nterr u pti o n a n d bri d gi n g 
wit h L M W H will n ot be all o we d at t his ti me. 
6. 3.  
C at heter A bl ati o n Visit ( Peri pr oce d ur al Visit, Visit 3, D a y 0) 
T he f oll o wi n g acti vities a n d/ or assess me nts are perf or me d a n d t he o utc o mes rec or de d i n t he 
e C R F: 
 A d mi nister a n d dis pe nse st u d y me dicati o n; t h e S p o ns or will s u p pl y st u d y s u bjects wit h 
e d o xa ba n a n d V K A f or t he p os t-a blati o n st u d y peri o d; 
 S u bjects ra n d o mize d t o e d o xa ba n will ta ke e d o xa ba n i n t he e ve ni n g of t he da y bef ore t he 
a blati o n pr oce d ure. T he i nter v al bet wee n t he last i nta ke of e d o xa ba n a n d t he pr oce d ure 
m ust n ot e xcee d 1 8 h o urs. After t he a blati o n, st u d y me dicati o n m ust be re-starte d o n t he 
da y of pr oce d ure b ut n o earlier  t ha n 6 h o urs p ost-s heat h re mo val a n d o nl y after a de q uate 
he m ostasis has bee n ac hie ve d. 
 O btai n I N R a n d V K A d ose i nf or mati o n ( V K A s u bjects o nl y); 
 Vital si g ns ( heart rate, bl o o d press ure, b o d y wei g ht);  
 1 2-lea d E C G rec or di n g; 
 T E E or alter nati vel y i ntracar diac ec h ocar di o gra m - will be perf or me d d uri n g t he h os pital 
sta y relate d t o t he pr oce d ure directl y bef ore cat heter a blati o n or t he da y bef ore ( u p t o 
2 4 h o urs bef ore a blati o n). If T E E or i ntracar diac ec h ocar di o gra m is p ositi ve, i.e., s h o ws 
cl ots, t he car diac a blati o n pr oce d ure will be  ca ncele d a n d t he patie nt will be s witc he d 
fr o m st u d y me dicati o n t o sta n dar d of care a n d will e nter a 3 0- da y f oll o w- u p peri o d; 


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 Cat heter a blati o n pr oce d ure; 
 U nfracti o nate d he pari n ( U F H) a d mi nistrati o n/ A C T m o nit ori n g;  
 Bl o o d dra w f or ce ntral la b orat or y a nal ysis i ncl u di n g safet y para meters (I N R, li ver 
f u ncti o n, ser u m c he mistr y, a n d he mat ol o g y) as descri be d i n Secti o n 9. 7. 
 O nl y i n w o me n of c hil d beari n g p ote ntial: uri ne test f or pre g na nc y. F urt her m ore, 
pre g na nc y tests are carrie d o ut w he ne ver t here are cli nical i n dicati o ns f or t he e xiste nce of 
a pre g na nc y; 
 C o nc o mita nt me dicati o ns; 
 Re vie w of treat me nt c o m plia nce a n d i nterr u pti o ns. A ntit hr o m b otic re gi me n c o m plia nce is 
ac hie ve d b y assessi n g s u bject c o m plia nce ( b ot h b y pill c o u nt, self-re p orti n g/ p h ysicia n-
re p orti n g a n d b y I N R val ues f or V K A s u bjects o nl y). I n case of a s us pecte d st u d y 
e n d p oi nt, a n a d diti o nal assess me nt f or s u bject c o m plia nce t o t he assi g ne d re gi me n m ust 
be perf or me d. 
 ( S) A Es a n d s us pecte d cli nical e n d p oi nts e x perie nce d b y t he s u bject since t he last visit. 
 A Es (i ncl u di n g a b n or mal la b orat or y fi n di n gs a n d d uri n g u nsc he d ule d visits), e n d p oi nt 
e ve nts, a n d a d verse e ve nts of s pecial i ntere st ( A E SI) s h o ul d be re p orte d as s o o n as site 
pers o n nel lear n of t he e ve nt. E n d p oi nt  e ve nt a n d A E re p orti n g s h o ul d occ ur 
t hr o u g h o ut t he st u d y a n d n ot be restricte d t o s pecific visits. If A L T or A S T > 3 x U L N 
wit h si m ulta ne o us T B L > 2 x U L N is o bser ve d, t he n al kali ne p h os p hatase ( A L P) s h o ul d 
be deter mi ne d. 
6. 3. 1.  
E d o x a b a n St u d y Ar m 
S u bjects will be re q uire d t o ha ve  c o m plete d at least 2 1 ( u p t o + 7) da ys of a ntic oa g ulati o n wit h 
e d o xa ba n. It is ma n dat or y t hat i n t he pre-a blati o n peri o d, t he o nce- dail y d ose  of e d o xa ba n is ta ke n 
i n t he e ve ni n g.  
If a s u bject has ta ke n t he st u d y dr u g i n t he e ve ni n g a n d t he T E E/i ntracar diac ec h ocar di o gra m is 
ne gati ve, t he pr oce d ure ca n be pe rf or me d i n t he m or ni n g of t he ne xt da y. T he i nter val bet wee n 
t he last i nta ke of e d o xa ba n a n d t he pr oce d ure sh o ul d n ot e xcee d 1 8 h o urs. After t he a blati o n, st u d y 
me dicati o n m ust be re-starte d o n t he da y of pr o ce d ure n o earlier t ha n 6 h o urs p ost-s heat h re m o val 
a n d o nl y o nce a de q uate he m ost asis has bee n ac hie ve d. 
Ti mi n g of t he last d ose of e d o xa ba n pri or t o t he ca t heter a blati o n pr oce d ure a n d t he first d ose after 
t he pr oce d ure will be rec or de d i n t he e C R F. 
6. 3. 2.  
V K A St u d y Ar m 
Bef ore a blati o n, eac h s u bject m ust be i n t he I N R ra n ge of 2. 0- 3. 0 f or t he last  1 0 da ys pri or t o t he 
cat heter a blati o n. T his will nee d t o be d oc u me nte d b y fre q ue nt I N R meas ure me nts, at least o nce 
per wee k i n t he pre-a blati o n peri o d. I N R m ust be meas ure d o n t he da y of or t he da y pri or t o t he 
sc he d ule d a blati o n pr oce d ure. O n t he da y of, or t he da y pri or t o, t h e sc he d ule d a blati o n pr oce d ure, 
s u bjects I N R s h o ul d be wit hi n t he ra n ge 2. 0- 3. 0. If I N R is ≥1. 5 a n d < 2. 0 or if I N R is > 3. 0 a n d 
≤3. 5 t he pr oce d ure ma y be perf or me d at t he I n ves ti gat or’s discreti o n. Ot her wise, t he s u bject is 


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n ot  eli gi ble  f or  perf or mi n g  t he  cat heter  a bla ti o n  (t he  s u bject  will  be  s witc he d  fr o m  st u d y  
me dicati o n t o sta n dar d of care a n d will e nter t he 3 0- da y f oll o w- u p peri o d).  
D uri n g t he cat heter a blati o n pr oce d ure, V K A will be  use d wit h o ut i nterr u pti o n a n d bri d gi n g wit h 
L M W H will n ot be all o we d at t his ti me. 
6. 3. 3.  
A ntic o a g ul ati o n D uri n g C at heter A bl ati o n 
D uri n g a blati o n, he pari n s h o ul d be gi ve n t o mai ntai n a n A C T > 3 0 0 s ( 2 ). He pari n (sta n dar d of 
care treat me nt) s h o ul d be a d mi nistere d ( 1 0 0 U/ k g b ol us) pri or t o or i m me diatel y f oll o wi n g tra ns-
se ptal p u nct ure d uri n g A F a blati o n pr oce d ures a n d a dj uste d t o ac h ie ve a n d mai ntai n a n A C T of 
3 0 0 t o 4 0 0 sec o n ds. A C T le vels s h o ul d be c hec ke d  at 1 5- 2 0- mi n ute i nter vals u ntil t hera pe utic 
a ntic oa g ulati o n is ac hie ve d a n d t he n at 3 0- mi n ute  i nter vals f or t he d urati o n of t he pr oce d ure. 
He pari n a ntic oa g ulati o n will be partiall y re verse d wit h pr ota mi ne a n d s heat hs re m o ve d at a n A C T 
< 2 5 0 sec o n ds ( 1 5 ). 
6. 3. 4.  
A ntic o a g ul ati o n P ost C at heter A bl ati o n 
F oll o wi n g c o m pleti o n of t he cat heter a blati o n pr oce d ure, all s u bjects will c o nti n ue recei vi n g 
treat me nt  wit hi n  t heir  st u d y  ar m  u ntil  Da y  9 0  p ost- pr oce d ure.  F or  patie nts  ra n d o mize d  t o  
e d o xa ba n, after t he a blati o n, st u d y me dicati o n m ust be re-starte d o n t he da y of pr oce d ure n o 
earlier t ha n 6 h o urs p ost-s heat h re m o val a n d o nl y o nce a de q uate he m ostasis has bee n ac hie ve d. 
F or s u bjects ra n d o mize d t o V K A w he n after a b lati o n, t he s u bjects’ a ntic oa g ulati o n is m ore 
c o nsta nt, t he fre q ue nc y of I N R meas ure me nts ma y be l o wer t ha n i n t he pre-a blati o n peri o d. 
H o we ver, i n t he p ost-a blati o n peri o d, at least m o nt hl y I N R c o ntr ols are re q uire d. 
6. 4.  
H os pit al Disc h ar ge ( Visit 4; o pti o n al) 
T his visit ma y be perf or me d at t he discreti o n of  t he I n vesti gat or. T he f oll o wi n g acti vities a n d/ or 
assess me nts are perf or me d at t he h os pital disc har g e visit a n d t he o utc o mes rec or de d i n t he e C R F: 
 O btai n I N R a n d V K A d ose i nf or mati o n ( V K A s u bjects o nl y); 
 Vital si g ns ( heart rate, sitti n g bl o o d press ure, b o d y wei g ht);  
 1 2-lea d E C G rec or di n g; 
 C o nc o mita nt me dicati o ns (c ha n ges); 
 ( S) A Es a n d s us pecte d cli nical e n d p oi nts e x perie nce d b y t he s u bject since t he last visit. 
6. 5.  
Diff usi o n- Wei g hte d  M a g netic  Res o n a nce  I m a gi n g  ( Selecte d  sites  o nl y)  ( Visit  5, 
D a y 4) 
At selecte d sites, t he f oll o wi n g acti vities a n d/ or assess me nts are perf or me d a n d t he o utc o mes 
rec or de d i n t he e C R F: 
 Vital si g ns ( heart rate, sitti n g bl o o d press ure, b o d y wei g ht);  
 D W- M RI or diff usi o n wei g hte d i ma gi n g fl ui d atte n uate d i n versi o n rec o ver y 
( D WI- F L AI R) will be perf or me d 4 da ys ± 2 da ys p ost cat heter a blati o n; 
 ( S) A Es a n d s us pecte d cli nical e n d p oi nts e x perie nce d b y t he s u bject since t he last visit. 


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6. 6.  
Site Visit ( Visit 6, D a y 3 0) 
T he f oll o wi n g acti vities a n d/ or assess me nts are perf or me d a n d t he o utc o mes rec or de d i n t he 
e C R F: 
 O btai n I N R a n d V K A d ose i nf or mati o n ( V K A s u bjects o nl y); 
 Vital si g ns ( heart rate, sitti n g bl o o d press ure, b o d y wei g ht);  
 1 2-lea d E C G rec or di n g; 
 Bl o o d dra w f or ce ntral la b orat or y a nal ysis of  safet y para meters (I N R, li ver f u ncti o n, 
ser u m c he mistr y, a n d he mat ol o g y); as descri be d i n Secti o n 9. 7 . 
 O nl y i n w o me n of c hil d beari n g p ote ntial: uri ne test f or pre g na nc y. F urt her m ore, 
pre g na nc y tests are carrie d o ut w he ne ver t here are cli nical i n dicati o ns f or t he e xiste nce of 
a pre g na nc y; 
 C o nc o mita nt me dicati o ns (c ha n ges); 
 Re vie w of treat me nt c o m p lia nce a n d i nterr u pti o ns;  
 ( S) A Es a n d s us pecte d cli nical e n d p oi nts e x perie nce d b y t he s u bject since t he last visit. 
6. 7.  
O pti o n al Site Visit/ Tele p h o ne  Assess me nt ( Visit 7, D a y 6 0) 
T he f oll o wi n g acti vities a n d/ or assess me nts are perf or me d a n d t he o utc o mes rec or de d i n t he 
e C R F:  A  pers o nal  visit  is  o pti o nal  f or  t h ose  patie nts  w h o  d o  n ot  ha ve  t he  o pti o n  of  I N R  
meas ure me nt b y t heir ge neral practiti o ner. 
 O btai n I N R a n d V K A d ose i nf or mati o n ( V K A s u bjects o nl y); 
 Vital si g ns ( heart rate, sitti n g bl o o d press ure , b o d y wei g ht; o nl y d o ne if perf or me d as 
pers o nal visit);  
 C o nc o mita nt me dicati o ns (c ha n ges); 
 Re vie w of treat me nt c o m plia nce a n d i nterr u pti o ns.  
 ( S) A Es a n d s us pecte d cli nical e n d p oi nts e x perie nce d b y t he s u bject since t he last visit. 
6. 8.  
E n d of Tre at me nt ( Visit 8, D a y 9 0) 
At Da y 9 0, t he s u bject will eit her  disc o nti n ue t he treat me nt c o m pletel y or will be c o nti n ue d o n 
a n y of t he a p pr o ve d O A C dr u gs per p h ysicia n's di screti o n. Detaile d s witc hi n g pr ot oc ols acc or di n g 
t o me dicati o n la bel will be pr o vi de d.  
T he E O T visit is perf or me d f or s u bjects w h o ha ve  a pre mat ure disc o nti n uati o n of t heir assi g ne d 
O A C- base d re gi me n or w h o ha ve m o difie d t heir I C  after ra n d o mizati o n wit h f ull wit h dra wal of 
I C (see details Secti o n 6. 1 1 ). F or t hese s u bjects, t he sc he d uli n g of t he E O T re mai ns u nc ha n ge d 
(i.e. 9 0 ± 5 da ys). I n s uc h cases, t he E O T visit is t he e n d- of-st u d y visit/c o ntact. 
T he f oll o wi n g acti vities a n d/ or assess me nts are perf or me d a n d t he o utc o mes rec or de d i n t he 
e C R F: 
 O btai n I N R a n d V K A d ose i nf or mati o n ( V K A s u bjects o nl y); 


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 Vital si g ns ( heart rate, sitti n g bl o o d press ure, b o d y wei g ht);  
 1 2-lea d E C G rec or di n g; 
 Bl o o d dra w f or ce ntral la b orat or y a nal ysis of  safet y para meters (I N R, li ver f u ncti o n, 
ser u m c he mistr y, a n d he mat ol o g y) as descri be d i n Secti o n 9. 7 ; 
 C o nc o mita nt me dicati o ns (c ha n ges); 
 Re vie w of treat me nt c o m p lia nce a n d i nterr u pti o ns;  
 ( S) A Es a n d s us pecte d cli nical e n d p oi nts e x perie nce d b y t he s u bject since t he last visit. 
 T he tra nsiti o n me dicati o n a n d t he pr o per dail y d osi n g is e x plai ne d t o t he s u bject i ncl u di n g 
c o nfir mati o n t hat t he s u bject u n der sta n ds t he pr o per dail y d osi n g;  
 Dis pe nsati o n of t he tr a nsiti o n st u d y me dicati o n. 
 
6. 9.  
E n d of St u d y Visit, P ost-tre at me nt F oll o w- u p ( Visit 9, D a y 1 2 0) 
All ra n d o mize d s u bjects will ha ve  a p ost-treat me nt c o ntact at 3 0-3 5 da ys after t he E O T visit t o 
c ollect data o n c o nc o mita nt me dicati o ns, S A Es , a n d ot her safet y e ve nts of i nterest. 
T he f oll o wi n g acti vities a n d/ or assess me nts are perf or me d a n d t he o utc o mes rec or de d i n t he 
e C R F: 
 O btai n I N R a n d V K A d ose i nf or mati o n ( V K A s u bjects o nl y); 
 Vital si g ns ( heart rate, sitti n g bl o o d press ure, b o d y wei g ht);  
 C o nc o mita nt me dicati o ns (c ha n ges); 
 ( S) A Es a n d e n d p oi nt e ve nts e x perie nce d b y t he s u bject si nce t he last visit. 
 
6. 1 0.  
Misse d Visits 
E ver y eff ort s h o ul d be ma de t o e ns ure s u bjects re t ur n f or t heir o n-site visits. If t he s u bject is 
u na ble t o ret ur n f or a n o n-site vi sit, t he I n vesti gat or, or desi g nee, m ust d oc u me nt i n t he e C R F t he 
reas o n t he s u bject was u na ble t o c om plete t he visit. T he I n vesti gat or s h o ul d als o ma ke e ver y eff ort 
t o c o ntact t he s u bject, wit hi n t he visit wi n d o w, t o c ollect t he s u bject’s vital stat us as well as 
i nf or mati o n relate d t o p ote ntial A Es, safet y data, an d h os pitalizati o ns. 
6. 1 1.  
M o dific ati o n of I C after R a n d o miz ati o n 
S u bjects are sc he d ule d t o ha ve re g ular st u d y c o ntacts e ver y m o nt h u ntil t he E n d of St u d y Visit is 
c o m plete d (i.e., 3 0 da ys after t he E O T Visit).  
I n acc or da nce wit h t he Declarati o n of Helsi n ki a n d ot her a p plica ble  re g ulati o ns, a s u bject has t he 
ri g ht  t o  wit h dra w  c o nse nt  fro m st u d y  partici pati o n  at  a n y  ti me  a n d  f or  a n y  reas o n  wit h o ut  
prej u dice t o his or her f ut ure me dical car e b y t he p h ysicia n or at  t he i nstit uti o n. 


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T his pr ot oc ol ma kes a disti ncti o n bet wee n re q uest  t o disc o nti n ue ( 1) a n y or all st u d y me dicati o n, 
( 2) o n site visits, ( 3) tele p h o ne c o ntacts, ( 4) c ollecti o n of cli nical f oll o w- u p data, ( 5) c ollecti o n of 
vital stat us a n d ( 6) f u ll wit h dra wal of I C. 
D uri n g t he treat me nt p hase, all s u bjects are f oll o we d  f or 9 0 da ys irres pecti ve of c ha n ges i n t he 
a ntit hr o m b otic re gi me n. He ncef ort h, d uri n g i n terr u pti o n or f oll o wi n g disc o nti n uati o n of st u d y 
me dicati o n, s u bjects c o nti n ue t o ha ve re g ular st u d y visits or tele p h o ne assess me nts u ntil t he 9 0-
da y E O T visit is c o m plete d. 
If t he s u bject ca n n ot ret ur n f or a n i n- pers o n visit, a tele p h o ne visit is sc he d ule d u nless s u bject 
re q uests n ot t o be c o ntacte d b y tele p h o ne. C ollecti o n of a vaila ble cli nical data or vital stat us, 
eit her at t he i nter ve nti o nal ce nter, at t he referri n g h os pital, wit h t he ge neral practiti o ner, or t he 
m u nici pal re gistries c o nti n ues u nle ss e x plicitl y disall o we d b y s u bject. 
C ollecte d data u p t o t he date of f ull wit h dra wal of I C are use d i n t he fi nal a nal ysis. 
Rec or ds i n t he e C R F d oc u me nt m o dificati o ns t o t h e I C as detaile d a b o ve (i ncl u di n g le vel a n d date 
of m o dificati o n or wit h dra wal). 
6. 1 1. 1.  
S u bjects L ost t o F oll o w- U p 
All s u bjects s h o ul d be e nc o ura ge d  t o ret ur n f or pr ot oc ol-re q uire d o n-site visits or tele p h o ne 
assess me nts f or e val uati o n d uri n g t he cli nical f oll o w- u p. If a s u bject is u na ble t o ret ur n f or a cli nic 
visit, s u bject s h o ul d be c o ntacte d  b y tele p h o ne t o o btai n s u bject re q uire d i nf or mati o n. All atte m pts 
s h o ul d be d oc u me nte d i n t he s o urce d oc u me nts. If t he s u bject d oes n ot res p o n d t o tele p h o ne calls, 
t he n t he I n vesti gat or m ust se n d a certifie d letter t o t he s u bject. O nl y after faili n g t o c o ntact t he 
s u bject at t he fi nal f oll o w- u p visit will t he s u bject be c o nsi dere d l ost t o f oll o w- u p after last c o ntact 
e xce pt f or m ortalit y if a vaila ble vi a m u nici palit y re gistries. It m ust be a hi g h pri orit y t o o btai n at 
least s ur vi val data o n all s u bjects l ost t o f oll o w- u p. W he n a s u bject is l ost t o f oll o w- u p a n E n d-
of- St u d y F or m is c o m plete d. 
6. 1 2.  
E n d of Tri al Defi niti o n 
All ra n d o mize d s u bjects will ha ve a c o ntact pla n ne d 3 0- 3 5 da ys after t h e E O T visit, t o c ollect data 
o n tar gete d c o nc o mita nt me dicati o ns, S A Es, a n d ot her A E SI. T he fi nal c o ntact is t he p ost-
treat me nt f oll o w- u p visit sc he d ule d at 3 0- 3 5 da ys after t he E O T visit. T he st u d y is dee me d 
c o m plete d as s o o n as t he fi nal c o ntact of t he last  s u bject is perf or me d i n all ce nters a n d i n all 
partici pati n g c o u ntries. 
 


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7.  
O U T C O M E A S S E S S M E N T S 
7. 1.  
Pri m ar y Effic ac y E n d p oi nt 
C o m p osite  of  all-ca use  deat h,  str o ke  (isc he mi c,  he m orr ha gic,  or  u n deter mi ne d),  a n d  Maj or  
Blee di n g (I S T H defi niti o n), a nal yze d as ti me t o first occ urre nce of a n y c o m p o ne nt. 
7. 2.  
Pri m ar y S afet y E n d p oi nt 
Maj or Blee di n g (I S T H defi niti o n), a nal yze d as ti me t o first occ urre nce of Maj or Blee di n g. 
7. 3.  
Sec o n d ar y E n d p oi nts 
Effic ac y: 
 C o m p osite of all-ca use deat h, str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d, acc or di n g 
t o alter nati ve defi niti o n (1 ); see Secti o n 7. 4. 2  f or details) a n d Maj or Blee di n g (I S T H 
defi niti o n) 
 C o m p osite of str o ke (isc he mic, he m orr ha gic , or u n deter mi ne d) S E E, a n d C V m ortalit y  
 C o m p osite of str o ke (isc he mic, he m orr ha g ic, or u n deter mi ne d) S E E, a n d all-ca use 
m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) a n d TI A 
 Str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Str o ke (isc he mic) 
 Str o ke ( he m orr ha gic) 
 Str o ke ( u n deter mi ne d) 
 S E E 
 TI A 
 Fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n-fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d)  
 Disa bli n g str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n- disa bli n g str o ke (isc he mic,  he m orr ha gic, or u n deter mi ne d) 
S afet y: 
 Maj or Blee di n g ( defi ne d b y TI MI, B A R C ( 2 or hi g her)) 
 Maj or a n d Cli nicall y Rele va nt N o n- Ma j or ( C R N M) Blee di n g (I S T H defi niti o n) 
 C R N M Blee di n g (I S T H defi niti o n) 
 Mi n or Blee di n g (I S T H defi niti o n) 
 A n y Blee di n g 
 I C H 


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 Life-t hreate ni n g blee di n g 
 Fatal Maj or Blee di n g (I S T H defi niti o n) 
 N o n-fatal Maj or Blee di n g (I S T H defi niti o n) 
 Fatal Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or hi g her]) 
 N o n-fatal Maj or Blee di n g ( defi ne d  b y TI MI, B A R C [ 2 or hi g her]) 
 Safet y para meters s uc h as A Es, S A Es, la b orat or y para meters, E C G a n d vital si g ns. 
 
All a dj u dicate d e n d p oi nts are a nal yze d as ti me t o first occ urre nce of a n y of its c o m p o ne nts. 
F or all e n d p oi nts bli n dl y a dj u dica te d b y t he C E C, t he C E C’s i nter pretati o n pre vails a n d is use d i n 
t he statistical a nal yses. 
7. 3. 1.  
Ot her E n d p oi nts 
 Rele va nt H E O R para meters: 
o  N u m ber of s u bjects wit h ca ncellati o n of a blati o n pr oce d ure d ue t o i na de q uate 
a ntic oa g ulati o n 
o  N u m ber of h os pital a d missi o ns d ue t o C V ca uses ( be y o n d a blati o n pr oce d ure), 
i ncl u di n g b ut n ot li mite d t o o verall, f or blee di n g, S E E, ve n o us t hr o m b osis, etc. 
Re mar k:   H os pital a d missi o ns d ue t o C V  ca uses i ncl u de, b ut are n ot li mite d t o 
E D, I C U, C V war d. 
o  Mea n le n gt h of sta y ass ociate d wit h t he differe nt t y pe of h os pital a d missi o ns, s uc h 
as E D, I C U a n d C V war ds 
o  A d diti o nal o ut patie nt p h ysicia n or n urse visits t hat are C V e ve nt relate d o utsi de 
sc he d ule d visits as defi ne d b y st u d y pr ot oc ol 
 Sile nt cere bral lesi o ns as de fi ne d b y D W- M RI p ost a blatio n pr oce d ure (at preselecte d 
ce nters) 
 Car diac mar kers 
 
7. 4.  
E n d p oi nt Defi niti o ns 
All s us pecte d cli nical e n d p oi nts are a dj u di cate d b y a n i n de pe n de nt C E C (see Secti o n 1 6. 1. 2 ) 
wit h o ut k n o wle d ge of t he act ual assi g ne d treat me n t. Mai n a dj u dicati o n criteria are me nti o ne d 
bel o w. F urt her details o n t hese defi niti o ns a n d h o w t he y will be a ssesse d are pr o vi de d i n t he C E C 
C harter.  
T he re q uire me nts f or c ollecti n g a n d s u b mitti n g t he s o urce d oc u me nts f or a p pr o priate a dj u dicati o n 
of t he re p orte d pri mar y a n d sec o n dar y e n d p oi nt e ve nts will be pr o vi de d t o t he sites/I n vesti gat ors 
se paratel y i n t he Stu d y O perati o ns Ma n ual. 


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F or all e n d p oi nts bli n dl y a dj u dica te d b y t he C E C, t he C E C’s i nter pretati o n pre vails a n d is use d i n 
t he statistical a nal yses. 
 
7. 4. 1.  
Blee di n g 
Blee di n g will be classifie d acc or di n g t o t he I S T H defi niti o ns ( 1 6, 1 7 ). Blee di n g e ve nts will als o be 
classifie d acc or di n g t o B A R C ( 1 8 ) a n d TI MI (2 2, 2 3 ) classificati o ns f or descri pti ve p ur p oses o nl y 
(see Secti o n 1 6. 3  f or f urt her details) 
7. 4. 2.  
Effic ac y E n d p oi nt Defi niti o ns 
T he f oll o wi n g efficac y e n d p oi nt de fi niti o ns will be a p plie d: 
- 
A str o ke is defi ne d b y a n ac ute e pis o de of f ocal or gl o bal ne ur ol o gical d ysf u ncti o n 
ca use d b y brai n, s pi nal c or d, or reti nal vasc ular i nj ur y as a res ult of he m orr ha ge or 
i nfarcti o n. T he e ve nt classifies as a str o ke rat her t ha n a TI A base d o n a n y of t he 
f oll o wi n g: 
– D urati o n of ne ur ol o gical d ysf u ncti o n > 2 4 h o urs. 
– D urati o n of ne ur ol o gical d ysf u ncti o n < 2 4 h o urs i n case of i ma gi n g- d oc u me nte d ne w 
he m orr ha ge or i nfarcti o n. 
– A ne ur ol o gical d ysf u ncti o n res ulti n g i n deat h ( 2 4 ). 
Str o ke will be s u b- di vi de d i nt o isc he mic, he m orr ha g ic or u n deter mi ne d. Str o ke is 
cate g orize d as disa bli n g a n d n o n- disa bli n g str o ke usi n g t he m o difie d Ra n ki n Scale ( m R S) 
sc ore. 
- 
TI A  is defi ne d b y a n y ne ur ol o gical d ysf u ncti o n n ot satisf yi n g t he a b o ve criteria f or 
str o ke, s pecificall y if lasti n g < 2 4 h o urs wit h o ut i ma gi n g- d oc u me nte d ac ute brai n 
i nfarcti o n. 
T hese defi niti o ns of TI A a n d str o ke wi del y c orres p o n d wit h t he “ U p date d sta n dar dize d 
e n d p oi nt defi niti o ns f or tra nscat heter a ortic  val ve i m pla ntati o n” p u blis he d b y t he V A R C- 2 
gr o u p a n d wit h t h ose “ Defi niti o ns f or Car di o vasc ular E n d p oi nt E ve nts i n Cli nical Trials” 
p u blis he d b y a n A C C/ A H A tas k f orce ( 2 5, 2 6 ). 
- 
A n alter n ati ve defi niti o n of str o ke  will be a p plie d defi ni n g str o ke as a n a br u pt o nset, 
o ver mi n utes t o h o urs, of a f ocal ne ur ol o gical deficit i n t he distri b u ti o n of a si n gle brai n 
arter y t hat is n ot d ue t o a n i de ntifia ble n o n vasc ular ca use (i.e., brai n t u m or or tra u ma), a n d 
t hat eit her lasts at least 2 4 h o urs or res ults i n deat h wit hi n 2 4 h o urs of o nset (1 ). 
C orres p o n di n g t o t his  alter n ati ve defi niti o n, TI A is defi ne d as a n a br u pt o nset, o ver 
mi n utes t o h o urs, of a f ocal ne ur ol o gical deficit i n t he distri b uti o n of a si n gle brai n arter y, 
t hat lasts less t ha n 2 4 h o urs a n d is n ot d ue t o a n i de ntifia ble n o n- vascular ca use (i.e., brai n 
t u m or or tra u ma) a n d d oes n ot satisf y t he str o ke defi niti o n a b o ve (1 ). 
- 
A n S E E  is defi ne d as a n arterial e m b olis m res ulti n g i n cli nical isc he mia, e xcl u di n g t he 
ce ntral ner v o us s yste m ( C N S), c or o nar y  a n d p ul m o nar y arterial circ ulati o n (1 ). 
- 
C V m ort alit y , defi ne d as car diac or vasc ular deat h acc or di n g t o Aca de mic Researc h 
C o ns orti u m  ( A R C) (2 7 ). 
 


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8.  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T S. 
8. 1.  
P h ar m ac o ki netic V ari a ble(s) 
N ot a p plica ble. 
 
8. 2.  
C ar di ac M ar kers  
E vi de nce s u g gests t hat t he car diac bi o mar kers N- ter mi nal fra g me nt B-t y pe natri uretic pe pti de 
( N T- pr o B N P) a n d car diac tr o p o ni n hi g h se nsiti vit y (c T n- hs) are i n de pe n de ntl y ass ociate d wit h 
ris k of str o ke i n A F (2 8 ). N o n- ge netic car diac bi o mar kers s uc h as N T- pr o B N P a n d c T n- hs will be 
a nal yze d i n all patie nts at scree ni n g/ra n d o mizati o n.   
T he res ults will be re vie we d a n d c o m pare d t o  t he ce ntral la b orat or y’s n or mal ra n ges. 


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9.  
S A F E T Y A S S E S S M E N T S 
Safet y  assess me nts  t hat  are  c o m p o ne nts  of  t he  st u d y  e n d p oi nt  assess me nts  (e. g.  blee di n g  
e n d p oi nts) are detaile d i n Secti o n 7. 4  a n d m ust be c ollecte d i n t he A E/ O utc o me e C R F pa ge(s). 
9. 1.  
A d verse E ve nt C ollecti o n a n d Re p orti n g 
All cli nical A Es (see Secti o n 9. 2 f or defi niti o ns) occ urri n g after t he s u bject si g ns t he I C F a n d u p 
t o 3 0 da ys after t he last d ose of st u d y me dicati o n (ie, t he f ollo w- u p peri o d), w het her o bser ve d b y 
t he I n vesti gat or or re p orte d b y t he s u bject, will be rec or de d o n t he A E e C R F pa ge.  Me dical 
c o n diti o ns (i ncl u di n g la b orat or y va l ues/ vital si g ns t hat are o ut of ra n ge) t hat were dia g n ose d or 
k n o w n t o e xist pri or t o I C will be rec or de d as part of me dical hist or y.   
All A Es, S A Es, A E SIs are t o be re p orte d acc or di n g t o t he pr oce d ures i n Secti o n 9. 5 .   
All  la b orat or y  res ults,  vital  si g ns,  a n d  E C G  re s ults  or  fi n di n gs  s h o ul d  be  a p praise d  b y  t he  
I n vesti gat or t o deter mi ne t heir cli nical si g nifica nce.  Is olate d a b n or mal la b orat or y res ults, vital 
si g n fi n di n gs, or E C G fi n di n gs (i.e., n ot part of a re p orte d dia g n osis) s h o ul d be re p orte d as A Es if 
t he y are s y m pt o matic, lea d t o st u d y dr u g disc o nti n uati o n, d os e re d ucti o n, re q uire c orrecti ve 
treat me nt, or c o nstit ute a n A E i n t he I n vesti gat or’s cli nical j u d g me nt. 
At eac h visit, t he I n vesti gat or will deter mi n e w het her a n y A Es ha ve occ urre d b y e val uati n g t he 
s u bject.  A Es ma y be directl y o bser ve d, re p orte d s p o nta ne o usl y b y t he s u bject or b y q uesti o ni n g 
t he s u bject at eac h st u d y visit.  S u bjects s h o ul d be q uesti o ne d i n a ge neral wa y, wit h o ut as ki n g 
a b o ut t he occ urre nce of a n y s pecific s y m pt o ms.  T h e I n vesti gat or m ust assess all A Es t o deter mi ne 
seri o us ness, se verit y, a n d ca usalit y, i n acc or da nce wit h t he defi niti o ns i n Secti o ns 9. 2 a n d 9. 3 .  
T he I n vesti gat or’s assess me nt m ust be clearl y d oc u me nte d i n t he site’s s o urce d oc u me ntati o n wit h 
t he I n vesti gat or’s si g nat ure.   
Al wa ys re p ort t he dia g n osis as t he A E or S A E te r m.  W he n a dia g n osis is u na vaila ble, re p ort t he 
pri mar y si g n or s y m pt o m as t he A E or S A E ter m wit h a d diti o nal details i ncl u de d i n t he narrati ve 
u ntil t he dia g n osis bec o mes a vaila bl e.  If t he si g ns a n d s y m pt o ms are disti nct a n d d o n ot s u g gest 
a c o m m o n dia g n osis, re p ort t he m as i n di vi d ual e ntries of A E or S A E.   
F or e ve nts t hat are seri o us d ue t o h os pitalizati o n, t he reas o n f or h os pitalizati o n m ust be re p orte d 
as t he S A E ( dia g n osis or s y m pt o m re q uiri n g h os pitaliz ati o n).  A pr oce d ure is n ot a n A E or S A E, 
b ut t he reas o n f or t he pr oce d ure ma y be a n A E or  S A E.  Pre- pla n ne d ( pri or t o si g ni n g t he I C F) 
pr oce d ures or treat me nts re q uiri n g h os pitalizati o n f or pre-e xisti n g c o n diti o ns t hat d o n ot w orse n 
i n se verit y s h o ul d n ot be rep orte d as S A Es (see Secti o n 9. 2 f or Defi niti o ns).   
F or deat hs, t he u n derl yi n g or i m me di ate ca use of d eat h s h o ul d al wa ys be re p orte d as a n S A E.   
A n y  seri o us,  u nt o war d  e ve nt  t hat  ma y  occ ur  s u bs e q ue nt  t o  t he  re p orti n g  peri o d  t hat  t he  
I n vesti gat or assesses as relate d t o st u d y dr u g s h o ul d als o be rep orte d a n d ma na ge d as a n S A E. 
 


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9. 2.  
Defi niti o ns 
9. 2. 1.  
A d verse E ve nt  
A n y u nt o war d me dical occ urre nce i n a s u bject a d mi nistere d a p har mace utical pr o d uct a n d w hic h 
d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h  t his treat me nt. A n A E ca n t heref ore be a n y 
u nfa v o ura ble  a n d  u ni nte n de d  si g n  (i ncl u di n g  a n  a b n or mal  la b or at or y  fi n di n g  f or  e xa m ple),  
s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal (in vesti gati o nal) pr o d uct, 
w het her or n ot c o nsi dere d relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct. 
9. 2. 2.  
U ne x pecte d A d verse E ve nt 
A n u ne x pecte d A E is a n A E, t he nat ure or se verit y  of w hic h is n ot c o nsiste nt wit h t he refere nce 
safet y i nf or mati o n of a n y of t he st u d y me dicati o n. T he desi g nati o n of e x pecte d or u ne x pecte d 
m ust be deci de d fr o m t he pers pecti ve of pre vi o us l y descri be d A Es, n ot o n t he basis of w hat mi g ht 
be a ntici pate d fr o m p har mac ol o gical pr o perties of a me dici nal pr o d uct. T he i n vesti gat or ca n 
pr o vi de his j u d ge me nt o n t he e x pecte d ness/ u ne x pect e d ness of a re p orte d A E t o t he s p o ns or a n d 
t his will be ta ke n i nt o acc o u nt f or t he s p o ns or’s j u d ge me nt of e x pecte d ness. H o we ver, t he fi nal 
deter mi nati o n of e x pecte d ness is t he res p o nsi bilit y of D SE a n d n ot t he I n vesti gat or. 
9. 2. 3.  
E x pecte d A d verse E ve nt 
A n e x pecte d A E is a n e ve nt w h ic h is descri be d i n t he refere nce safet y i nf or mati o n of t he st u d y 
dr u gs i n nat ure, se verit y or i nci de nce. 
9. 2. 4.  
Seri o us A d verse E ve nt  
A n S A E or reacti o n is a n y u nt o war d me dical occ urre nce t hat at a n y d ose: 
 res ults i n deat h 
 is life-t hreate ni n g 
T he ter m “life-t hreate ni n g” i n t he defi niti o n of   “seri o us” refers t o a n e ve nt i n w hic h t he 
s u bject was at ris k of deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt w hic h 
h y p ot heticall y mi g ht ha ve ca use d d eat h if it were m ore se vere 
 re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xis ti n g h os pitalizati o n 
 res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y 
 is a c o n ge nital a n o mal y/ birt h defect 
O R 
 is a n y ot her me dicall y i m p orta nt c o n diti o n (see bel o w). 
 
N ote:  Me dical  a n d  scie ntific  j u d ge me nt  s h o ul d  be  e xercise d  i n  deci di n g  w het her  e x pe dite d  
re p orti n g is a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt medical e ve nts t hat ma y n ot be 
i m me diatel y life-t hreate ni n g or res ult i n deat h or h os pitalizati o n, b ut ma y je o par dise t he s u bject 
or ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he defi niti o n a b o ve. 
T hese  s h o ul d  als o  us uall y  be  c o nsi dere d  seri o u s.  E xa m ples  i ncl u de  aller gic  br o nc h os pas m,  
c o n v ulsi o ns, a n d bl o o d d yscrasias  or de vel o p me nt of dr u g de pe n de nc y or dr u g a b use. 


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N ote: 
 A pr oce d ure is n ot a n A E or S A E, b ut t he reas o n f or t he pr oce d ure ma y be a n A E or 
S A E. 
 Treat me nt re q uiri n g h os pitaliza ti o ns f or pre-e xisti n g c o n diti o ns w hic h d o n ot w orse n i n 
se verit y are n ot S A Es. 
9. 2. 5.  
A d verse E ve nts of S peci al I nterest 
9. 2. 5. 1.  
C o m bi ne d Ele v ati o ns of A m i n otr a nsfer ases a n d Bilir u bi n 
T here was n o cli nicall y c o ncer ni n g si g nal of dr u g- i n d uce d li ver i nj ur y ass ociate d wit h e d o xa ba n 
base d o n t he e xte nsi ve gl o bal P hase 3 e x perie n ce i n v ol vi n g o ver 3 4, 1 0 0 e d o xa ba n s u bject- years 
e x p os ure ( wit h me dia n dr u g e x p os ure of ~ 2. 5 y ears a m o n g ~ 1 4, 0 0 0 e d o xa ba n s u bjects). H o we ver, 
t here  will  be  o n g oi n g  m o nit ori n g  of  he patic  e ve nts,  i ncl u di n g  c o m bi ne d  ele vati o ns  of  
a mi n otra nsferases a n d bilir u bi n ( A L T or A S T > 3 x U L N wit h si m ulta ne o us T B L > 2 x U L N), 
partic ularl y t h ose wit h o ut e vi de nce of c h olestasis ( A L P ≥2 x U L N is c o nsi dere d e vi de nce of 
p ossi ble c h olestasis) a n d wit h o ut alter n ati ve eti ol o g y f or he pat ocell ular da ma ge. 
C o m bi ne d  ele vati o ns  of  a mi n otra nsferases  a n d  bilir u bi n,  eit her  seri o us  or  n o n-seri o us  a n d  
w het her or n ot ca usall y relate d, s h o ul d al wa ys be re p orte d t o t he S p o ns or as s o o n as p ossi ble 
f oll o wi n g t he pr oce d ures o utli ne d i n Secti o n 9. 5  f or S A E re p orti n g. 
I n cases of li ver la b orat or y a b n or malities, or e vi de nce of li ver d ysf u ncti o n, it is i m p orta nt t o 
e ns ure t hat t he eti ol o g y of li ver i nj ur y is i de n tifie d a n d st u d y s u bjects are m o nit ore d u ntil t he li ver 
la b orat or y assess me nts ret ur n t o n or mal. 
 
9. 3.  
Cl assific ati o n f or A E assess me nt 
9. 3. 1.  
Se verit y Assess me nt 
T he se verit y of a n A E is gra de d as f oll o ws: 
Mil d:    
  
Disc o mf ort n ote d, b ut n o disr u pti o n of n or mal dail y acti vit y. 
M o derate:   
Disc o mf ort s ufficie nt t o re d uce or affect n or mal dail y acti vit y. 
Se vere:    
I na bilit y t o w or k or  perf or m n or mal dail y acti vit y. 
9. 3. 2.  
C a us alit y Assess me nt  
T he I n vesti gat or s h o ul d assess ca usal relati o ns hi p bet wee n a n A E a n d t h e assi g ne d a ntic oa g ula nt-
base d re gi me n (i.e., e d o xa ba n- base d or V K A- base d) o n t he basis or his/ her cli nical j u d g me nt a n d 
t he f oll o wi n g defi niti o ns.  T he ca usalit y assess me nt s h o ul d be ma de base d o n t he a vaila ble 
i nf or mati o n a n d ca n be u p date d as ne w i nf or mati o n bec o mes a vaila ble. 
 1 = Relate d: 
T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m t he assi g ne d a ntic oa g ula nt-
base d re gi me n a d mi nistrati o n, a n d ca n n ot be  reas o na bl y e x plai ne d b y t he s u bject’s 


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cli nical state or ot her fa ct ors (e. g., disease u n der st u d y, c o nc urre nt diseases, a n d 
c o nc o mita nt me dicati o ns). 
T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m t he assi g ne d a ntic oa g ula nt-
base d re gi me n a d mi nistrati o n, a n d is a k n o w n reacti o n t o a n y of t he st u d y 
me dicati o ns (i.e. t he c o m p o ne nts of eac h st u d y re gi me n) u n der st u d y or its 
c he mical gr o u p, or is pre d icte d b y k n o w n p har mac ol o g y. 
 2 = N ot Relate d: 
T he A E d oes n ot f oll o w a reas o na ble se q ue nce fr o m t he assi g ne d a ntic oa g ula nt-
base d re gi me n a d mi nistrati o n, or ca n be reas o na bl y e x plai ne d b y t he s u bject’s 
cli nical state or ot her fa ct ors (e. g., disease u n der st u d y, c o nc urre nt diseases, a n d 
c o nc o mita nt me dicati o ns). 
9. 3. 3.  
Acti o n T a ke n Re g ar di n g t he Assi g ne d A ntit hr o m b otic Re gi me n 
F or eac h st u d y treat me nt, t he acti o n ta ke n after a n A E m ust be rec or de d i n t he e C R F as deli neate d 
bel o w: 
1 = D ose N ot C ha n ge d: N o c ha n ge i n d osa ge was ma de. 
2 = Dr u g Wit h dra w n: Per ma ne ntl y st o p pe d. 
3 = D ose Re d uce d: T he d osa ge was re d uce d. 
4 = Dr u g I nterr u pte d: Te m p oraril y st o p pe d. 
5 = D ose I ncrease d: T he d osa ge was i ncrease d. 
9. 3. 4.  
Ot her Acti o n T a ke n f or E ve nt 
1 = N o ne: N o treat me nt was re q uire d. 
2 = C o nc o mita nt me dicati o n re q uire d: Prescri pti o n a n d/ or o ver-t he-c o u nter 
me dicati o n were re q uire d t o treat t he A E. 
3 = C o nc o mita nt me dicati o n per ma ne ntl y disc o nti n ue d: Prescri pti o n a n d/ or o ver-
t he-c o u nter me dicati o n ot her t ha n t he assi g ne d a ntic oa g ula nt- base d re gi me n 
was per ma ne ntl y disc o nti n ue d d ue t o t he A E.  
4 = C o nc o mita nt me dicati o n te m p oraril y i n terr u pte d: Prescri pti o n a n d/ or o ver-t he-
c o u nter me dicati o n ot her t ha n t he assi g ne d a ntic oa g ula nt- base d re gi me n was 
te m p oraril y i nterr u pte d d ue t o t he A E.  
5 = Ot her. 
9. 3. 5.  
A d verse E ve nt O utc o me 
1 = Rec o vere d/ Res ol ve d: T he s u bject f ull y rec o vere d fr o m t he A E wit h n o 
resi d ual effect o bser ve d. 
2 = Rec o vere d/ Res ol ve d wit h Se q uelae: T h e resi d ual effects of t he A E are still 
prese nt a n d o bser va ble. I ncl u de  se q uelae/resi d ual effects. 
3 = N ot Rec o vere d/ N ot Res ol ve d: T he A E itself is still prese nt a n d o bser va ble. 


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4 = Fatal 
5 = U n k n o w n 
T he I n vesti gat or s h o ul d f oll o w s u bjects wit h A E s u ntil t he e ve nt has res ol ve d or t he c o n diti o n has 
sta bilize d.  I n case of u nres ol ved A Es i ncl u di n g si g nifica nt a b n or mal la b orat or y val ues at t he e n d 
of st u d y assess me nt, t hese e ve nts will be f o ll o we d u p u ntil res ol uti o n or u ntil t he y bec o me 
cli nicall y n ot rele va nt. 
 
9. 4.  
Ti mi n g of A d verse E ve nt Re p orti n g 
All  A Es  m ust  be  rec or de d  a n d  re p orte d  fr o m  t h e  state d  starti n g  p oi nt  of  t he  cli nical  trial  
(i m me diatel y after si g ni n g I C) i ncl u di n g A Es ta ki n g place d uri n g t he a d mi nistrati o n of ot her 
dr u gs. E ve n if t he s u bject has n ot yet recei ve d t he i n vesti gati o nal treat me nt, u nt o war d me dical 
occ urre nces ha ve t o be treate d as A Es. 
T he peri o d of A E re p orti n g is defi ne d as f oll o ws: 
A Es t hat occ ur wit hi n 3 0 da ys after t he last  d ose of t he assi g ne d st u d y treat me nt, w hic h are 
re p orte d t o t he I n vesti gat or (re gar dless of t he date of a f oll o w- u p visit) m ust be rec or de d i n t he 
e C R F. 
 
9. 5.  
Re p orti n g S A Es/ A Es 
9. 5. 1.  
D oc u me nt ati o n 
T o effecti vel y e val uate t he safet y pr ofile of t he st u d y treat me nts, t his st u d y will re p ort all ( S) A Es 
occ urri n g after t he s u bject si g ns t he I C a n d u p t o 3 0 da ys after t he last d ose of t he assi g ne d 
treat me nt, w het her o bser ve d b y t he I n vesti gator or re p orte d b y t he s u bject. All A Es will be 
rec or de d o n t he A E/ O utc o me e C R F pa ge(s) a n d i ncl u de: 
 A n y c o m p o ne nts of t he st u d y e n d p o i nt assess me nts (see Secti o n 7 ); 
 A E t hat meet seri o us ness criteria (see Secti o n 9. 2. 4 );  
 A E t hat res ult i n i nterr u p ti o n or disc o nti n uati o n of t he assi g ne d st u d y treat me nt; 
 A E t hat meet t he criteria f or A E SI (see Secti o n 9. 2. 5 );  
 A n y ot her A E. 
All la b orat or y res ults a n d vital si g ns s h o ul d be e val uate d b y t he I n vesti gat or re gar di n g cli nical 
si g nifica nce.  Is olate d ab n or mal la b orat or y res ults or vital si g n fi n di n gs t hat are n ot part of a 
dia g n osis  s h o ul d  be  re p orte d  as  A Es  or  S A Es .  Me dical  c o n diti o ns  (i ncl u di n g  la b orat or y  
val ues/ vital si g ns t hat ar e o ut of ra n ge) t hat were dia g n ose d or  k n o w n t o e xist pri or t o I C will be 
rec or de d as part of me dical hist or y. 
All S A Es are t o be re p orte d acc or d i n g t o t he pr oce d ures i n Secti o n 9. 5. 2 .  Al wa ys re p ort t he 
dia g n osis as t he A E or S A E ter m.  W he n a dia g n osis is u na vaila ble, re p ort t he pri mar y si g n or 
s y m pt o m as t he A E or S A E ter m wit h a d diti o nal details i ncl u de d i n t he narrati ve u ntil t he 


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dia g n osis bec o mes a vaila ble.  If t he si g ns a n d s y m pt o ms are disti nct an d d o n ot s u g gest a c o m m o n 
dia g n osis, re p ort t he m as i n di vi d ua l e ntries of A E or S A E.  F or e ve nts t hat are seri o us d ue t o 
h os pitalizati o n, t he reas o n f or h os pitalizati o n m ust  be re p orte d as t he S A E ( dia g n osis or s y m pt o m 
re q uiri n g h os pitalizati o n). 
A Es ma y be directl y o bser ve d, re p orte d s p o nta ne o usl y b y t he s u bjec t or b y q uesti o ni n g t he s u bject 
at eac h st u d y visit.  S u bjects s h o ul d be q uesti o ne d i n a ge neral wa y, wit h o ut as ki n g a b o ut t he 
occ urre nce  of  a n y  s pecific  s y m pt o ms.   T he  I n ve sti gat or  m ust  assess  all  A Es  t o  deter mi ne  
seri o us ness, se verit y, a n d ca usalit y, i n acc or da nce wit h t he defi niti o ns i n Secti o ns 9. 2  a n d 9. 3 .  
T he I n vesti gat or’s assess me nt m ust be clearl y d oc u me nte d i n t he site’s s o urce d oc u me ntati o n wit h 
t he I n vesti gat or’s si g nat ure. 
I n case of a n occ urre nce of a n ( S) A E, t he I n vesti gat or a p plies t he f oll o wi n g r ules: 
 E ns ure a p pr o priate me dical treat me nt a n d deci de w het her t o disc o nti n ue or i nterr u pt a n y 
of t he st u d y me dicati o ns. 
 C o m plete t he i nitial A E/ O utc o me e C R F pa ge u p o n e ve nt a ware ness. 
 Rec or d t he e ve nt, its ma na ge me nt, a n d o utc o me i n t he  e C R F pa ge. 
 F or S A Es, re p ort i n t he e C R F wit hi n 2 4 h o urs of recei vi n g k n o wle d ge of t he occ urre nce. 
I n t he e ve nt t hat all t he re q uire d i nf or mati o n is n ot a vaila ble, t he i nf or mati o n w hic h is 
a vaila ble is t o be se nt wit h o ut dela y ( wit hi n  2 4 h o urs), a n d t he o utsta n di n g data rela ye d as 
s o o n as a vaila ble t hereafter. A ns wer a n y q ueries relate d t o t he re p o rte d S A E as s o o n as 
p ossi ble. 
 F or A E SIs, re p ort wit hi n 2 4 h o urs  of recei vi n g k n o wle d ge of t he occ urre nce as defi ne d f or 
S A Es a b o ve. 
 F or A Es, o btai n all data re q uire d i ncl. a n y i nf or mati o n w hic h, is o nl y a vaila ble after 
c o nsi dera ble  dela y  (i.e.  h os pital  re p or ts,  o utc o mes,  res ol uti o n  e n d  dates),  as  s o o n  as 
a v ail a ble  
 C o m p o ne nts of t he st u d y e n d p oi nt assess me nts w hic h res ult i n deat h m ust be re p orte d as 
S A Es wit hi n 2 4 h o urs  of t he I n vesti gat or’s a ware ness. 
9. 5. 2.  
N otif yi n g  Re g ul at or y  A ut h orities,  I n vesti g at ors  a n d  I nstit uti o n al  Re vie w 
B o ar d/I n de pe n de nt Et hics C o m mittee 
Detaile d S A E pr ocessi n g, distri b uti o n a n d re p orti n g will be lai d o ut i n s p o ns or’s S A E Fl o w Pla n. 
S p o ns or a n d/ or C o ntract Resear c h Or ga nizati o n ( C R O) will i nf or m  I n vesti gat ors, I nstit uti o nal 
Re vie w B oar ds (I R Bs)/I n de pe n de nt Et hics C o m mitt ees (I E Cs), a n d re g ulat or y a ut h orities of a n y 
S us pecte d U ne x pecte d Seri o us A d verse E ve nt R eacti o ns ( S U S A Rs) occ urri n g i n t he st u d y or 
ot her  s p o ns or  st u dies  of  t he  i n vesti gati o nal  pr o d uct,  as  a p pr o priate  per  l ocal  re p orti n g  
re q uire me nts. 
I n t he E U c o u ntries, it is t he S p o ns or’s res p o nsi bilit y t o re p ort S U S A Rs t o re g ulat or y a ut h orities 
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St u d y e n d p oi nts are cli nicall y a ntici pate d e ve nts i n A F s u bjects recei vi n g a ntit hr o m b otic t hera p y 
a n d  will  be  peri o dicall y  re vi e we d  b y  t he  D S M B  i n  a  bli n de d  ma n ner  t o  e ns ure  pr o m pt  
i de ntificati o n of a n y cli nicall y c o ncer ni n g safet y iss ues. 
 
9. 6.  
Re p orti n g of Pre g n a nc y/ E x p os ure i n Uter o 
T he s p o ns or or desi g nee m ust be n otifie d of a n y s u bject t hat bec o mes pre g na nt w hile partici pati n g 
i n a cli nical st u d y. All pre g na ncies m ust be f oll o we d t o c o ncl usio n t o deter mi ne t heir o utc o me. 
T his  i nf or mati o n  is  i m p orta nt  f or  b ot h  dr u g  sa fet y  a n d  p u blic  healt h  c o ncer ns.  It  is  t he  
res p o nsi bilit y of t he I n vesti gat or, or desi g nee, t o re p ort a n y preg na nc y i n a s u bject, w hic h occ urs 
d uri n g t he st u d y. 
If a n y st u d y s u bject bec o mes, or is f o u n d t o be, pre g na nt w hile recei vi n g, or wit hi n 3 0 da ys of 
disc o nti n ui n g t he i n vesti gati o nal pr o d uct, t he I n ve sti gat or s h o ul d c o ntact t he Me dical M o nit or t o 
disc uss s u bject ma na ge me nt a n d recei ve f urt her i nf or mati o n. N otificati o n of t he pre g na nc y s h o ul d 
be  s u b mitte d  i n  t he  e C R F  ( A E SIs)  wit hi n  2 4  h o urs  a n d  re p orte d  usi n g  E x p os ure  i n  Uter o  
Re p orti n g f or m ( pa per f or m).  
If it is t he part ner, rat her t ha n t he s u bject, w h o is f o u n d t o be  pre g na nt, t he E x p os ure i n Uter o 
Re p orti n g F or m s h o ul d be c o m plete d wit h t he s u bj ects’ I D n u m ber, a n d year of birt h. Details 
re gar di n g t he part ner s h o ul d be e ntere d i n t he narrati ve Secti o n of t he E x p os ure i n Uter o Re p orti n g 
f or m if a c o nse nt of t he trial s u bject’s part ner has bee n o btai ne d b y t he I n vesti gat or. 
If t he pre g na nc y is t o be ter mi nate d, t he a ntici pate d date of ter mi nati o n sh o ul d be pr o vi de d. If t he 
pre g na nc y e n ds f or a n y reas o n bef ore t he a nti ci pate d date, t he I n vest i gat or s h o ul d n otif y t he 
S p o ns or. If t he o utc o me of t he pre g na nc y meets t he criteri a f or i m me di ate cl assific ati o n as a 
S A E  (i.e.  p ost- p art u m  c o m plic ati o ns,  s p o nt a ne o u s  a b orti o n,  still birt h,  ne o n at al  de at h,  or 
c o n ge nit al  a n o m al y,  i ncl u di n g t h at  i n  a n  a b orte d  fet us), t he I n vesti gat or s h o ul d f oll o w t he 
pr oce d ures f or re p orti n g a n S A E.  At t he c o m pleti o n of t he pre g na nc y, t he I n vesti gat or will 
d oc u me nt t he o utc o me of t he pre g na nc y i n a f oll o w- u p E x p os ure i n Uter o Re p orti n g F or m. 
 
9. 7.  
Cli nic al L a b or at or y E v al u ati o ns 
Refer t o t he La b orat or y Ma n ual f or detaile d i nst r ucti o ns of sa m ple c ollecti o n, st ora ge, a n d 
s hi p me nt. T he res ults will be re vie we d a n d c o m pare d t o t he ce ntral la b ora t or y’s n or mal ra n ges. 
T he visits at w hic h t hese sa m ples will be c ollec te d are s h o w n i n t he sc he d ule of assess me nts 
( Secti o n 1 6. 9 ). 
T he f oll o wi n g safet y la b orat or y e val uati o ns ar e perf or me d i n i n di vi d ual bl o o d sa m ples.  
 Li ver F u ncti o n Pa nel 
o  T B L (c o nj u gate d/ u nc o nj u gate d perf or me d w he n t otal ser u m bilir u bi n ≥2 m g/ d L) 
o  A L T 
o  A S T 
o  A L P 


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 Ser u m C he mistr y Pa nel 
o  Creati ni ne 
 He mat ol o g y Pa nel i ncl u di n g 
o  W B C c o u nt wit h differe ntial if ele vate d 
o  Re d Bl o o d Cell c o u nts a n d stat us (e. g., he m o gl o bi n, he mat ocrit) 
o  Platelet c o u nt 
 I N R ( o nl y i n s u bjects ra n d o mize d t o V K A) 
I n w o me n of c hil d beari n g p ote ntial, a uri ne test f or pre g na nc y will be perf or me d at scree ni n g, at 
baseli ne, a n d at Da y 3 0. F urt her m or e, pre g na nc y te sts are carrie d o ut w he ne ver t here are cli nical 
i n dicati o ns f or t he e xiste nce of a pre g na nc y. 
All ot her assess me nts are c ollecte d fr o m l ocal la b orat or y res ults f or tests d o ne as part of r o uti ne 
care. L ocal la b orat or y assess me nts are use d t o verif y eli gi bilit y a n d f or para meters t hat re q uire 
m o nit ori n g acc or di n g t o l ocal r o uti ne. 
 
9. 8.  
Vit al Si g ns 
T he f oll o wi n g para meters are rec or de d f or vital si g ns: 
 Heart Rate (at all visits p ost scree ni n g) 
 B P, sitti n g diast olic a n d s yst olic B P (at all visits) 
 Wei g ht (at all visits) 
 Hei g ht ( o nl y at ra n d o mizati o n) 
 
9. 9.  
Electr oc ar di o gr a ms 
T wel ve-lea d  E C Gs  are  c ollecte d  acc or di n g  t o  t he  sc he d ule  of  assess me nts  ( Secti o n  1 6. 9 ).  
I n vesti gati o nal sites will utilize l ocal E C G e q uip me nt a n d rec or d perti ne nt i nf or mati o n i n t he 
e C R F w hile preser vi n g all rec or de d E C G traci n gs as s u bject s o urce d oc u me ntati o n.  
 
9. 1 0.  
P h ysic al E x a mi n ati o n Fi n di n gs 
T he I n vesti gat or or a lice nse d te a m me m ber perf or ms tar gete d p h ys ical e xa mi nati o n at Scree ni n g. 
T his p h ysical e xa mi nati o n c o nsists of assess me nt of eac h of t he rele va nt (i ncl u di n g b ut n ot li mite d 
t o car diac, ne ur ol o gic, p ul m o nar y, GI) maj or b o d y s yste ms. A n y cli nicall y si g nifica nt fi n di n gs 
m ust be rec or de d i n t he e C R F u n der me dical hist or y. 
 


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9. 1 1.  
M a g netic Res o n a nce I m a gi n g: Diff usi o n- Wei g hte d I m a gi n g 
Pr oce d ure-ass ociate d str o ke, as t h e m ost se vere disa blin g c o m plicati o n, is rare a n d occ urs i n less 
t ha n 1 % of s u bjects u n derg oi n g a blati o n. Ma g netic res o na n ce i ma gi n g ( M RI) i de ntifie d ne w 
e m b olic lesi o ns i n 4 0- 5 0 % of cases. P ositi ve M RI fi n di n gs ma y occ ur i n patie nts wit h o ut a p pare nt 
ne ur ol o gical deficit a n d are t heref ore classifie d as “as y m pt o matic” or “sile nt”. Sile nt cere bral 
e ve nts  ( S C E)  are  n ot  u ni q ue  t o  A F  a blati o n  b ut  ha ve  bee n  i de ntifie d  after  nearl y  a n y  C V  
i nter ve nti o ns, i ncl u di n g c or o nar y a n gi o gra p h y i n 1 5 %, val ve s ur ger y i n 4 2 %, a n d b ot h o n-a n d 
off- p u m p C A B G i n 2 2 %. As a c o nse q ue nce, S C E or sile nt cere bral le si o ns ( S C L) ha ve bee n 
ter me d t he “e m b olic fi n ger pri nt” of a s pecific C V i nter ve nti o n (2 9 ). 
I n c o m parati ve st u dies, S C E ( D WI- M RI p ositi ve o nl y) a p pear t o be a p pr o xi matel y 3 ti mes m ore 
c o m m o n c o m pare d t o usi n g a defi niti o n of sile nt  cere bral lesi o ns ( S C L; wit h o ut fl ui d atte n uate d 
i n verse rec o ver y se q ue nce [ F L AI R] p ositi vit y). W hereas t he F L AI R se q ue nce ma y t ur n p ositi ve 
wit hi n da ys after t he isc he mic e ve nt, S C E de fi niti o n is hi g hl y se nsitive f or earl y p hases of 
isc he mic brai n da ma ge. 
D W- M RI will be perf or me d i n a s u bset of st u d y s ites i n or der t o assess t he i nci de nce of S C E/ S C L 
u n der t he N O A C e d o xa ba n as c o m pare d t o c urre nt st a n dar d of care ma na ge me nt of u ni nterr u pte d 
V K A i n patie nts u n der g oi n g a n a blati o n pr oce d ure. 
T he M RI o utc o mes of i nterest i ncl u de b ut are n ot li mite d t o: ac ute D WI i nfarct prese nt or n ot, 
n u m ber of ac ute D WI i nfarcts prese nt, v ol u me of  eac h ac ute D WI i nfarct, t otal ac ute D WI i nfarct 
v ol u me, w hite matter lesi o n v ol u me o n T 2/ F L AI R, gre y matter ( G M) lesi o n v ol u me (ac ute a n d 
c hr o nic i nfarcts) o n T 2/ F L AI R. 
T he M RI pr ot oc ol will be pr o vi de d i n its e ntire t y i n t he Trial Site I ma gi n g Ma n ual a n d will be 
a da pte d acc or di n g t o t he M RI ve n d or a n d s pecificati o ns. 


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1 0.  
S T A TI S TI C A L M E T H O D S 
A ge neral descri pti o n of t he statis tical met h o ds use d is o utli ne d bel ow. A m ore detaile d statistical 
a nal ysis pla n ( S A P) will be pr o vi de d i n a se parate d oc u me nt. T he S A P will als o acc o m m o date 
pr ot oc ol a me n d me nts or u ne x pecte d iss ues i n st u d y e xec uti o n or data t hat affect pla n ne d a nal yses, 
a n d will pr o vi de m ore details o n t he a nal ytic a p pr oac hes, c o di n g g ui deli nes, ce ns ori n g of ti me-
t o-e ve nt varia bles, a n d o ut p ut ta bles a n d fi g ures. T o preser ve t he i ntegrit y of t he statistical a nal ysis 
a n d cli nical st u d y c o ncl usi o ns, t he S A P will be fi nalize d pri or t o data base l oc k. 
 
1 0. 1.  
A n al ysis Sets 
1 0. 1. 1.  
I nte nt-t o- Tre at A n al ysis Set 
T he I nte nt-t o-treat (I T T) a nal ysis set c o nsists of  all ra n d o mize d s u bjects irres pecti ve w het her t he y 
recei ve d a si n gle d ose of t he ra n d o mize d st u d y re gi me n or n ot. 
A nal yses will be base d o n t he ra n d o mize d treat me nt re gi me n e ve n if a s u bject i na d verte ntl y 
recei ves  t he  i nc orrect  dr u g(s)  or  d osa ge  or  has  his/ her  e d o xa ba n  d ose  a dj uste d  ( decrease d/  
i ncrease d) o ne or m ore ti mes d uri n g t he st u d y. T he refere nce date f or c o nsi derati o n of e n d p oi nts 
is t he date a n d ti me of r a n d o mizati o n. 
1 0. 1. 2.  
M o difie d I nte nt-t o- Tre at A n al ysis Set 
T he m o difie d I nte nt-t o- Treat ( mI T T) a nal ysis set c o nsists of all ra n d o mize d s u bjects w h o recei ve d 
at least o ne d ose of st u d y e d o xa ba n or st u d y V K A acc or di n g t o I X R S assi g n me nt.  
A nal yses will be base d o n t he ra n d o mize d treat me nt re gi me n e ve n if a s u bject i na d verte ntl y 
recei ves  t he  i nc orrect  dr u g(s)  or  d osa ge  or  has  his/ her  e d o xa ba n  d ose  a dj uste d  ( decrease d/  
i ncrease d) o ne or m ore ti mes d uri n g t he st u d y. T he refere nce date f or c o nsi derati o n of e n d p oi nts 
is t he date a n d ti me of first i ntake of st u d y e d o xa ba n or st u d y V K A. 
1 0. 1. 3.  
Per Pr ot oc ol A n al ysis Set 
T he Per Pr ot oc ol ( P P) a nal ysis se t c o nsists of all ra n d o mize d s u bjects w h o recei ve d at least o ne 
d ose of t he st u d y re gi me n a n d d o n ot ha ve a n y of  t he f oll o wi n g maj or pr ot oc ol vi olati o ns: 
 N ot u n der g oi n g a cat heter a blati o n  
 N o A F 
 K n o w n c o ntrai n dicati o n f or O A C 
 A maj or vi olati o n of t he i ncl usi o n criteria 
 A maj or vi olati o n of t he e xcl usi o n criteria 
T he f ull list of maj or vi olati o ns wi ll be descri be d i n t he S A P a n d finalize d bef ore data base l oc k.  
T he list a n d t he e xcl usi o ns will be c o nfir me d i n a bli n de d wa y, i.e. wit h o ut k n o wle d ge of t he 
ra n d o mize d st u d y re gi me n a n d of t he cli nical o utc o mes. 


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A nal yses will be base d o n t he ra n d o mize d treat m e nt re gi me n, e ve n if a s u bject i na d verte ntl y 
recei ves t he i nc orrect dr u g(s) or d osa ge or has his/ her e d o xa ba n d osa ge a dj uste d ( decrease d/ 
i ncrease d) o ne or m ore ti mes d uri n g t he st u d y. T he refere nce date f or c o nsi derati o n of e n d p oi nts 
is t he date a n d ti me of first i ntake of st u d y e d o xa ba n or st u d y V K A. 
1 0. 1. 4.  
S afet y A n al ysis Set 
T he Safet y ( S A F) a nal ysis set c o nsists of all ra n d o mize d s u bjects w h o rece i ve d at least o ne d ose 
of t he st u d y e d o xa ba n or st u d y V K A acc or di n g t o I X R S assi g n me nt. 
A nal yses will be base d o n t he ra n d o mize d trea t me nt re gi me n, e ve n if t he s u bject’s e d o xa ba n 
d osa ge  is  a dj uste d  after  ra n d o mizati o n,  u nless  a  s u bject  i na d verte ntl y  recei ves  t he  i nc orrect  
dr u g(s) or d osa ge d uri n g t he e nti re st u d y, i n w hic h case t he s u bject will be gr o u pe d acc or di n g t o 
t he treat me nt act uall y recei ve d. T he refere nce date f or c o nsi deratio n of e n d p oi nts is t he date of 
first st u d y me dicati o n i nta ke. 
N ote: T his S A F a nal ysis set will be use d f or t he safet y para meters (e. g. A Es, vital si g ns, la b orat or y 
para meters, etc.) as descri be d u n der Secti o n 9 . 
 
1 0. 2.  
Ge ner al St atistic al C o nsi der ati o ns 
Acc or di n g t o t he o bjecti ves of t his st u d y, t he statistical a nal ysis s h o ul d be i nter prete d i n a p urel y 
e x pl orat or y- descri pti ve wa y. N o  f or mal c o nfir mat or y statistical testi n g is pla n ne d. 
All a nal yses will be perf or me d o n o bser ve d data  o nl y. N o missi n g data will be i m p ute d. Data o n 
s u bjects w h o d o n ot reac h a s pecific e n d p oi nt will be ce ns ore d i n t he c orres p o n di n g statistical 
a nal yses. 
Ra w data will be prese nte d wit h t he e xact precis i o n ( deci mal p oi nts) wit h w hic h it was c ollecte d. 
T he p- val ues will be prese nte d i n t he e n d- of-te xt ta bles e xactl y as t he y are i n s u p p orti n g statistical 
d oc u me nts ( 4 deci mal p oi nts). T he te xt a n d i n-te xt ta bles will dis pla y p- val ues wit h t hree deci mal 
places, as l o n g as, t he decisi o n f o r statistical si g nifica nce will n ot be c ha n ge d b y r o u n di n g.  
T he n u m ber of deci mal places t o dis pla y f or calc ul ate d data will be deter mi ne d b y t he scale of 
meas ure me nt. N o deci mal places will be dis p la ye d if t he s mallest calc ulate d val ue is ≥1 0 0; O ne 
( 1) deci mal place will be dis pla ye d w he n all calc ulate d val ues are wit hi n t he i nter val ( 1 0, 1 0 0), 
wit h 1 0 bei n g i ncl usi ve; T w o ( 2) deci mal places w ill be dis pla ye d w he n all calc ulate d val ues are 
wit hi n  ( 1,  1 0),  wit h  1  bei n g  i ncl usi ve;  a n d  s o  o n  f or  e ve n  s maller  scales  of  meas ure me nt.  
Perce nta ges will be re p orte d wit h  e xactl y o ne deci mal place.  
F or c o nti n u o us varia bles, statistical s u m mar ies will i ncl u de n ( n u m ber of s u bjects wit h n o n-
missi n g data), mea n, me dia n, sta n dar d de viati o n, mi ni m u m a n d ma xi m u m. Mea ns a n d me dia ns 
will be dis pla ye d t o o ne m ore deci mal places t ha n t he ra w or calc ulate d data; sta n dar d de viati o n 
a n d ot her dis persi o n statistics will ha ve t wo m ore deci mal places; a n d mi ni m u m a n d ma xi m u m 
val ues will be dis pla ye d t o t he sa me n u m ber of  deci mal places as t he ra w or calc ulate d data. 
F or cate g orical varia bles, statistical s u m maries will i ncl u de c o u nts a n d perce nta ges. Perce nta ges 
will be re p orte d wit h e xactl y o ne deci mal place. I n ge neral, perce nta ges are base d o n t he t otal 
n u m ber of s u bjects wit h i nf or mati o n a vaila ble (ie n o n- missi n g data). F or A E a n d i nci de nce base d 


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a nal yses, perce nta ges will be base d o n t he t otal n u m b er of s u bjects i n t he a nal ysis set of i nterest 
a n d i n t hat treat me nt re gi me n. 
T he  statistical  data  a nal ysis  will  be  perf or me d  b y  a  C R O  u n der  t he  g ui da nce  of  t he  st u d y  
bi ostatisticia n usi n g S A S Versi o n 9. 3 or hi g her. 
 
Defi niti o n of ter ms: 
‘Over all St u dy Peri o d ’:   T his peri o d is defi ne d as t he ti me fr o m t he refere nce date ( date a n d ti me 
of ra n d o mizati o n or date a n d ti me of firs t d ose of st u d y me dicati o n) t o Da y 9 0/ E O T. 
‘Over all St u dy Peri o d + 3 0 d ays ’:   T his peri o d is defi ne d as t he ti me fr o m t he refere nce date 
( date a n d ti me of ra n d o mizati o n or date a n d ti me of first d ose of st u d y me dicati o n) t o Da y 9 0/ E O T 
+ 3 0 da ys. 
‘P ost- a bl ati o n St u dy Peri o d ’:   T his peri o d is defi ne d as t he ti me fr o m t he e n d of t he cat heter 
a blati o n pr oce d ure t o Da y 9 0/ E O T. 
‘P ost- a bl ati o n St u dy Peri o d + 3 0 d ays ’:   T his peri o d is defi ne d as t he ti me fr o m t he e n d of t he 
cat heter a blati o n pr oce d ure t o Da y 9 0/ E O T + 3 0 da ys. 
 
F oll o w- u p is ce ns ore d at t he last  date of k n o w n f oll o w- u p stat us i n s u bjects wit h i nc o m plete 
f oll o w- u p. I n vesti gat ors are i nstr ucte d t o c o m plete f oll o w- u p as m uc h as p ossi ble irres pecti ve of 
c ha n ges or disc o nti n uati o n of st u d y me dicati o n. 
All a dj u dicate d e n d p oi nts are a nal yze d as ti me t o first occ urre nce of a n y of its c o m p o ne nts. 
F or all s pecific e n d p oi nts bli n dl y a dj u dicate d b y t he C E C, t he C E C’ s i nter pretati o n pre vails a n d 
is use d i n t he statistical a nal yses. 
T he a nal ysis set a n d a nal ysis peri o d t o be use d f or t he mai n a nal ysis of t he vari o us a dj u dicate d 
e n d p oi nts is prese nte d bel o w: 
E n d p oi nt(s) 
Pri m ar y a n al ysis set   
Pri m ar y a n al ysis peri o d 
Pri mar y  
P P 
p ost-a blati o n peri o d 
Pri mar y safet y  
mI T T 
o verall st u d y peri o d 
Sec o n dar y efficac y  
P P 
p ost-a blati o n peri o d 
Sec o n dar y safet y  
mI T T 
o verall st u d y peri o d 
 
H o we ver, i n s u p ple me ntal a nal yses, ot her c o m bi nati o ns of a nal ysis sets a n d a nal ysis peri o ds ma y 
be c o nsi dere d t o e val uate t he r o b ust ness of t he mai n a nal yses o n a dj u dicate d efficac y a n d/ or safet y 
e n d p oi nts. Details o n t hese a nal yses  will be descri be d i n t he S A P. 
 


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1 0. 3.  
St u d y P o p ul ati o n D at a 
S u bject dis p ositi o n will be s u m marize d f or eac h  ra n d o mize d treat me nt a n d i n t otal f or t he I T T 
a nal ysis set. T he n u m ber of s u bjects f or eac h de fi ne d a nal ysis set b y treat me nt gr o u p will als o be 
ta b ulate d. 
T he  de m o gra p hic  a n d  baseli ne  c haracteristics  i ncl u di n g  baseli ne  disease  stat us  will  be  
s u m marize d descri pti vel y b y treat me nt gr o u p f or t he I T T, mI T T, P P a n d S A F a nal ysis sets. 
E x p os ure  t o  st u d y  me dicati o n  (e d o xa ba n  a n d  V K A)  will  be  s um marize d  usi n g  descri pti ve  
statistics b y treat me nt gr o u p f or t he mI T T, P P a n d S A F a nal ysis sets. I nterr u pti o ns a n d per ma ne nt 
disc o nti n uati o ns (see Secti o n 5. 2. 3 ) will be s u m marize d b y treat me nt gr o u p f or t he sa me a nal ysis 
sets. 
T he ti me i n t hera pe utic ra n ge ( T T R) (I N R: 2. 0- 3. 0, i ncl usi ve) will be esti mate d f or eac h s u bject 
ra n d o mize d t o t he V K A ar m usi n g t he i nter p olati o n met h o d of R ose n daal (3 0 ). 
1 0. 4.  
St atistic al A n al ysis 
1 0. 4. 1.  
A n al ysis of A dj u dic ate d Effic ac y E n d p oi nts 
T he f oll o wi n g e n d p oi nts are c o nsi dere d as efficac y e n d p oi nts: 
 C o m p osite of all-ca use deat h, str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) a n d Maj or 
Blee di n g [I S T H defi niti o n] ( pri m ary effic acy e n d p oi nt ) 
 C o m p osite of all-ca use deat h, str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d, acc or di n g 
t o alter nati ve defi niti o n (1 ); see Secti o n 7. 4. 2 . f or details) a n d Maj or Blee di n g (I S T H 
defi niti o n) 
 C o m p osite of str o ke (isc he mic, he m orr ha gic , or u n deter mi ne d) S E E, a n d C V m ortalit y  
 C o m p osite of str o ke (isc he mic, he m orr ha g ic, or u n deter mi ne d) S E E, a n d all-ca use 
m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) a n d TI A 
 Str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Str o ke (isc he mic) 
 Str o ke ( he m orr ha gic) 
 Str o ke ( u n deter mi ne d) 
 S E E 
 TI A 
 Fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n-fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d)  
 Disa bli n g str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
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F or all e n d p oi nts bli n dl y a dj u dica te d b y t he C E C, t he C E C’s i nter pretati o n pre vails a n d is use d i n 
t he statistical a nal ysis. 
F or eac h of t he pri mar y a n d sec o n dar y efficac y e n d p oi nts, a p pr o priate s u m mar y statistics (e. g. 
e ve nt rate) i ncl u di n g 9 5 % c o nfi de nce i nter val ( CI) will be pr o vi de d.  
F or eac h of t he e n d p oi nts, t he ti me fr o m refere nce da te t o t he first occ urre nce of a n e ve nt ( base d 
o n C E C a dj u dicati o n) is a nal yze d usi n g a C o x pr o p orti o nal hazar d m o del wit h treat me nt re gi me n 
as a fact or, t o pr o vi de p oi nt esti mates a n d 9 5 %  CI f or t he hazar d rati o ( H R). De pe n di n g o n t he 
a nal ysis peri o d use d i n t he statistical a nal ysis, s u bjects wit h o ut a n occ urre nce of a n e ve nt will be 
ce ns ore d at t he last date of t he a nal ysis peri o d or at t he last date of k n o w n o utc o mes stat us. T he 
latter is deter mi ne d a n i n di vi d ual basis f or s u bjects wit h i nc o m plete f oll o w- u p. 
T he para meter esti mate β  ( = l n ( H R), its sta n dar d err or, p- val ue, a n d 9 5 % c o nfi de nce li mits are 
calc ulate d  acc or di n g  t o  t he  ma xi m u m  partia l  li keli h o o d  met h o d  ( M L),  wit h  Bresl o w’s  
a p pr o xi mati o n f or ties ( S A S P H R E G pr oce d ure). 
F or ti me t o first e ve nt a nal yses base d o n t he ‘ o verall st u d y peri o d’, ‘ o verall st u d y peri o d + 
3 0 da ys’, ‘ p ost-a blati o n st u d y peri o d’ a n d p ost-a blati o n st u d y peri o d + 3 0 da ys’, c u m ulati ve e ve nt 
rates o ver ti me are s u m marize d usi n g t he Ka pla n- Meier met h o d. 
1 0. 4. 2.  
A n al ysis of A dj u dic ate d S afet y E n d p oi nts 
T he f oll o wi n g e n d p oi nts are c o nsi dere d as safet y e n d p oi nts: 
 Maj or Blee di n g [I S T H defi niti o n] ( pri m ary s afety e n d p oi nt ) 
 Maj or Blee di n g [ defi ne d b y TI MI, B A R C ( 2 or hi g her)] 
 Maj or or C R N M blee di n g [I S T H defi niti o n] 
 C R N M blee di n g [I S T H defi niti o n] 
 Mi n or blee di n g [I S T H defi niti o n] 
 A n y blee di n g 
 I C H 
 Life-t hreate ni n g blee di n g 
 Fatal Maj or Blee di n g [I S T H defi niti o n] 
 N o n-fatal Maj or Blee di n g [I S T H defi niti o n] 
 Fatal Maj or Blee di n g [ defi ne d b y TI MI, B A R C ( 2 or hi g her)] 
 N o n-fatal Maj or Blee di n g [ defi ne d b y TI MI, B A R C ( 2 or hi g her)] 
 
All t hese e n d p oi nts will be a nal yze d usi n g t he sa me me t h o d ol o g y as descri be d i n Secti o n 1 0. 4. 1 . 


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1 0. 4. 3.  
A n al ysis of Ot her P ar a meters 
All para meters me nti o ne d i n Secti o n 7. 3. 1  will be s u m marize d descri pti vel y b y treat me nt 
re gi me n f or t he I T T, mI T T, a n d P P a nal ysis sets. 
 
1 0. 4. 4.  
S afet y A n al yses 
1 0. 4. 4. 1.  A d verse E ve nt A n al yses 
A d verse e ve nts meeti n g t he criteria defi ne d i n Secti o n  9. 1 will be rec or de d i n t he e C R F a n d c o de d 
b y s yste m or ga n class a n d preferre d ter m usi n g t he Me dical Dic ti o nar y f or Re g ulat or y Acti vities 
( Me d D R A), versi o n 1 9. 1 or ne wer. 
Treat me nt-e mer ge nt a d verse e ve nts ( T E A Es) are defi ne d as e ve nts w hic h star t o n or after a n y first 
d ose of t he assi g ne d st u d y me dicati o n re gi me n or starte d pri or t o b ut  t he n w orse ne d after a n y first 
d ose of t he assi g ne d st u d y me dicati o n re gi me n. A n A E t hat occ urs m ore t ha n 3 0 da ys after t he date 
of t he last d ose of t he assi g ne d st u d y me dicati o n re gi me n will  n ot be c o u nte d as a T E A E. 
T he A E a nal ysis will be base d o n t he S A F a nal ys is set. T E A Es will be s u m marize d b y treat me nt 
gr o u p. T he i nci de nce of T E A Es will be prese n te d b y treat me nt gr o u p, b y relati o ns hi p t o t he 
assi g ne d st u d y re gi me n, a n d b y se verit y.  If m ore t ha n o ne A E is c o de d t o t he sa me preferre d ter m 
f or t he sa me s u bject, t he s u bject will be c o u nte d o nl y o nce f or t hat preferre d ter m usi n g t he greatest 
se verit y a n d strictest ca usalit y f or t he s u m marizati o n b y se verit y a n d ca usal relati o ns hi p. Fre q ue nt 
T E A Es (re p orte d b y at least 5 % re s p. 1 % of s u bjects i n a n y treat ment gr o u p) will be s u m marize d 
b y re gi me n gr o u p. 
T he i nci de nce of deat h, S A Es, dr u g-relate d S A Es, a n d A Es lea di n g t o per ma ne nt disc o nti n uati o n 
of t he assi g ne d st u d y re gi me n will be s u m marize d.  All A Es rec or de d will be i ncl u de d i n a data 
listi n g a n d a listi n g t o dis pla y t he c o di n g of A Es will be pre pare d as well. 
1 0. 4. 4. 2.  Cli nic al L a b or at or y E v al u ati o n A n al yses 
T he cli nical la b orat or y e val uati o ns  f or eac h sc he d ule d test a n d t he c ha n ge fr o m baseli ne will be 
s u m marize d f or t he S A F a nal ysis set b y treat me nt gr o u p. S hift ta bles (i n cate g ories of l o w, n or mal, 
a n d hi g h) will be pr o vi de d f or eac h treat me nt re gi me n f or selecte d la b orat or y para meters. Als o, 
t he n u m ber a n d perce nta ge of s u bjects wit h cli nicall y rele va nt a b n or mal la b orat or y val ues w hile 
o n st u d y dr u g will be calc ulate d f or eac h treat m e nt re gi me n f or selecte d la b orat or y para meters. 
All a b n or mal la b orat or y val u es will be prese nte d i n a listi n g. M ore details w ill be pr o vi de d i n t he 
S A P. 
1 0. 4. 4. 3.  Vit al Si g ns A n al yses 
Vital si g ns at eac h e val uati o n p oi nt a n d t he c ha n ge  fr o m baseli ne will be s u m marize d f or t he S A F 
a nal ysis set b y treat me nt gr o u p. M ore de tails will be pr o vi de d i n t he S A P. 


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1 0. 4. 4. 4.  Electr oc ar di o gr a m A n al yses 
T he E C G e val uati o ns at ra n d o mizati o n, car diac a blati o n visit, h os pital disc ha r ge, Da y 3 0 a n d Da y 
9 0 will be s u m marize d b y treat me nt gr o u p base d o n S A F a nal ysis set. M ore details o n t he E C G 
a nal ysis will be pr o vi de d i n t he S A P. 
1 0. 4. 4. 5.  P h ysic al E x a mi n ati o n A n al yses 
A p h ysical e xa mi nati o n will o nl y be pe rf or me d at t he Scree ni n g visit. 
C o u nts  a n d  perce nta ges  of  p h ysical  e xa mi nati o n  fi n di n gs  will  be  s u m marize d  b y  treat me nt  
re gi me n base d o n S A F a nal ysis set. 
1 0. 4. 5.  
Ot her A n al yses 
Details o n a n y ot her a nal yses, if a p pl ica ble, will be gi ve n i n t he S A P. 
 
1 0. 5.  
I nteri m A n al yses 
N ot a p plica ble. 
 
1 0. 6.  
D at a a n d S afet y M o nit ori n g B o ar d  
T here will be a n i n de pe n de nt D S M B t o pr otect t he ri g hts, safet y  a n d well- bei n g of s u bjects 
partici pati n g i n t his st u d y. T he D S M B will be i n v ol ve d i n t he ma na ge me nt of t his cli nical st u d y 
ser vi n g as t he safet y m o nit ori n g a d vis or y gr o u p f or t he st u d y. T he pri mar y r ole of t he D S M B will 
be t o e xa mi ne t he safet y data (i nci de nce of Maj or Blee di n gs, C R N M bl ee di n g, or ot her safet y 
e n d p oi nts,  or  s us pecte d  relate d  ( S) A Es)  o n  a n  o n g oi n g  ma n ner  a n d  t o  alert  t he  E xec uti ve  
C o m mittee i n case of a n y cli nicall y c o ncer ni n g safet y iss ues. 
T he fre q ue nc y a n d e xte nt of t he data re vie ws b y t he D S M B, details a b o ut t he re vie ws a n d st o p pi n g 
r ules  or  criteria  f or  e val uati n g  nee d  f or  st u d y  pr ot oc ol  m o dificati o ns  will  be  descri be d  a n d  
s pecifie d i n t he D S M B c harter.  
 
1 0. 7.  
S a m ple Size Deter mi n ati o n 
T he pri mar y efficac y e n d p oi nt is t he i nci de nce of a c o m p osite of all-ca use deat h, str o ke (isc he mic, 
he m orr ha gic or u n deter mi ne d), a n d Maj or Blee di n g e ve nts (I S T H defi niti o n) d uri n g t he peri o d 
fr o m t he e n d of t he cat heter a blati o n pr oce d ure t o Da y 9 0/ E O T.  
A rate of u p t o 3 % of  t he c o m bi ne d pri mar y e n d p oi nt ca n be e x pecte d i n t he V K A ar m as o bser ve d 
fr o m  p u blis he d  st u dies  a n d  retr os pecti ve  a nalyses.  Base d  o n  a  ver y  rece nt  st u d y  i n v ol vi n g  
u ni nterr u pte d a ntic oa g ulati o n wit h V K A, a sli g htl y  l o wer rate of t he c o m bi ne d e n d p oi nt of a b o ut 
2 % ca n be a ntici pate d ( V E N T U R E A F [ 5 ]).  
I n a lar ge retr os pecti ve case series, fatal o utc o me i n cat heter a blati o n of A F has bee n f o u n d t o 
occ ur i n 0. 1 % ( 3 1 ). Ne ur ol o gical c o m plicati o ns ( p ost o perati ve str o ke/ TI A) were re p orte d i n 1. 0 % 
of patie nts u n der g oi n g a blati o n i n o ne lar ge s ur ve y ( 3 2 ). I n a n ot her s ur ve y, str o ke ( 0. 2 3 %) a n d 


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TI A ( 0. 7 1 %) ha ve bee n re p orte d se paratel y ( 9 ). I n t he C O M P A R E st u d y, patie nts u n der c o nti n ue d 
a ntic oa g ulati o n wit h warfari n e x perie nce d 0. 2 5 % str o kes ( 1 4 ). I n a m ore rece nt st u d y i n v ol vi n g 
N O A Cs, a rate 2. 1 % of str o kes has bee n f o u n d u n der V K A ( 1 0 ). Maj or Blee di n g c o m plicati o ns 
ha ve occ urre d wit h i nci de nces of 3. 3 8 % ( p ost o p he m orr ha ge) a n d 0. 5 8 % ( p ost o p he m orr ha ge 
re q uiri n g tra nsf usi o n) i n a lar ge s ur ve y (3 2 ). A n i nci de nce of 0. 3 8 % of Maj or Blee di n g e ve nts has 
bee n re p orte d i n t he C O M P A R E st u d y u n der c o nti n ue d a d mi nistra ti o n of warfari n (1 4 ). U n der 
i nterr u pte d V K A, t he i nci de nce of Maj or Blee di n g was 4. 2 % i n a n ot her rece nt st u d y ( 1 0 ). I n a 
f urt her rece nt st u d y i n vesti gati n g t w o re gi me ns of u ni nterr u pte d a ntic oa g ulati o n, 2. 2 % of Maj or 
Blee di n g e ve nts occ urre d i n t he warfari n gr o u p ( 1 1 ). I n a meta-a nal ysis c o veri n g a br oa der ra n ge 
of patie nts u n der g oi n g de vice i m pla ntati o n, 2. 8 % of patie nts were  s ufferi n g fr o m Maj or Blee di n g 
e ve nts u n der c o nti n ue d oral a ntic oa g ulati o n ( 3 3 ). 
Base d u p o n t his pre dicte d rate, a f or mal sa m ple  size deter mi nati o n base d o n n o n-i nferi orit y or 
s u peri orit y of e d o xa ba n vers us V K A is n ot feasi ble. T he st u d y size is pla n ne d base d u p o n t he 
pri mar y c o m p osite e n d p oi nt t o i n cl u de a n a de q uate n u m ber of s u bjects t hat wi ll pr o vi de t he 
e x pecte d i nci de nce rates o n t he pr i mar y e n d p oi nt. T heref ore, t he pla n is t o i ncl u de 4 5 0 s u bjects 
i n t he P P st u d y p o p ulati on (s u bjects w h o ha ve u n der g o ne t he a blati o n pr oce d ure a n d c o m pleti n g 
t he st u d y). I n or der t o ac hie ve t his, a p pr o xi matel y 5 6 0 s u bjects will nee d t o be e nr olle d i n t he 
st u d y. T he st u d y will be st o p pe d o nce t he n u m ber of 4 5 0 s u bjects bel o n gi n g t o t he P P a nal ysis set 
is reac he d. 
 


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1 1.  
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E 
T he I n vesti gat or/i n vesti gati o nal site will per mit st u d y-relate d m o nit ori n g, a u dits, I E C re vie w a n d 
re g ulat or y  i ns pecti o ns  b y  pr o vi din g  direct  access  t o  s o urce  data/ d oc u me nts.   Direct  access  
i ncl u des per missi o n t o e xa mi ne, a nal yze, verif y a n d re pr o d uce a n y rec or ds a n d re p orts t hat are 
i m p orta nt t o t he e val uatio n of a cli nical st u d y. 
 
1 1. 1.  
M o nit ori n g a n d I ns pecti o ns 
T he S p o ns or, site m o nit ors, a n d re g ulat or y a ut h orit y i ns pect ors are res p o nsi ble f or c o ntacti n g a n d 
visiti n g t he I n vesti gat or f or t h e p ur p ose of i ns pecti n g t he faci lities a n d, u p o n re q uest, i ns pecti n g 
t he vari o us rec or ds of t he st u d y (e. g., e C R Fs, s o urce data, a n d ot her perti ne nt d oc u me nts). 
T he m o nit or is res p o nsi ble f or visiti n g site(s) at re g ular i nter vals (as detaile d i n t he M o nit ori n g 
Pla n) t hr o u g h o ut t he st u d y t o verif y a d here nce t o t he pr ot oc ol; c o m plete ness, acc urac y, a n d 
c o nsiste nc y of t he data; a n d a d here nce t o I nter nati o nal C o nfere nce o n Har m o nizati o n G o o d 
Cli nical Practice ( G C P) a n d l ocal re g ulati o ns o n t he c o n d uct of cli nical researc h.  T he m o nit or is 
res p o nsi ble f or i ns pecti n g t he e C R Fs a n d e ns uri n g c o m plete ness of t he st u d y esse ntial d oc u me nts.  
T he m o nit or s h o ul d ha ve access t o s u bject me dical rec or ds a n d ot her st u d y-relate d rec or ds nee de d 
t o verif y t he e ntries o n t he e C R Fs. 
T he  m o nit or  will  c o m m u nicate  de viati o ns  fr o m  t he  pr ot oc ol,  S O Ps,  G C P  a n d  a p plica ble  
re g ulati o ns  t o  t he  I n vesti gat or  a n d  will  e ns ure t hat  a p pr o priate  acti o n  desi g ne d  t o  pre ve nt  
rec urre nce of t he detecte d de viati o ns is ta ke n a n d d oc u me nte d. 
T he I n vesti gat or a grees t o c o o pera te wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms detecte d i n t he 
c o urse of t hese m o nit ori n g visits  are a d dresse d a n d d oc u me nte d. 
I n acc or da nce wit h G C P a n d t he S p o ns or’s a u dit pla ns, t his st u d y ma y be selecte d f or a u dit b y 
re prese ntati ves fr o m s p o ns or.  I ns pecti o n of site facilities (e. g., p har mac y, dr u g st ora ge areas, 
la b orat ories, etc.) a n d re vie w of st u d y relate d rec or ds will occ ur i n or der t o e val uate t he st u d y 
c o n d uct a n d c o m plia nce wit h t he pr ot oc ol, G C P,  a n d a p plica ble re g ulat or y re q uire me nts. 
I n t he e ve nt t hat a re g ulat or y a ut h orit y i nf or ms t he I n vesti gat or  t hat it i nte n ds t o c o n d uct a n 
i ns pecti o n, s p o ns or s hall be n otifie d i m me diatel y. 
 
1 1. 2.  
D at a C ollecti o n 
T he e C R F c o m pleti o n s h o ul d be ke pt c urre nt t o e na b le t he m o nit or t o re vie w t he s u bject’s stat us 
t hr o u g h o ut t he c o urse of t he st u d y.  T he e C R F is c o m plete d b y t he I n vesti gat or or q ualifie d 
desi g nee.   C o m plete d  e C R Fs  are  re vie we d  a n d  e-si g ne d  b y  t he  I n ves ti gat or  ( or  b y  a  s u b-
I n vesti gat or, wit h per missi o n of t he S p o ns or). 
 
1 1. 3.  
D at a M a n a ge me nt 
Eac h s u bject will be i de ntifie d i n t he data base b y a u ni q ue s u bject I D n u m ber as defi ne d b y t he 
s p o ns or. 


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T o e ns ure t he q ualit y of cli nical data acr oss al l s u bjects a n d sites, a Cli nical Data Ma na ge me nt 
re vie w will be perf or me d o n s u bject data acc or di n g t o s pecificati o ns gi ve n t o t he C R O.  Data i n 
t he e C R F is vette d electr o nicall y b y pr o gra m me d data r ules wit hi n t he a p plicati o n. Q ueries 
ge nerate d b y r ules a n d raise d b y re vie wers will be ge nerate d wit hi n t he electr o nic data ca pt ure 
( E D C) a p plicati o n.  D uri n g t his re vie w, s u bject data will be c hec ke d f or c o nsiste nc y, o missi o ns, 
a n d a n y a p pare nt discre pa ncies. 
Data recei ve d fr o m e xter nal s o urces s uc h as ce ntral la bs will be rec o ncile d t o t he cli nical data base. 
S A Es i n t he cli nical data base will be rec o ncile d wit h t he safet y data base. 
 
1 1. 4.  
St u d y D oc u me nt ati o n a n d St or a ge 
T he I n vesti gat or will mai ntai n a Si g nat ure List of  a p pr o priatel y q ualifie d pers o ns t o w h o m he/s he 
has dele gate d st u d y d uties.  All pe rs o ns a ut h orize d t o ma ke e ntries a n d/ or c orrecti o ns o n e C R Fs 
will be i ncl u de d o n t he Si g nat ure List. 
S o urce d oc u me nts are ori gi nal d oc u me nts, data, a n d rec or ds fr o m w hic h t he s u bject’s e C R F data 
are o btai ne d.  T hese i ncl u de b ut are n ot li mite d t o  h os pital rec or ds, cli nical a n d office c harts, 
la b orat or y a n d p har mac y rec or ds, diaries, micr ofic hes, X-ra ys, a n d c orres p o n de nce. 
T he I n vesti gat or a n d st u d y staff are res p o nsi ble f or mai ntai n i n g a c o m pre he nsi ve a n d ce ntralize d 
fili n g  s yste m  ( Trial  Master  File)  of  all  st u d y-relate d  (esse ntial)  d oc u me ntati o n,  s uita ble  f or  
i ns pecti o n at a n y ti me b y re prese ntati ves fr o m s p o ns or a n d/ or a p plica ble re g ulat or y a ut h orities. 
Esse ntial d oc u me nts i ncl u de: 
 S u bject files c o ntai ni n g I Cs, a n d s u p p orti n g c o pies of s o ur ce d oc u me ntati o n as use d f or 
e C R Fs c o m pleti o n. I n a d diti o n, all ori gi nal  s o urce d oc u me nts s u p p orti n g e ntries i n t he 
e C R Fs m ust be mai ntai ne d a n d be rea dil y a vaila ble. 
 St u d y files c o ntai ni n g t he pr ot oc ol  wit h all a me n d me nts, I B, co pies of rele va nt esse ntial 
d oc u me nts re q uire d pri or t o c o m me nci n g a cli nical st u d y, a n d all c orres p o n de nce t o a n d 
fr o m t he I E C/I R B a n d S p o ns or. 
 Rec or ds relate d t o t he st u d y me dicati o ns deli vere d i ncl u di n g ac k n o wle d g me nt of recei pt at 
site, acc o u nta bilit y rec or ds a n d fi nal reco nciliati o n a n d a p plic a ble c orres p o n de nce. 
I n a d diti o n, all ori gi nal s o urce d oc u me nts s u p p orti n g e ntries i n t he e C R Fs m ust be mai ntai ne d 
a n d be rea dil y a vaila ble. 
Esse ntial cli nical trial d oc u me nt s (i ncl u di n g case re p ort f or ms) other t ha n s u bject's me dical files 
m ust be ke pt f or at least 1 5 y ears after c o m pleti o n or disc o nti n uati o n of t he trial. S u bject's me dical 
files s h o ul d be retai ne d i n acc or da nce wit h a p plica ble le gisl ati o n a n d i n acc or da nce wit h t he 
ma xi m u m  peri o d  of  ti me  per mitte d  b y  t he  h os pital,  i nstit uti o n  or  pri vate  practice.  It  is  t he  
res p o nsi bilit y of t he s p o ns or t o i nf or m t he I n vesti gat or/i nstit uti o n as t o w he n t he cli nical trial 
d oc u me nts n o l o n ger nee d t o be retai ne d.  
N o st u d y d oc u me nt s h o ul d be destr o ye d wit h o ut pr i or writte n a gree me nt bet wee n s p o ns or a n d t he 
I n vesti gat or.  S h o ul d t he I n vesti gat or wis h t o assi g n t he st u d y rec or ds t o a n ot her part y or m o ve 


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t he m t o a n ot her l ocati o n, he/s he m ust n otif y D SE i n writi n g of t he ne w res p o nsi ble pers o n a n d/ or 
t he ne w l ocati o n. 
 
1 1. 5.  
Rec or d Kee pi n g 
Rec or ds of s u bjects, s o urce d oc u me nts, m o nit ori n g visit l o gs, data c orrecti o n f or ms, e C R Fs, 
i n ve nt or y of st u d y pr o d uct, re g ulat or y d oc u me nts (e. g., pr ot oc ol a n d a me n d me nts, I E C/I R B 
c orres p o n de nce  a n d  a p pr o vals,  a p pr o ve d  a n d  si g ne d  I Cs,  I n vesti gat or’s  A gree me nt,  cli nical  
s u p plies recei pts, distri b uti o n a n d ret ur n rec or ds), a n d ot her s p o ns or c orres p o n de nce pertai ni n g t o 
t he st u d y m ust be ke pt i n a p pr o priate st u d y files at t he site.  S o urce d oc u me nts i ncl u de all 
rec or di n gs a n d o bser vati o ns or n otati o ns of cli nical acti vities a n d all re p or ts a n d rec or ds necessar y 
f or t he e val uati o n a n d rec o nstr ucti o n of t he cli nical st u d y.  T hese rec or ds will be retai ne d i n a 
sec ure file f or t he peri o d re q uire d b y t he i nstit uti o n or s ite p olic y.  Pri or t o tra nsfer or destr ucti o n 
of t hese rec or ds, t he S p o ns or m ust be n otifie d i n writi n g a n d be gi ve n t he o p p ort u nit y t o f urt her 
st ore s uc h rec or ds. 


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1 2.  
FI N A N CI N G A N D I N S U R A N C E 
1 2. 1.  
Fi n a nces 
Pri or t o starti n g t he st u d y, t he Pri nci pal I n vesti g at or a n d/ or i nstit uti o n will si g n a cli nical st u d y 
a gree me nt wit h t he s p o ns or or wit h a n a ut h orize d  re prese ntati ve of s p o ns or.  T his a gree me nt will 
i ncl u de t he fi na ncial i nf or mati o n a gree d u p o n b y t he parties. 
 
1 2. 2.  
Rei m b urse me nt, I n de m nit y, a n d I ns ur a nce 
Rei m b urse me nt, i n de m nit y a n d i ns ura nce s hall be  a d dresse d i n a se parate a gree me nt o n ter ms 
a gree d u p o n b y t he parties. 
T he S p o ns or pr o vi des i ns ura nce f or st u d y s u bjects t o ma ke a vaila ble c o m pe nsati o n i n case of 
st u d y-relate d i nj ur y. 


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1 3.  
P U B LI C A TI O N P O LI C Y 
A st u d y site ma y n ot p u blis h res ults of a st u d y u ntil after a c o or di nate d m ultice nter p u blicati o n 
has bee n s u b mitte d f or p u blicati o n or u ntil o ne y ear after t he st u d y has en de d, w hic he ver occ urs 
first.  T heref ore, t he st u d y site will ha ve t he o p p ort u nit y t o p u blis h t h e res ults of t he st u d y, 
pr o vi de d  t hat  s p o ns or  a n d  t he  e xec uti ve  c o m mittee  has  ha d  t he  o p p ort u nit y  t o  re vie w  a n d  
c o m me nt o n t he st u d y site’s pr o p ose d p u blicati o n pri o r t o its bei n g s u b mitte d f or p u blicati o n wit h 
t he a d vice of c o m pa n y pate nt c o u ncil a n d i n acc or d wit h nee ds f o r s u bject pr otecti o n. 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 8 9 of 1 0 9 
 
1 4.  
E T HI C S A N D S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N 
1 4. 1.  
C o m pli a nce St ate me nt, Et hics  a n d Re g ul at or y C o m pli a nce 
T his st u d y will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples t hat ha ve t heir 
ori gi n  i n  t he  Declarati o n  of  Helsi n ki,  t he  I C H  c o ns oli date d  G ui deli ne  E 6  f or  G C P  
( C P M P/I C H/ 1 3 5/ 9 5), a n d a p plica ble re g ulat or y re q uire me nt(s): 
 E ur o pea n C o m missi o n Dir ecti ve ( 2 0 0 1/ 2 0/ E C A pr 2 0 0 1); 
 E ur o pea n C o m missi o n Dir ecti ve ( 2 0 0 5/ 2 8/ E C A pr 2 0 0 5); 
 E ur o pea n Data Pr otecti o n Directi ve 9 5/ 4 6/ E C; 
 Ot her a p plica ble l ocal re g ulati o ns. 
 
1 4. 2.  
S u bject C o nfi de nti alit y 
T he I n vesti gat ors a n d t he S p o ns or will preser ve t he c o nfi de ntialit y of all s u bjects ta ki n g part i n 
t he st u d y, i n acc or da nce wit h G C P, t he r ules lai d d o w n f or t he pr otecti o n of i n di vi d uals wit h 
re gar d t o t he pr ocessi n g of pers o nal data a n d t he free m o ve ment of s uc h data  a n d ot her l ocal 
re g ulati o ns. 
F or  E U  st u d y  ce nters,  t he  S p o ns or  will  o bser ve  t he  r ules  lai d  d o w n  i n  t he  E ur o pea n  Data  
Pr otecti o n Directi ve 9 5/ 4 6/ E C o n t h e pr otecti o n of i n di vi d uals wit h  re gar d t o t he pr ocessi n g of 
pers o nal data a n d t he free m o ve me nt of s uc h data. 
T he I n vesti gat or m ust e ns ure t hat t he s u bject’s a n o n y mit y is mai ntai ne d.  O n t he e C R Fs or ot her 
d oc u me nts s u b mitte d t o t he S p o ns or, s u bjects s h o u l d be i de ntifie d b y a u ni q ue s u bject I D n u m ber 
as desi g nate d b y t he s p o ns or. T he I n vesti gat or m ust o bliterate a n y pri vate i nf or mati o n c o ntai ne d 
o n d oc u me nts (e. g. na me or a d dress) pri or t o pass i n g t he m o n t o t he s p o nsor or C R O.  D oc u me nts 
t hat are n ot f or s u b missi o n t o eit her S p o ns or or C R O (e. g., si g ne d I C) s h o ul d be ke pt i n strict 
c o nfi de nce b y t he I n vesti gat or. 
I n c o m plia nce wit h G C P G ui deli nes, it is re q uire d t hat t he I n vesti gat or a n d i nstit uti o n per mit 
a ut h orize d re prese ntati ves of t h e c o m pa n y, of t he re g ulat or y a ge n c y(s), a n d t he I E C/I R B direct 
access t o re vie w t he s u bject’s ori gi nal me dical re c or ds f or verificati o n of st u d y-relate d pr oce d ures 
a n d data.   
 
1 4. 3.  
I nf or me d C o nse nt Pr oce d ure 
Bef ore a s u bject’s partici pati o n i n t he st u d y, it is t he I n vesti gat or’s res p o nsi bilit y t o o btai n freel y 
gi ve n c o nse nt, i n writi n g, fr o m t he s u bject afte r a de q uate e x pla nati o n of t he ai ms, met h o ds, 
a ntici pate d be nefits, a n d p ote ntial  hazar ds of t he st u d y a n d bef ore a n y pr ot oc ol-s pecific scree ni n g 
pr oce d ures or a n y st u d y dr u gs are a d mi nistere d.  S u bjects m ust  ha ve t he o p p ort u nit y t o as k 
q uesti o ns a n d recei ve satisfact or y a ns wers t o t hei r i n q uiries, a n d m ust ha ve a de q uate ti me t o 
deci de w het her or n ot t o partici pate i n t he st u d y.  T he writte n I C F is pre pare d i n t he l ocal 
la n g ua ge(s) of t he p ote ntial s u bject p o p ulati o n. 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 9 0 of 1 0 9 
 
 
1 4. 4.  
Re g ul at or y C o m pli a nce 
T he  st u d y  pr ot oc ol,  s u bject  i nf o r mati o n  a n d  c o nse nt  f or m,  t he  I n vesti gat or’s  Br oc h ure,  a n y  
s u bject diar y car d or writte n i nstr ucti o ns t o be give n t o t he s u bject, a vaila ble safet y i nf or mati o n, 
s u bject recr uit me nt pr oce d ures, i nf or mati o n a b o ut pa y me nts a n d c o m pe nsati o n a vaila ble t o t he 
s u bjects a n d d oc u me ntati o n e vi de nci n g t he I n vesti gat or’s q ualificati o ns s h o ul d be s u b mitte d t o 
t he I E C/I R B f or et hical re vie w a n d a p pr o val acc or di n g t o l ocal re g ulati o ns, pri or t o t he st u d y start.  
T he writte n a p pr o val s h o ul d i d e ntif y all d oc u me nts re vie we d b y na me a n d versi o n. 
C ha n ges i n t he c o n d uct of t he st u d y or pla n ne d a nal ysis will be d oc u me nte d i n a pr ot oc ol 
a me n d me nt a n d/ or t he S A P. 
All s u bse q ue nt s u bsta ntial pr ot oc ol a me n d me nts a n d c ha n ges t o t he I C F will be s u b mitte d t o t he 
I E C/I R B f or a p pr o val. T he I n vesti gat or s h o ul d n otif y t he I E C/I R B of de viati o ns fr o m t he pr ot oc ol 
or S A Es occ urri n g at t he site a n d ot her a d vers e e ve nt re p orts recei ve d fr o m S p o ns or/ C R O, i n 
acc or da nce wit h l ocal pr oce d ures. 
As re q uire d b y l ocal re g ulati o ns, t he S p o ns or’s l ocal Re g ulat or y Affairs gr o u p or dele gate will 
i ns ure all le gal as pects are c o vere d, a n d a p pr o val of t he a p pr o priate re g ulat or y b o dies o btai ne d, 
pri or t o st u d y i nitiati o n, a n d t hat i m ple me ntati o n of c ha n ges t o t he i nitial pr ot oc ol a n d ot her 
rele va nt st u d y d oc u me nts ha p pe n o nl y after t he a p pr o priate n otificati o n of or a p pr o val b y t he 
rele va nt re g ulat or y b o dies. 
 
1 4. 5.  
Pr ot oc ol De vi ati o ns 
T he I n vesti gat or c o n d ucts t he st u d y i n c o m plia nce w it h t he pr ot oc ol a gree d t o b y s p o ns or a n d, if 
re q uire d, b y t he re g ulat or y a ut h orit y(ies) a n d b y t he E C. 
Acti o ns ta ke n t o eli mi nate i m me di ate s u bject hazar d(s) t hat de viat e fr o m a n y pr ot oc ol pr oce d ures 
are mar ke d / fla g ge d as a de viati o n. T he s p o ns or a n d site m o nit or m ust be n otifie d of all i nte n de d 
or u ni nte n de d de viati o ns t o t he pr ot oc ol (e. g., i ncl usi o n/e xcl usi o n criteria, d osi n g) o n a n e x pe dite d 
basis. T he I n vesti gat or, or pe rs o n desi g nate d b y t he I n vesti gat or, s h o ul d d oc u me nt a n d e x plai n 
a n y  de viati o n  fr o m  t he  a p pr o ve d  pr ot oc ol  a n d  n o tif y  t he  E C  of  a n y  pr ot oc ol  de viati o ns  i n  
acc or da nce wit h l ocal pr oce d ures. 
E ve n  if  a  s u bject  was  i neli gi ble  or  i na d verte ntl y  recei ve d  t he  i nc orrect  dr u g  or  d osa ge,  
disc o nti n ue d or i nterr u pte d t he assi g ne d treat me n t re gi me n, or ref use d t o f urt her u n der g o o n-site 
visits, cli nical f oll o w- u p data s h o ul d still be c ollecte d u p t o Da y 9 0 after cat heter a blati o n (i.e., 
E O T). 
 
1 4. 6.  
S u p pl y of Ne w I nf or m ati o n Affect i n g t he C o n d uct of t he St u d y 
W he n ne w i nf or mati o n bec o mes a vaila ble t hat ma y a d versel y affect t he safet y of s u bjects or t he 
c o n d uct of t he st u d y, t he S p o ns or w ill i nf or m all I n vesti gat ors in v ol ve d i n t he cli nical st u d y, 
E Cs/I R Bs, a n d re g ulat or y a ut h orities of s uc h i nf or mati o n, a n d w he n nee de d, will a me n d t he 
pr ot oc ol a n d/ or s u bject i nf or mati o n. 








Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 9 4 of 1 0 9 
 
1 5.  
R E F E R E N C E S 
1.  
Gi u glia n o R P, R uff C T, Bra u n wal d E, M u r p h y S A, Wi vi ott S D, Hal peri n J L, et 
al. E d o xa ba n vers us warfari n i n patie nts wit h atrial fi brillati o n. N E n gl J Me d. 
2 0 1 3; 3 6 9( 2 2): 2 0 9 3- 2 1 0 4. 
2.  
Kirc h h of P, Be n ussi S, K otec ha D, A hlss o n A, Atar D, Casa dei B, et al. 2 0 1 6 E S C 
G ui deli nes f or t he ma na ge me nt of atrial  fi brillati o n de vel o pe d i n c olla b orati o n 
wit h E A C T S: T he Tas k F orce f or t he ma na ge me nt of atrial fi brillati o n of t he 
E ur o pea n S ociet y of Car di ol o g y ( E S C) De ve l o pe d wit h t he s pecial c o ntri b uti o n of 
t he E ur o pea n Heart R h yt h m Ass ociatio n ( E H R A) of t he E S C E n d orse d b y t he 
E ur o pea n Str o ke Or ga nisati o n ( E S O). E ur o pace 2 0 1 6 A u g 2 7 e p u b 
3.  
Cra wf or d T, Oral H. C urre nt stat us a n d o utc o mes of cat heter a blati o n f or atrial 
fi brillati o n. Heart R h yth m 2 0 0 9; 6( 1 2 S u p pl): S 1 2- 1 7. 
4.  
H ussei n A A, Marti n D O, Sali ba W, Patel D, Kari m S, Batal O, et al. 
Ra di ofre q ue nc y a blati o n of atrial fi brill ati o n u n der t hera pe utic i nter nati o nal 
n or malize d rati o: a safe a n d efficaci o us peri pr oce d ural a ntic oa g ulati o n strate g y. 
Heart R h yt h m 2 0 0 9; 6( 1 0): 1 4 2 5- 1 4 2 9. 
5.  
Ca p pat o R, Marc hli ns ki F E, H o h nl oser S H , Naccarelli G V, Xia n g J, Wil ber DJ, et 
al. U ni nterr u pte d ri var o xa ba n vs. u ni nterr u pte d vita mi n K a nta g o nists f or cat heter 
a blati o n i n n o n- val v ular atrial fi brillati o n. E ur Heart J. 2 0 1 5 ; 2 1; 3 6( 2 8): 1 8 0 5-
1 8 1 1.  
6.  
C he n J, T o d d D M, H oci ni M, Larse n T B, B o n gi or ni M G, Bl o mstr ö m- L u n d q vist 
C.; Scie ntific I nitiati ve C o m mittee, E ur o p ea n Heart R h yt h m Ass ociati o n. C urre nt 
peri pr oce d ural ma na ge me nt of a blati o n f or atrial fi brillati o n i n E ur o pe: res ults of 
t he E ur o pea n Heart R h yt h m Ass ociatio n s ur ve y. E ur o pace  2 0 1 4; 1 6( 3): 3 7 8 – 3 8 1.  
7.  
E d o xa ba n I B, versi o n 1 6. 0, J U N 2 0 1 6. 
8.  
H o k usai V T E I n vesti gat ors, B uller H R, Dec o us us H, Gr oss o M A, Merc uri M, 
Mi d del d or p S, et al. E d o xa ba n vers us wa rfari n f or t he treat me nt of s y m pt o matic 
ve n o us t hr o m b oe m b olis m. N E n gl J Me d. 2 0 1 3; 3 6 9( 1 5): 1 4 0 6- 1 4 1 5. 
9.  
Ca p pat o R, Cal ki ns H, C he n S A, Da vies W, Iesa ka Y, Kal ma n J, et al. U p date d 
w orl d wi de s ur ve y o n t he met h o ds, efficac y, a n d safet y of cat heter a blati o n f or 
h u ma n atrial fi brillati o n. Circ Arr h yt h m  Electr o p h ysi ol. 2 0 1 0 Fe b; 3( 1): 3 2- 3 8.  
1 0.  
Pr o vi de ncia R, Marij o n E, Al be n q ue J P, et al. Ri var o xa ba n a n d da bi gatra n i n 
patie nts u n der g oi n g cat heter a blati o n of atrial fi brillati o n. E ur o pace 
2 0 1 4; 1 6: 1 1 3 7 – 1 1 4 4. 
1 1.  
La k kire d d y D, Re d d y Y M, Di Biase L, et  al. Feasi bilit y a n d Safet y of 
U ni nterr u pte d Ri var o xa ba n f or Peri pr o ce d ural A ntic oa g ulati o n i n Patie nts 
U n der g oi n g Ra di ofre q ue nc y A blati o n f or At rial Fi brillati o n. J A m C oll Car di ol 
2 0 1 4; 6 3: 9 8 2 – 8. 
1 2.  
Ar yal M R, U kai g we A, Pa n dit A, Kar mac har ya P, Pra d ha n R, Mai nali N R, et al. 
Meta-a nal ysis of efficac y a n d safet y of ri var o xa ba n c o m pare d wit h warfari n or 
da bi gatra n i n patie nts u n der g oi n g cat heter  a blati o n f or atrial fi brillati o n. A m J 
Car di ol. 2 0 1 4; 1 1 4( 4): 5 7 7- 8 2.  


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 9 5 of 1 0 9 
 
1 3.  
P ha n K, Wa n g N, Pis o n L, K u mar N, H it os K, T h o mas S P. Ri var o xa ba n vers us 
warfari n or da bi gatra n i n patie nts u n der g oi n g cat heter a blati o n f or atrial 
fi brillati o n: A meta-a nal ysis. I nt J Car di ol. 2 0 1 5; 1 8 5: 2 0 9- 1 3.  
1 4.  
Di Biase L, B ur k har dt J D, Sa nta n geli P, et  al. Peri pr oce d ural Str o ke a n d Blee di n g 
C o m plicati o ns i n Patie nts U n der g oi n g Ca t heter A blati o n of Atrial Fi brillati o n 
Wit h Differe nt A ntic oa g ulati o n Ma na ge me nt. Circ ulati o n. 2 0 1 4; 1 2 9( 2 5): 2 6 3 8-
2 6 4 4. 
1 5.  
Cal ki ns H, K uc k K H, Ca p pat o R, Br u ga da J, Ca m m AJ, C he n S A, et al. 2 0 1 2 
H R S/ E H R A/ E C A S e x pert c o nse ns us state me nt o n cat heter a n d s ur gical a blati o n 
of atrial fi brillati o n: rec o m me n dati o ns f or patie nt selec ti o n, pr oce d ural tec h ni q ues, 
patie nt ma na ge me nt a n d f oll o w- u p, defi n iti o ns, e n d p oi nts, a n d researc h trial 
desi g n. E ur o pace 2 0 1 2; 1 4( 4): 5 2 8- 6 0 6. 
1 6.  
Patel M R, Ma haffe y K W, Gar g J, Pa n G, Si n ger D E, Hac ke W et al. Ri var o xa ba n 
vers us Warfari n i n N o n val v ular At rial Fi brillati o n. N E n gl J Me d. 
2 0 1 1; 3 6 5( 1 0): 8 8 3- 8 9 1 
1 7.  
Stic herli n g C, Mari n F, Bir nie D, B o ria ni G, Cal ki ns H, Da n G A, et al. 
A ntit hr o m b otic ma na ge me nt i n patie nts u n der g oi n g electr o p h ysi ol o gical 
pr oce d ures: a E ur o pea n Heart R h yt h m Ass ociati o n ( E H R A) p ositi o n d oc u me nt 
e n d orse d b y t he E S C W or ki n g Gr o u p T hr o m b osis, Heart R h yt h m S ociet y ( H R S), 
a n d Asia Pacific Heart R h yt h m S ociet y ( A P H R S). E ur o pace. 2 0 1 5; 1 7( 8): 1 1 9 7- 2 1 4 
1 8.  
Me hra n R, Ra o S V, B hatt D L, Gi bs o n C M , Cai xeta A, Ei kel b o o m J, et al. 
Sta n dar dize d blee di n g defi niti o ns f or car di o vasc ular cli nical trials: a c o nse ns us 
re p ort fr o m t he Blee di n g Aca de mic Researc h C o ns orti u m. Circ ulati o n. 
2 0 1 1; 1 2 3( 2 3): 2 7 3 6- 2 7 4 7. 
1 9.  
Sc h ul ma n S, Kear o n C. Defi niti o n of Maj or Blee di n g i n cli nical i n vesti gati o ns of 
a nti he m ostatic me dici nal pr o d ucts i n n o n-s u r gical patie nts. J T hr o m b Hae m ost. 
2 0 0 5; 3( 4): 6 9 2- 6 9 4. 
2 0.  
Kaatz S, A h ma d D, S p yr o p o ul os A C, Sc h ul ma n S, S u bc o m mittee o n C o ntr ol of 
A ntic oa g ulati o n. Defi niti o n of cli nicall y re le va nt n o n- Maj or Blee di n g i n st u dies of 
a ntic oa g ula nts i n atrial fi brillati o n a n d ve n o us t hr o m b oe m b olic disease i n n o n-
s ur gical patie nts: c o m m u nicati o n fr o m t he S S C of t he I S T H. J T hr o m b Hae m ost. 
2 0 1 5; 1 3( 1 1): 2 1 1 9- 2 1 2 6. 
2 1.  
B hatt D L, Cr yer B L, C o nta nt C F, C o he n M, La nas A, Sc h nitzer TJ, et al. 
Cl o pi d o grel wit h or wit h o ut o me praz ole i n c or o nar y arter y disease. N E n gl J Me d. 
2 0 1 0; 3 6 3( 2 0): 1 9 0 9- 1 7. 
2 2.  
Wi vi ott S D, Bra u n wal d E, Mc Ca be C H, M o nt alesc ot G, R uz yll o W, G ottlie b S, et 
al. Pras u grel vers us cl o pi d o grel  i n patie nts wit h ac ute c or o nar y s y n dr o mes. N E n gl 
J Me d. 2 0 0 7; 3 5 7( 2 0): 2 0 0 1- 1 5. 
2 3.  
B o vill E G, Terri n M L, St u m p D C, Ber ke A D, Fre deric k M, C olle n D, et al. 
He m orr ha gic e ve nts d uri n g t hera p y wit h  rec o m bi na nt tiss ue-t y pe plas mi n o ge n 
acti vat or, he pari n, a n d as piri n f or ac ute m y ocar dial i nfarcti o n. Res ults of t he 
T hr o m b ol ysis i n M y ocar dial I nfarcti o n ( TI MI), P hase II Trial. A n n I nter n Me d. 
1 9 9 1; 1 1 5( 4): 2 5 6- 6 5. 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 9 6 of 1 0 9 
 
2 4.  
Tzi kas A, H ol mes Jr D R, Gaf o or S, et al. Perc uta ne o us left atrial a p pe n da ge 
occl usi o n: t he M u nic h c o nse ns us d oc u me nt o n defi niti o ns, e n d p oi nts a n d data 
c ollecti o n re q uire me nts f or cli nical st u dies. E ur oI nter ve nti o n 2 0 1 6; 1 2( 1): 1 0 3- 1 1 1. 
2 5.  
Ka p petei n A P, Hea d SJ, Gé nére u x P, et  al. U p date d sta n dar dize d e n d p oi nt 
defi niti o ns f or tra nscat heter a ortic va l ve i m pla ntati o n: t he Val ve Aca de mic 
Researc h C o ns orti u m- 2 c o nse ns us d oc u me nt. E ur Heart J. 2 0 1 2; 3 3( 1 9): 2 4 0 3-
2 4 1 8. 
2 6.  
Hic ks K A, Tc he n g J E, B oz k urt B, et al . 2 0 1 4 A C C/ A H A Ke y Data Ele me nts a n d 
Defi niti o ns f or Car di o vasc ular E n d p oi nt E v e nts i n Cli nical Trials: A Re p ort of t he 
A merica n C olle ge of Car di ol o g y/ A merica n Heart Ass ociati o n Tas k F orce o n 
Cli nical Data Sta n dar ds ( Writi n g C o m mitt ee t o De vel o p Car di o vasc ular E n d p oi nts 
Data Sta n dar ds). Circ ul ati o n. 2 0 1 5; 1 3 2( 4): 3 0 2- 6 1. 
2 7.  
C utli p D E, Wi n dec ker S, Me hra n R, B oa m A, C o he n DJ, va n Es G A, et al. 
Cli nical e n d p oi nts i n c or o nar y ste nt tria ls: a case f or sta n dar dize d defi niti o ns. 
Circ ulati o n. 2 0 0 7; 1 1 5( 1 7): 2 3 4 4- 5 1. 
2 8.  
Hijazi Z, Li n d bäc k J, Ale xa n der J H, et  al. T he A B C (a ge, bi o mar kers, cli nical 
hist or y) str o ke ris k sc ore: a bi o mar ker- b ase d ris k sc ore f or pre dicti n g str o ke i n 
atrial fi brillati o n. E ur He art J. 2 0 1 6; 3 7( 2 0): 1 5 8 2- 1 5 9 0. 
2 9.  
De ne ke T, Jais P, Sca gli o ne M, et al. S ile nt Cere bral E ve nts/ Lesi o ns Relate d t o 
Atrial Fi brillati o n A blati o n: A Cli nical  Re vie w. J Car di o vasc Electr o p h ysi ol. 
2 0 1 5; 2 6( 4): 4 5 5- 4 6 3. 
3 0.  
R ose n daal F R, Ca n ne gieter S C, va n der Me er FJ, Briet E. A met h o d t o deter mi ne 
t he o pti mal i nte nsit y of oral a ntic oag ula nt t hera p y. T hr o m b os hae m ost. 
1 9 9 3; 6 9( 3): 2 3 6- 9. 
3 1.  
Ca p pat o R, Cal ki ns H, C he n S A et al. Pre vale nce a n d ca uses of fatal o utc o me i n 
cat heter a blati o n of atrial  fi brillati o n. J A m C oll Car di ol. Ma y 1 2 2 0 0 9; 5 3( 1 9): 
1 7 9 8 – 1 8 0 3. 
3 2.  
Des h m u k h A, Patel NJ, Pa nt S, et al. I n - h os pital c o m plicati o ns ass ociate d wit h 
cat heter a blati o n of atrial fi brillati o n i n t he U nite d States bet wee n 2 0 0 0 a n d 2 0 1 0: 
a nal ysis of 9 3 8 0 1 pr oce d ures. Circ ulati o n 2 0 1 3;  1 2 8( 1 9): 2 1 0 4- 1 2. 
3 3.  
Ber nar d M L, S h ot well M, Nietert PJ, et al. Meta- A nal ysis of Blee di n g 
C o m plicati o ns Ass ociate d Wit h Car d iac R h yt h m De vice I m pla ntati o n. Circ 
Arr h yt h m Electr o p h ysi ol. 2 0 1 2; 5( 3): 4 6 8- 4 7 4. 
3 4.  
C oc kcr oft D W, Ga ult M H. Pre dicti o n of creati ni ne cleara nce fr o m ser u m 
creati ni ne. Ne p hr o n. 1 9 7 6; 1 6( 1): 3 1- 4 1. 
3 5.  
Le ve y, A S, Ste ve ns L A, Sc h mi d C H, et al. f or t he C K D- E PI C hr o nic Ki d ne y 
Disease E pi de mi ol o g y C olla b orati o n): A Ne w E q uati o n t o esti mate Gl o mer ular 
Filtzrati o n Rate. A n n I nter n Me d 2 0 0 9; 1 5 0: 6 0 7- 6 1 2. 
3 6.  
Ver ma A, Cair ns J A, Mitc hell L B, et al. 2 0 1 4 F oc use d U p date of t he Ca na dia n 
Car di o vasc ular S ociet y G ui deli nes f or t h e Ma na ge me nt of Atrial Fi brillati o n. Ca n 
J Car di ol. 2 0 1 4; 3 0( 1 2): 1 1 1 4- 1 1 3 0. 
 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 9 7 of 1 0 9 
 
1 6.  
A P P E N DI C E S 
1 6. 1.  
St u d y Or g a ni z ati o n 
1 6. 1. 1.  
D at a a n d S afet y M o nit ori n g B o ar d  
T here will be a n i n de pe n de nt D S M B t o pr otect t he ri g hts, safet y a n d well- bei n g of s u bjects 
partici pati n g i n t he st u d y. T he D S M B c o nsists of  q ualifie d scie ntists, w h o are n ot I n vesti gat ors 
i n t he st u d y a n d n ot ot her wise directl y ass ociate d wit h t he s p o ns or, a n d has t he pri mar y r ole 
i n e xa mi ni n g t he safet y data a n d ot her perti ne nt data. T he D S M B m o n it ors st u d y data i n a n 
u n- bli n de d, o n g oi n g ma n ner a n d alerts t he E xec u ti ve C o m mittee i n case of a n y cli nicall y 
c o ncer ni n g safet y iss ues. 
T he fre q ue nc y a n d e xte nt of t he data re vie w s b y t he D S M B, details a b o ut t he re vie ws a n d 
st o p pi n g r ules or criteria f or e val uati n g nee d f or st u d y pr ot oc ol m o dificati o ns will be descri be d 
a n d s pecifie d i n t he D S M B c harter. T he D S M B ca n rec o m me n d m o dificati o n of t he st u d y 
pr ot oc ol, or st u d y, or treat me nt re gi me n t o t he E xec uti ve C o m mittee base d o n pre-s pecifie d 
r ules descri be d i n t he D S M B c harter. 
All  acti vities  of  t he  D S M B  will  be  d oc u me nte d.   T his  d oc u me ntati o n  will  i ncl u de  data  
s u m maries a n d a nal yses (see Secti o n 1 0. 6 ) pr o vi de d t o t he D S M B as well as mi n utes of t he 
meeti n gs.  T he d oc u me ntati o n will re mai n c o nfi de ntial wit hi n t he D S M B u ntil t he st u d y is 
c o m plete d. A n i n de pe n de nt statisticia n w h o is n ot  ot her wise i n v ol ve d i n t he st u d y will pre pare 
t he re q uire d data o ut p uts a n d pr o vi de t he o ut p uts t o t he D S M B  as per t he D S M B c harter. 
1 6. 1. 2.  
Cli nic al E ve nts C o m mittee  
A n i n de pe n de nt C E C re vie ws a n d a dj u dicates t h e f oll o wi n g e ve nts i n a bli n de d ma n ner a n d 
wit h o ut a n y k n o wle d ge of t he s u bjec t’s assi g ne d treat me nt re gi me n: 
 Maj or Blee di n g; 
 C R N M blee di n g; 
 Mi n or blee di n g; 
 Deat h fr o m a n y ca use; 
 S us pecte d str o ke; 
 S us pecte d S E E; 
 S us pecte d MI; 
 S us pecte d TI A; 
Details a b o ut t he defi niti o ns  of t he e n d p oi nts ( Secti o n 7. 4 ), e n d p oi nt s u b-cate g ories a n d ot her 
C E C pr ocesses are descri be d i n t he C E C c harter. 
T he si n gle c o m p o ne nts of t he c o m p osite pri m ar y (a n d sec o n dar y e n d p oi nts me nti o ne d a b o ve 
are  e x pl ore d,  as  well  as  s pec ific  s u bcate g ories  (e. g.,  I C H,  isc he mic  str o ke)  a n d  e ve nt  
classificati o ns acc or di n g t o ot her defi niti o ns (e. g., B A R C, TI MI). 
1 6. 1. 3.  
E xec uti ve C o m mittee 
T he E xec uti ve C o m mittee will be res p o nsi ble f o r t he o verall desi g n, c o n d uct, a n d s u per visi o n 
of  t he  st u d y,  i ncl u di n g  t he  de vel o p me nt  of  a n y  pr ot oc ol  a me n d me nts.   T he  E xec uti ve  
C o m mittee will als o re vie w t he pr o gress of t he st u d y at re g ular i nter vals t o e ns ure s u bject 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 9 8 of 1 0 9 
 
safet y  a n d  st u d y  i nte grit y.   T he  E xec uti ve  C om mittee  will  be  c o m prise d  of  desi g nate d  
re prese ntati ves fr o m t he st u d y in vesti gat ors, C R O, a n d S p o ns or. 
1 6. 1. 4.  
O per ati o ns C o m mittee 
T he O perati o ns C o m mittee will be res p o nsi ble f or t he o n g oi n g m o nit ori n g of t he st u d y data 
a n d i m ple me ntati o n of ste ps t o i m pr o ve t he q ualit y of t he st u d y c o n d uct. T he O perati o nal 
C o m mittee will be c o m prise d of desi g nate d re pr ese ntati ves of C R Os a n d S p o ns or a n d will 
re p ort at re g ular i nter vals t o t he E xec uti ve C o m mittee o n t he pr o gress of t he st u d y. 
 
1 6. 2.  
S u b-st u d y 
S u bjects  i n  t his  st u d y  ma y  partici pate  i n  o ne  s u b-st u d y.  De dicate d  sites  are  i n vite d  f or  
partici pati o n acc or di n g t o sites ca pa bilities t o meet s pecific s u b-st u d y re q uire me nts a n d o n t he 
re q uire d n u m ber of o bser vati o ns. C urre ntl y, o ne s u b-st u d y is bei n g c o nsi dere d i n v ol vi n g D W-
M RI.  
 
 








Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 0 2 of 1 0 9 
 
1 6. 4.  
Defi niti o n of ter ms 
 
A b n or m al liver f u ncti o n  is defi ne d as c hr o nic he patic disease (e. g., cirr h osis) or 
bi oc he mical e vi de nce of si g nifica nt he pati c dera n ge me nt (e. g., bilir u bi n > 2 ti mes 
t he U L N, i n ass ociati o n wit h as partate tra nsa mi nase/ala ni ne tra nsa mi nase/al kali ne 
p h os p hatase > 3 ti mes t he U L N, a n d s o f ort h). 
A b n or m al re n al f u ncti o n  is defi ne d as c hr o nic dial ysis, re nal tra ns pla ntati o n, or 
ser u m creati ni ne ≥2 0 0 m ol/ L ( ≥2. 2 6 m g/ d L). 
C o n gestive he art f ail ure  is defi ne d as t he c urre nt prese nce or pri or hist or y of 
cli nical c o n gesti ve heart re q uiri n g me di cal atte nti o n a n d me dical t hera p y or 
d oc u me nte d ejecti o n fracti o n ≤3 5 % (left ve ntric ular s yst olic d ysf u ncti o n). 
Di a betes mellit us  i ncl u des dia betes re q uiri n g treat me nt wit h diet o nl y or wit h 
p har mac ol o gic t hera p y (i ns uli n, oral h y p o gl yce mic a ge nts). 
D oc u me nte d cli nic al nee d  is defi ne d as a k n o w n rec or d i n a n y f or m (i ncl. writte n, 
electr o nic or ver bal) rec or di n g perti ne nt s u bject data wit h re gar d t o t he cli nical 
reas o n f or t he c h oice of a n alter nati ve medicati o n. T his reas o n  m ust be ca pt ure d 
a n d pre- declare d bef ore s u bject ra n d o mizati o n. 
L a bile I N Rs  is defi ne d as u nsta ble or hi g h I N Rs or p o or ti me i n t hera pe utic ra n ge 
(e. g., < 6 0 %) w hile o n a vita mi n K a nta g o nist. 
Hy perte nsi o n  is defi ne d as h y perte nsi o n re q uiri n g p har mac ol o gic t hera p y t o 
mai ntai n a B P < 1 4 0/ 8 5 m m H g or u ntreate d h y perte nsi o n d oc u me nte d b y B P > 1 4 0 
m m H g s yst olic or > 9 0 m m H g diast olic o n t w o se parate occasi o ns. 
S E E:   A n a br u pt e pis o de of arterial i ns ufficie nc y ass ociate d wit h cli nical or 
ra di ol o gical e vi de nce of arterial occlusi o n i n t he a bse nce of ot her li kel y 
mec ha nis ms (e. g., at her oscler osis, i nstr u me ntati o n)  
Str oke:   A str o ke is defi ne d b y a n ac ute e piso de of f ocal or gl o bal ne ur ol o gical 
d ysf u ncti o n ca use d b y brai n, s pi nal c or d, or reti nal vasc ular i nj ur y as a res ult of 
he m orr ha ge or i nfarcti o n. T he e ve nt classifi es as a str o ke rat her t ha n a TI A base d 
o n a n y of t he f oll o wi n g: 
- 
D urati o n of ne ur ol o gical d ysf u ncti o n > 2 4 hrs. 
- 
D urati o n of ne ur ol o gical d ysf u ncti o n < 2 4 hrs i n case of i ma gi n g-
d oc u me nte d ne w he m orr ha ge or i nfarcti o n. 
- 
A ne ur ol o gical d ysf u ncti o n res ulti n g i n deat h ( 2 4 )     
TI A :   TI A is defi ne d b y a n y ne ur ol o gical d ysf u ncti o n n ot sa tisf yi n g t he a b o ve 
criteria f or str o ke, s pecificall y if last i n g < 2 4 h wit h o ut i ma gi n g- d oc u me nte d ac ute 
brai n i nfarcti o n.  
 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 0 3 of 1 0 9 
 
1 6. 5.  
C o m p o ne nts of t he C H A D S 2, C H A2D S 2- V A Sc Sc ore a n d H A S- B L E D Sc ore 
 
T a ble 1 6. 4: C o m p o ne nts of t he C H A D S 2 Sc ore 
C H A D S 2- V A Sc 
Sc ore 
C o n gesti ve heart fail ure 
1 
H y perte nsi o n (s yst olic > 1 6 0 m m H g) 
1 
A ge > 7 5 y ears 
1 
Dia betes mellit us 
1 
Pri or cere bral isc he mia 
2 
M a xi m u m sc ore 
6 
 
T a ble 1 6. 5: C o m p o ne nts of t he C H A 2D S 2- V A Sc S c ore 
C H A 2D S 2- V A Sc 
Sc ore 
C o n gesti ve heart fail ure 
1 
H y perte nsi o n  
1 
A ge ≥7 5 y ears 
2 
Dia betes mellit us 
1 
Str o ke/ tra nsie nt isc he mic attac k ( TI A)/t hr o m b o-e m b olis m ( T E) 
2 
Vasc ular disease ( pri or m y ocar dial i nfarcti o n [ MI], peri p heral arter y 
disease [ P A D], or a ortic pla q ue) 
1 
A ge d 6 5 t o 7 4 y ears 
1 
Se x cate g or y (i.e., fe male se x) 
1 
M a xi m u m sc ore
1 0 
 
T a ble 1 6. 6: C o m p o ne nts of t he H A S- B L E D Sc ore 
H A S- B L E D  
Sc ore 
H y perte nsi o n hist or y (s yst olic bl o o d press ure > 1 6 0 m m H g s yst olic)  
1 
A b n or mal re nal f u ncti o n ( dial ysis, tra ns pla nt, ser u m creati ni ne 
> 2. 6 m g/ d L or > 2 0 0 m ol/ L) 
1 
A b n or mal li v er f u ncti o n (cirr h osis or bilir u bi n > 2 x U L N [ u p per li mit of 
n or mal] wit h as partate tra nsa mi nase [ A S T]/ala ni ne tra nsa mi nase [ A L T]/ 
al kali ne p h os p hatase [ A L P] > 3 x U L N) 
1 
Pre vi o us hist or y of str o ke  
1 
Pri or Maj or Blee di n g or pre dis p ositi o n t o blee di n g (e. g., a ne mia) 
1 
La bile I N Rs ( u nsta ble/ hi g h i nter nati o nal n or malize d rati o [I N Rs], ti me i n 
t hera pe utic ra n ge [ T T R] < 6 0 %) 
1 
El derl y (a ge > 6 5 y ears) 
1 
Dr u g usa ge (i.e., a nti platelet a ge nts, n o n -ster oi dal a nti-i nfla m mat or y dr u gs 
[ N S AI Ds]) 
1 
E xcessi ve alc o h ol use ( ≥8 dri n ks/ wee k) 
1 
M a xi m u m sc ore
9 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 0 4 of 1 0 9 
 
1 6. 6.  
Esti m ati o n of Cre ati ni ne Cle ar a nce ( Cr C L) 
 
Cre ati ni ne Cle ar a nce Usi n g C oc kcr oft- G a ult F or m ul a (3 4 ) 
T he C oc kcr oft- Ga ult f or m ula f or t he calc ulati o n of Cr C L will be use d i n t his st u d y. 
Creati ni ne Cleara nce f or Males:  
Cr C L = [ 1 4 0 – a ge ( years)] x [ b o d y wei g ht ( k g)] / [ 7 2 x ser u m creati ni ne ( m g/ d L)]  
 
Creati ni ne Cleara nce f or Fe males:  
Cr C L = 0. 8 5 x [ 1 4 0 – a ge ( years)] x [ b o d y wei g ht ( k g)] / [ 7 2 x ser u m creati ni ne 
( m g/ d L)] 
 
 
T he C hr o ni c Ki d ne y Dise ase E pi de mi ol o g y E q u ati o n ( C K D- E PI) t o esti m ate t he 
gl o mer ul ar filtr ati o n r ate ( G F R)   
 
T he ta ble is ta ke n o ut of t he p u blicati o n i n  A n nals of I nter nal me dici ne 2 0 0 9 ( 3 5). 
 
 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 0 5 of 1 0 9 
 
 
1 6. 7.  
M o difie d R a n ki n Sc ale 
 
T a ble 1 6. 7: M o difie d R a n ki n Sc ale 
 
Sc ore   
Descri pti o n 
0  
N o s y m pt o ms at all 
1  
N o si g nifica nt disa bilit y des pite s y m pt o ms ; a ble t o carr y o ut all us ual d uties 
a n d acti vities 
2  
Sli g ht disa bilit y; u na ble t o carr y o ut all pre vi o us acti vities, b ut a ble t o l o o k 
after o w n affairs wit h o ut assista nce 
3  
M o derate disa bilit y; re q uiri n g s o me hel p, b ut a ble t o wal k wit h o ut 
assista nce 
4  
M o deratel y se vere disa bilit y; u na ble t o wal k wit h o ut assista nce a n d u na ble 
t o atte n d t o o w n b o dil y nee ds wit h o ut assista nce 
5  
Se vere disa bilit y; be dri d de n, i nc o nti ne nt, a n d re q uiri n g c o nsta nt n ursi n g 
care a n d atte nti o n 
6
 Dea d
 
 


Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 0 6 of 1 0 9 
 
 
1 6. 8.  
Re gi o n al G ui deli ne Rec o m me n d ati o ns f or I N R 
 
T a ble 1 6. 8: Re gi o n al G ui deli ne Rec o m me n d ati o ns f or I N R 
G ui deli ne 
Ref.  
T ar get I N R R a n ge  
 
E ur o pe a n d Asia 
(1 5 ) 
2. 0 – 3. 0 
 
Ca na da
 ( 3 6 ) 
2. 0 – 3. 0 
 
 
 






Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 0 9 of 1 0 9 
 
d As a n alter nati ve t o t he T A, a pers o nal visit is o pti o nal f or t h os e patie nts w h o d o n ot ha ve t he o pti o n of I N R meas ure me nt b y t heir ge neral practiti o ner.  
e S u bjects are tra nsiti o ne d t o a n a vaila ble mar kete d O A C of t he I n vesti gat or’s c h oice. T he I n ve sti gat or will f oll o w t he tra nsiti on strate g y i n t he a p pr o ve d pr o d uc t la bel. S u bjects w h o pre mat urel y 
disc o nti n ue st u d y O A C are re q ueste d t o c o nti n ue cli nical f oll o w- u p wit h st u d y visits acc or di n g t o t his sc he d ule.  
f All ra n d o mize d s u bjects  w h o are o n st u d y me dicati o n (st u d y e d o xa ba n or V K A) at 9 0 da ys, will ha ve a ma n dat or y p ost-treat me nt c o ntact at 3 0- 3 5 da ys after t he E O T visit t o c ollect data o n 
c o nc o mita nt me dicati o ns, seri o us A Es, a nd ot her safet y e ve nts of i nterest.  
g S u bjects eli gi ble t o partici pate i n t he st u d y pr o vi de writte n I C bef ore ra n d o mizati o n or a n y st u d y-s pecific pr oce d ures. O nce writte n I C is o btai ne d, s u bjects s h o ul d be ra n d o mize d wit h o ut dela y. 
h F or s u bjects ra n d o mize d t o e d o xa ba n: If s u bject is o n: (a) V K A, disc o nti n ue t he V K A, t he first d ose of e d o xa ba n ca n be starte d w he n I N R ≤2. 5; ( b) N O A C, disc o n ti n ue N O A C a n d start 
e d o xa ba n at t he ti me of t he ne xt sc he d ule d  N O A C d ose. F or s u bjects ra n d o mize d t o V K A: If s u bject is o n: (a) V K A, c o nti n ue wit h me dicati o n as pr o vi de d b y I X R S w he n I N R ≤2. 5; ( b) N O A C, 
disc o nti n ue t he N O A C a n d start V K A at t he ti me of t he ne xt sc hed ule d N O A C d ose. See Secti o ns 5. 2. 1 a n d 5. 2. 2  f or m ore detaile d i nf or mati o n 
i A p plica ble o nl y w he n a vaila ble rece nt l ocal la b orat or y res ults are of s ufficie nt acc urac y t o verif y t he patie nt’s eli gi bilit y a n d s u p p ort ra n d o mizati o n i n t he j u d ge me nt of t he i n vesti gat or a n d if 
Scree ni n g a n d Ra n d o mizati o n visits are c o m bi ne d. C hec k t he m ost rece nt res ults fr o m l ocal la b orat or y tests d o ne: He m o gl o bi n, pl atelet c o u nt, W B C ( wit h differe nt ial if ele vate d), A L T, A S T, 
t otal bilir u bi n (if ele vate d, deter mi ne c o nj u gate d/ u nc o nj u gate d bilir u bi n fracti o n), Creati ni ne, a n d Cr C L as esti mate d b y t he Coc kcr oft- Ga ult f or m ula.  
j Bl o o d dra w f or ce ntral la b orat or y a nal ysis as descri be d i n Secti o ns 6. 2  a n d 9. 7 .  Cr C L will be pr o vi de d as esti mate d b y t he C oc kcr oft- Ga ult f or m ula. I n di vi d ual bl o o d sa m ples are c ollecte d, 
st ore d a n d s hi p pe d acc or di n g t o t he La b orat or y Ma n ual.  
k W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve uri ne test f or pre g na nc y ( o bli gat or y at Visits 0, 3, a n d 6) a n d be willi ng a n d a ble t o a d here t o t he pr o hi biti o ns a n d restricti o ns s pecifie d i n 
t he pr ot oc ol. F urt her m ore, pre g na nc y tests are carrie d o ut w he ne ver t here are cli nical i n dicati o ns f or t he e xiste nce of a pre g na nc y.  
l S p o ns or s u p plies st u d y s u bjects wit h e d o xa ba n a n d V K A acc or di n g t o assi g ne d re gi me n at ra n d o mizati o n. Me dicati o n kits are assig ne d t hr o u g h t he I X R S. A cc o u nta bilit y f or me dicati o ns 
pr o vi de d is perf or me d at dis pe nsi n g visits a n d t he E O T visit  
m V K A s u bjects o nl y: I N R val ues a n d V K A d ose are c ollecte d a n d e ntere d i nt o t he e C R F eit her d uri n g t he o n-site visits or b y l ocal la b orat or y deter mi nati o n. I N R val ues a n d V K A d oses c ollecte d 
t hr o u g h t he ge neral practiti o ner or l ocal a ntic oa g ulati o n cli nic m ust als o be c o nsi dere d a n d c ollecte d b ut t his d oes n ot c o nsti t ute a wai ver f or s u bjects’ pla n ned T A or I N R deter mi nati o n d uri n g 
o n-site visits. I n a n y case t he st u d y p h ysicia n is res p o nsi ble  f or c hec ki n g t he I N R val ue a n d a da pti n g t he V K A d ose acc or di n gl y. 
n V K A s u bjects o nl y: Fre q ue nt I N R deter mi nati o ns u p o n i nitiati o n s h o ul d be o bt ai ne d u ntil s u bject’s I N R is  sta ble i n t he t hera pe utic ra n ge. It is e x pecte d t hat m ore fre q ue nt visits will be pla n ne d 
f or ‘ de n o v o’ s u bjects o n V K A t o a dj ust t he d ose wit h t he g oal of reac hi n g I N R 2. 0- 3. 0 wit hi n 6- 8 da ys after e nr ol me nt. O btai n s u bse q ue nt I N R deter mi nati o ns as per rec o m me n dati o ns a n d 
g ui deli nes pr o vi de d i n  t he l ocal a p pr o ve d la bel fr o m t he res pecti ve V K A man ufact urer (see Secti o n 6. 2 ). 
o Vital si g ns i ncl u de heart rate, sitti n g bl o o d press ure, b o d y wei g ht a n d hei g ht. Hei g ht o nl y nee ds t o be rec o r de d at ra n d o mizatio n.  
p T E E or i ntracar diac ec h ocar di o gra m will be perf or me d d uri n g t he h os pital sta y relate d t o t he pr oce d ure directl y bef ore cat heter  a blati o n or t he da y bef ore ( u p t o 2 4 h bef ore a blati o n). 
q D W- M RI will be perf or me d i n a s u bset of st u d y sites 4 da ys ± 2 da ys p ost cat heter a blati o n.  
r A ntit hr o m b otic re gi me n c o m plia nce is ac hie ve d b y assessi n g s u bjec t c o m plia nce at eac h visit ( b ot h b y pill c o u nt, self-re p orti n g/ p h ysicia n-re p orti n g a n d b y I N R val ues f or V K A s u bjects o nl y). 
I n case of a s us pecte d st u d y e n d p oi nt, a n a d diti o nal assess me nt f or s u bject c o m plia nce t o t he assi g ne d re gi me n m ust be perf or med.  
s ( S) A Es, e n d p oi nt e ve nts, a n d e ve nts of s pecial i nterest s h o ul d be re p orte d as s o o n as  site pers o n nel lear n of t he e ve nt. E n d p oi nt e ve nt a n d A E re p orti n g s h o ul d occ ur t hr o u g h o ut t he st u d y a n d 
n ot be restricte d t o s pecific visits. If A L T or A S T > 3 x U L N wit h si m ulta ne o us T B L > 2 x U L N is o bs er ve d, t he n A L P s h o ul d be deter mi n e d. Re p ort o n g oi n g all e n d p oi nts a n d all A Es i ncl u di n g 
a b n or mal la b orat or y fi n di n gs. A n y la b orat or y meas ure me nts perf or me d d uri n g u nsc he d ule d visits  are c ollecte d.