SIFNOS STUDY: RETROSPECTIVE STUDY IN PATIENTS WITH ATRIAL FIBRILLATION (AF) EXPOSED AND UNEXPOSED TO AN ORAL ANTICOAGULANT THERAPY BETWEEN 2016-2020 IN FRANCE
Conditions: Atrial Fibrillation
Sponsor: Pfizer

 
 
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SI F N O S S T U D Y: R E T R O S P E C TI V E S T U D Y I N P A TI E N T S 
WI T H A T RI AL FI B RILL A TI O N ( A F) E X P O S E D A N D 
U N E X P O S E D T O A N O R AL A N TI C O A G UL A N T T H E R A P Y 
B E T W E E N 2 0 1 6 -2 0 2 0 I N F R A N C E  
 
 
 
 
 
 
 
 
 
 
 
 
V ersi o n n° 4. 0  
0 6 D ec e m b er  2 0 2 1  
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
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T a bl e of c o nt e nts of t h e pr ot oc ol  
 
1.  
P R E S E N T A TI O N O F T H E P R OJ E C T T E A M  
4  
2.  
O BJ E C TI V E S A N D P U R P O S E S  
5  
2. 1.  
C o nt ext, o bj ecti v es a n d j ustific ati o n of t h e st u d y  
5  
2. 2.  
R es p ect of et hics  
6  
2. 3.  
J ustific ati o n of t h e p u blic i nt er est 
6  
2. 4.  
P u blic ati o n a n d c o m m u nic ati o n of t h e r es ults  
7  
3.  
M E T H O D OL O G Y  
7  
3. 1.  
St u d y d esi g n  
7  
3. 1. 1.  
D escri pti o n of t h e st u d y d esi g n  
7  
3. 1. 2.  
St u d y ti m e p eri o ds  
7  
3. 2.  
D escri pti o n a n d j ustific ati o n of t h e st u d y p o p ul ati o n  
7  
3. 2. 1.  
St u d y p o p ul ati o n  
7  
3. 2. 2.  
S u b p o p ul ati o ns  
8  
3. 3.  
St u d y siz e  
9  
3. 4.  
D at a s o urc es  
9  
3. 5.  
V ari a bl es  
9  
3. 5. 1.  
C o v ari at es  
9  
3. 5. 2.  
Ex p os ur e  
9  
3. 5. 3.  
Str atific ati o n  
9  
3. 6.  
D at a m a n a g e m e nt  
1 0  
3. 7.  
D at a tr e at m e nt a n d a n al ys es  
1 0  
3. 7. 1 O utc o m es of pri m ar y o bj ecti v es  
1 0  
3. 7. 2  
O utc o m es of s ec o n d ar y o bj ecti v es  
1 0  
3. 7. 2. 1  
T o d escri b e t h e c h ar act eristics of n o n -v al v ul ar A F p ati e nts ex p os e d a n d u n ex p os e d t o O A C 
a n d t o c o m p ar e t h e i nci d e nc e r at e of str o k e, m aj or bl e e di n g, a n d d e at h b et w e e n t h os e t w o 
p o p ul ati o ns  
1 0  
3. 7. 2. 2  
C o m p aris o n of t h e i nci d e nc e of str o k e, m aj or bl e e di n g, d e at h  
1 0  
3. 7. 2. 3 Esti m ati o n of t h e a n n u al st a n d ar diz e d i nci d e nc e r at e a n d pr ev al e nc e  
1 1  
3. 7. 2. 3  
D escri pti o n of O A C tr e at m e nt p att er ns  
1 1  
3. 7. 2. 4  
D escri pti o n of  t h e t h er a p e utic m a n a g e m e nt b ef or e/ aft er t h e first str o k e occ urri n g aft er 
i niti ati o n of O A C t h er a p y 
1 1  
3. 7. 2. 5 C o m p aris o n of H C R U a n d ass oci at e d c osts  
1 1  
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
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3. 7. 3  
O utc o m es of ex pl or at or y o bj ecti v es  
1 2  
3. 7. 3. 3 I d e ntific ati o n of s u b gr o u ps a m o n g p ati e nts wit h si mil ar pr ofil e wit h cl ust eri n g m o d els  
1 2  
3. 7. 4  
Str atifi e d a n al ys es  
1 2  
3. 7. 5  
S e nsiti vit y a n al ys es  
1 2  
3. 8  
Li mits of t h e st u d y 
1 2  
3. 9  
Mil est o n e a n d pr oj ect f e asi bilit y  
1 3  
4  
P RI V A C Y P R O T E C TI O N, D A T A S E C U RI T Y A N D C O N FI D E N TI ALI T Y  ( S ecti o n 
) 
1 4  
4. 1  
I nf or m ati o n of p ati e nts a n d ri g ht pr ot ecti o n 
1 4  
4. 1. 1  
I n di vi d u al i nf or m ati o n of t h e p ati e nts 
1 4  
4. 1. 2  
R es p ect of h u m a n ri g hts  
1 4  
4. 2  
D a t a s u p p ort a n d s ec urit y 
1 4  
4. 2. 1  
M a n a gi n g t h e ris k of r e -i d e ntific ati o n 
1 4  
4. 2. 2  
D at a s u p p ort  
1 5  
4. 2. 3  
D at a circ ul ati o n a n d m atc hi n g  
1 5  
5  
R E F E R E N C E S  
1 6  
6  
S U P PL E M E N T A R Y M A T E RI AL  
1 8  
A p p e n dix 1  
S N D S  d at a b as es pr es e nt ati o n a n d c o nt e nts  
1 8  
A p p e n dix 2  
List of fi g ur es a n d t a bl es 
2 1  
A p p e n dix 3  
I d e ntific ati o n of e v e nts of i nt er ests: str o k e a n d m aj or bl e e di n g 
2 6  
A p p e n dix 4  
I d e ntific ati o n of m e dic al hist or y a n d c o m or bi diti es 
2 7  
A p p e n dix 5  
I d e ntific ati o n of tr e at m e nts a n d l eft atri al a p p e n d a g e (L A A) occl usi o n 
2 8  
A p p e n dix 6  
D et ails o n H C R U a n al ysis  
2 9  
A p p e n dix 7  
3 0  
 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)
N o n- E n gli s h t e xt 
N o n- E n gli s h t e xt 

 
 
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1.  P R E S E N T A TI O N O F T H E P R OJ E C T T E A M  
Pfiz er a n d B M S  Pr oj ect T e a m ( R es p o nsi bl e f or d at a pr oc essi n g –  
, R T)  
, Pfiz er , 
 
, Pfiz er , 
 
, B M S , 
 
, B M S , 
 
 
 
I Q VI A Pr oj ect T e a m ( R es p o nsi bl e f or t h e i m pl e m e nt ati o n of d at a pr oc essi n g –  
 
, R M O)  
 
, I Q VI A, 
 
 
T his st u d y is s u p er vis e d b y a n e x p ert c o m mitt e e c o m pris e d of: 
Ex p ert 1: Pr 
, Dij o n, R e gi o n al U ni v ersit y H os pit al  
Ex p ert 2  : 
 ( M ars eill e, assist a nc e p u bli q u e-h ô pit a ux d e M ars eill e ( A P -H M)  
Ex p ert 3 : Pr 
, T o urs, R e gi o n al Uni v ersit y H os pit al  
Ex p ert 4  : Pr 
, P aris, Br oc a H os pit al, assist a nc e p u bli q u e-h ô pit a ux d e P aris ( A P H P)  
Ex p ert 5: Pr 
 U ni v ersit y of Li v er p o ol a n d Li v er p o ol H e art & C h est H os pit al, Li v er p o ol, U K   
 
T h e sci e ntific c o m mitt e e m et o n J ul y 2 2 , 2 0 2 1 t o d efi n e t h e o bj ecti v es of t h e st u d y, t h e diff er e nt p eri o ds of 
t h e st u d y a n d disc uss  o n t h e pr o p os e d m et h o d ol o g y. T his pr ot oc ol w as v ali d at e d b y all t h e m e m b ers of 
sci e ntific c o m mitt e e of t h e st u d y.  
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
N o n- E n gli s h t e xt 
N o n- E n gli s h t e xt 

5  
 
2.  O BJ E C TI V E S A N D P U R P O S E S  
 
2. 1.  
C o nt e xt , o bj ecti v es a n d j ustific ati o n of t h e st u d y  
 
Atri al fi brill ati o n ( A F) is a h e art r h yt h m dis or d er c a us e d b y a b n or m al el ectric al si g n als fr o m t h e atri a a n d is 
c h ar act eriz e d b y i n eff ecti v e atri al c o ntr acti o n a n d irr e g ul ar h e art b e ats. A F c a n occ ur i n t hr e e f or ms: p ar ox ys m al 
( e pis o d es l asti n g l ess t h a n 7 d a ys), p ersist e nt or p er m a n e nt (l asti n g m or e t h a n 7 d a ys) a n d irr e v ersi bl e ( 1).  
A m o n g p ati e nts wit h A F, m or e t h a n o n e -t hir d h a v e ass oci at e d v al v e dis e as e, c h ar act eriz e d b y mitr al st e n osis or 
v al v e pr ost h esis  ( 1). I n t his c as e, A F is c all e d “ v alv ul ar” (2 ). C o n v ers el y, i n p ati e nts wit h o ut ass oci at e d v al v ul ar 
p at h ol o g y, A F is s ai d t o b e " n o n -v al v ul ar" . 
I n Fr a nc e, t w o-t hir ds of A F p ati e nts ar e 7 5 y e ars of a g e a n d ol d er. T h e pr ev al e nc e of A F is a b o ut 1 % of t h e g e n er al 
p o p ul ati o n a n d i n cr e as es wit h a g e t o r e ac h 1 0 % of t h e p o p ul ati o n a g e d 8 0 y e ars a n d o v er. T h e m al e/f e m al e s ex 
r ati o of pr ev al e nt c as es is 3: 2 ( 3). T h e a bs ol ut e n u m b er of c as es is e q ui v al e nt b et w e e n m e n a n d w o m e n b ec a us e 
of t h e hi g h er lif e ex p ect a nc y i n w o m e n (4 ).  
S ev er al p at h o p h ysi ol o gic al m ec h a nis ms, i ncl u di n g bl o o d fl o w st asis, pr ot hr o m b otic st at e, a n d h y p erc o a g ul a bilit y 
i n d uc e d b y A F , c a n l e a d t o str o k e ( 5). Cli nic al si g ns m a y i ncl u d e s h ort n ess of br e at h at r est, f ati g u e, p al pit ati o ns, 
or c h est p ai n. A F  acc o u nts f or a p pr oxi m at el y 1 5 % of all str o k es ( 6).  
T h e t h er a p e utic m a n a g e m e nt  ai ms t o pr ev e nt t hr o m b o e m b olic c o m plic ati o ns (ris k m ulti pli e d b y 5), i n p artic ul ar 
t h e occ urr e nc e of isc h e mic str o k e, t o r e d uc e sy m pt o ms, t o pr ev e nt r ec urr e nc e of A F usi n g a nti arr h yt h mic 
tr e at m e nt a n d t o i m pr o v e t h e q u alit y of lif e of p ati e nts (4 ). T h e 2 0 1 4 G ui d eli n es of t h e Fr e nc h N ati o n al A ut h orit y 
f or H e alt h r ec o m m e n d i niti ati n g a n or al a ntic o a g ul a nt  (O A C )i n A F p ati e nts  t o pr ev e nt t h e ris k of str o k e i n t h e 
ev e nt  of a hi g h t hr o m b o e m b olic ris k i d e ntifi e d b y a  C H A 2 D S 2 -V A S C sc or e gr e at er t h a n or e q u al t o 2 . If t h e sc or e 
is e q u al t o 1, t h e i niti ati o n is t o b e disc uss e d acc or di n g t o ris k f act ors. A m o n g t h e O A Cs , t h e a nti vit a mi ns K ( V K A) 
( w arf ari n, ac e n oc o u m ar ol  - a n d fl ui n di o n e u ntil 2 0 1 7 ) w er e c o nsi d er e d as t h e r ef er e nc e dr u gs  u ntil 2 0 1 7 ; t h e 
dir ect or al a ntic o a g ul a nt ( D O A C) i ncl u di n g dir ect f act or X a i n hi bit ors (ri v ar ox a b a n a n d a pix a b a n) a n d dir ect 
t hr o m bi n i n hi bit or ( d a bi g atr a n) co ul d  b e pr escri b e d as a n alt er n ati v e  (4 ). R ec o m m e n d ati o ns  c o nc er ni n g t h e g o o d 
us e of O A Cs  h as b e e n u p d at e d i n 2 0 1 8  (5) . Si nc e t h e n, D O A C c a n als o b e pr escri b e d as a first -li n e tr e at m e nt i n 
n o n -v al v ul ar A F p ati e nts .    
T h e m ai n ris k ass oci at e d wit h t h e us e of O A Cs is t h e occ urr e nc e of s eri o us bl e e di n g ev e nts r e q uiri n g c ar ef ul us e 
a n d r e g ul ar tr e at m e nt r e ev al u ati o n. A m o n g p ati e nts wit h A F, s o m e p o p ul ati o ns h a v e t his ris k of bl e e di n g 
p ot e nti all y i ncr e as e d, es p eci all y t h e el d erl y a n d fr ail  ( 8, 9), or t h os e h a vi n g d e m e nti a ( 1 0). T h e ris k is als o 
i ncr e as e d i n p ati e nts wit h c or o n ar y art eri al  dis e as e  ( CA D ) d u e t o a ntit hr o m b otic t h er a p y wit h d u al a nti pl at el et 
a n d O A C ( 4). I n c as e of c o ntr ai n dic ati o n t o or al a ntic o a g ul ati o n, i n p artic ul ar b ec a us e of m aj or ris k of bl e e di n g, a 
l eft atri al a p p e n d a g e (L A A) occl usi o n m a y b e c o nsi d er e d t o pr ev e nt t h e ris k of t hr o m b o e m b olis m ( 1 1, 1 2) 
I n Fr a nc e, tw o pr evi o us st u di es p u blis h e d b y S a nt é P u bli q u e Fr a nc e d escri b e d t h e a n n u al r at e of a d ult p ati e nts 
n e wl y tr e at e d wit h O A C  f or A F usi n g d at a fr o m t h e N ati o n al H e alt h D at a S yst e m ( S N D S) , of w hic h t h e m ost r ec e nt 
p u bl is h e d i n 2 0 2 1 esti m at es i n 2 0 1 8 a st a n d ar diz e d r at e of 4 1 0/ 1 0 0, 0 0 0 i n h a bit a nts ( 6, 7). T o o ur k n o wl e d g e, n o 
s uc h r ec e nt Fr e nc h e pi d e mi ol o gic al d at a s p ecific t o A F u n ex p os e d t o O A C is a v ail a bl e.  
T h e us e of O A Cs a n d t h e ass oci at e d ris ks w er e ev al u at e d i n t h e N A C O R A st u d y c o n d uct e d i n 2 0 1 4 b y t h e N ati o n al 
H e alt h I ns ur a nc e  ( C N A M) i n c oll a b or ati o n wit h t h e N ati o n al A g e nc y f or M e dici n es a n d H e alt h Pr o d ucts S af et y 
( A N S M), usi n g d at a fr o m t h e S N D S. T his st u d y ass ess e d i n Fr a nc e, t h e h e m orr h a gic a n d t hr o m b o e m b olic ris ks i n 
A F p ati e nts ex p os e d t o V K A a n d D O A C (ri v ar ox a b a n a n d d a bi g atr a n o nl y), o v er a s h ort ex p os ur e p eri o ds of 6 
m o nt hs a n d a st u dy p eri o d fr o m 2 0 1 1 t o 2 0 1 2 ( 1 3, 1 4).  
Pfiz er a n d B M S l a b or at ori es c o n d uct e d t h e N A X O S st u d y, f oll o wi n g t h e m et h o d ol o g y of t h e N A C O R A st u d y, 
p u blis h e d i n 2 0 2 0 , f or t h e r e ass ess m e nt of t h e r ei m b urs e m e nt of a pix a b a n o n t h e d at a fr o m t h e S N D S. T h e 
N A X O S st u d y c o m p ar e d t h e 1 -y e ar ris k of occ urr e nc e of str o k e a n d s yst e mic e m b olis m  ( S E) a n d m aj or bl e e di n g 
i n p ati e nts i niti ati n g O A Cs ( a pix a b a n, ri v ar ox a b a n, d a bi g atr a n, a n d V K As) b et w e e n 2 0 1 4 a n d 2 0 1 6 wit h A F  ( 1 5).  
B y c o ntr ast, t h er e is n o s uc h  d at a  i n A F p ati e nts u n ex p os e d t o O A C  i n Fr a nc e. T his st u d y ai ms t o a d dr ess t h e l ac k 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
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of  s af et y d at a i n t h e p o p ul ati o n  of A F p ati e nts u n ex p os e d t o O A C o v er a r ec e nt p eri o d : 2 0 1 6-2 0 2 0 . It will als o 
s er v e as a n o p p ort u nity t o u p d at e d at a i n t h e p o p ul ati o n of ex p os e d p ati e nts si nc e n o n e w r es ults h a v e b e e n 
p u blis h e d si nc e 2 0 1 6 a n d t o f oc us o n s u b p o p ul ati o ns m ost at ris k . F urt h er m or e, t h e st u d y will all o w t o d escri b e 
t h e c h a n g es i n A F m a n a g e m e nt f oll o wi n g t h e r ec o m m e n d ati o ns iss u e d b y t h e H A S i n 2 0 1 8 . 
T h e o bj ecti v es of t h e SI F N O S st u d y ar e:  
Pri m ary o bj ectiv e  
T o esti m at e  t h e i nci d e nc e r at e of str o k e (isc h e mic or  h e m orr h a gic) , m aj or bl e e di n g  a n d d e at h i n b ot h 
n o n -v al v ul ar A F p ati e nts ex p os e d t o O A C ( V K A or D O A C) a n d u n ex p os e d t o O A C , ov er all a n d i n t h e 
f oll o wi n g s u b gr o u ps of i nt er est:  
•  El d erl y  ( ≥8 0  y e ars ol d)  
•  P ati e nts wit h C A D  
•  Fr ail  p ati e nts  
•  P ati e nts r e p ort e d wit h acti v e c a nc er  
•  P ati e nts r e p ort e d wit h p r evi o us str o k e 
 
S ec o n d ary o bj ectiv es  
- 
T o d escri b e t h e c h ar act eristics of n o n -v al v ul ar A F p ati e nts ex p os e d a n d u n ex p os e d t o O A C 
- 
T o c o m p ar e t h e i nci d e nc e r at e of str o k e, m aj or bl e e di n g, a n d d e at h b et w e e n t h os e t w o p o p ul ati o ns  
- 
T o esti m at e  t h e a n n u al i nci d e nc e a n d pr ev al e nc e of p ati e nts wit h n o n -v al v ul ar atri al fi brill ati o n ( A F) , 
ex p os e d a n d u n ex p os e d t o O A C   
- 
T o d escri b e t h e us e of or al a ntic o a g ul a nts ( O A Cs) i n n o n -v al v ul ar A F p ati e nts i niti ati n g tr e at m e nt ( A F 
p ati e nts ex p os e d t o  O A C  t h er a p y) 
- 
T o c o m p ar e H e alt hc ar e R es o urc e Utiliz ati o n  ( H C R U) a n d ass oci at e d  c osts b et w e e n  p ati e nts ex p os e d t o 
a pix a b a n, ri v ar ox a b a n, d a bi g atr a n, V K A  a n d  p ati e nts  u n ex p os e d t o O A Cs  
- 
T o d escri b e t h e t h er a p e utic m a n a g e m e nt b ef or e/ aft er t h e first str o k e occ urri n g aft er i niti ati o n of O A C 
ex p os ur e  
 
Ex pl or at ory o bj ectiv es  
- 
T o i d e ntif y s u b gr o u ps a m o n g A F p ati e nts wit h si mil ar pr ofil e  
 
2. 2.  
R es p ect of et hics  
 
T his st u d y d o es n ot i n v ol v e t h e c oll ecti o n, us e or tr a ns mitt al of i n di vi d u all y i d e ntifi a bl e p ati e nt / s u bj ect d at a. It 
will b e c o n d uct e d i n acc or d a nc e wit h t h e et hic al a n d Fr e nc h l e g al fr a m e w or k, t h e m ai n pri nci pl es of w hic h: 
r es p ect f or p e o pl e, b e n efic e nc e, n o n-m al efic e nc e a n d j ustic e. It will pr oc ess o nl y r ei m b urs e d ps e u d o n y miz e d 
d at a fr o m S N D S.  
 
2. 3.  
J ustific ati o n of t h e p u blic i nt er est  
 
Pfiz er a n d B M S n e e d f or sci e ntific r es e arc h p ur p os es, t o us e t h e N ati o n al H e alt h D at a S yst e m ( S N D S) d at a b as es 
i n or d er t o h a v e m or e r ec e nt d at a a n d t o c o nsi d er a n y c h a n g es i n t h e m a n a g e m e nt of A F  p ati e nts d uri n g t h e 
2 0 1 6 -2 0 2 0  p eri o d  a n d wi s h t o u p d at e t h e N A X O S st u d y (fi n aliz e d i n 2 0 1 6 a n d s u b mitt e d t o t h e a ut h oriti es i n 
2 0 2 0). U nli k e t h e pr evi o us N A X O S st u d y, t h e SI F N O S st u dy will ext e n d t h e e pi d e mi ol o gic al d at a t o all p ati e nts 
h a vi n g  n o n v al v ul ar A F  ( ex p os e d or u n ex p os e d  t o O A C). It will pr o vi d e d at a of  A F  p ati e nts , o n t h e ir s oci o-
d e m o gr a p hic c h ar act eristics , c ar e p at h w a ys a n d h e alt h c ar e r es o urc e utili zati o n  a n d i nci d e nc e r at e of  cli nic al 
o utc o m es. T h e i nci d e nc e  r at e o f cli nic al o utc o m es, str o k e, m aj or bl e e di n g, a n d m ort alit y will als o b e st u di e d  i n 
A F s u b p o p ul ati o ns of i nt er est . T his k n o wl e d g e is i nt e n d e d t o pr ovi d e a d diti o n al d at a t o o pti miz e t h e 
m a n a g e m e nt of p ati e nts i n r o uti n e pr actic e . 
 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
7  
 
2. 4.  
P u blic ati o n a n d c o m m u nic ati o n of t h e r es ults  
 
T h e r es ults of t his st u d y c o ul d b e c o m m u nic at e d tro u g h a sci e ntific p u blic ati o n i n a sci e ntific p e er r evi e w e d 
j o ur n al. T h e p u blic ati o n will b e writt e n i n c oll a b or ati o n wit h I Q VI A a n d Pfiz er/ B M S . P ost ers or or al pr es e nt ati o ns 
will  b e pr e p ar e d f or  r el ev a nt sci e ntific ev e nts. T h e r es ults will b e  pr es e nt e d as s u p p orti v e evi d e nc e i n r e g ul at or y 
s u b missi o ns t o Fr e nc h h e alt h a ut h oriti es, if n ec ess ar y. 
3.  M E T H O D OL O G Y   
3. 1.  
St u d y d esi g n  
3. 1. 1.   D escri pti o n of t h e st u d y d esi g n  
SI N F O S st u d y  is a n o bs er v ati o n al r etr os p ecti v e c o h ort st u d y usi n g Fr e nc h n ati o n al h e alt h i ns ur a nc e cl ai ms 
d at a b as e ( S N D S). A u ni q u e extr acti o n of A F p ati e nts ( ex p os e d or u n ex p os e d t o O A C t h er a p y) i n S N D S d at a will 
b e us e d t o c o n d uct t h e st u d y  fr o m 2 0 1 6 t o 2 0 2 0. 
T h e  o utc o m es  ar e ass ess e d by st u dy o bj ecti v e  a n d d efi n e d i n  A p p e n dix  2, T a bl e  1 . 
3. 1. 2.  St u d y ti m e p eri o ds  
P eri o ds a n d d at es of t h e st u d y  
I ncl usi o n p eri o d: P ati e nts will b e i ncl u d e d fr o m J a n u ar y 1 st, 2 0 1 6  t o D ec e m b er 3 1 st, 2 01 9 a n d t o D ec e m b er 3 1 st, 
2 0 2 0 i n s e nsiti vit y a n al ys es. 
N ot e: Giv e n t h e u nc ert ai nt y of t h e i m p act of t h e C ovi d 1 9 h e alt h crisis o n t h e m a n a g e m e nt of A F p ati e nts,  f or al l 
a n alys e s, t h e 2 0 2 0 d at a will b e excl u d e d b ut i ncl u d e d i n s e nsitivity a n alys es. 
I n d ex d at e f or t h e A F  p o p ul ati o n : T h e i n d ex d at e will c orr es p o n d t o t h e d at e of t h e first di a g n osis of A F , i d e ntifi e d 
b y  t h e d at e of t h e st art of L T D or of t h e i n d ex h os pit al st ay (p ati e nts n e wl y di a g n os e d A F d uri n g t h e st u d y p eri o d ) 
a n d if n ot fill e d i n (i. e.  i d e ntifi e d b y  t h e i niti ati o n of a n OA C ) t o t h e d at e of i niti ati o n of t h e OA C  f or O A C n e w 
us ers . 
Hist oric al p eri o d:  A l o o k b ac k p eri o d of 2  y e ars will b e c o nsi d er e d b ef or e t h e i n d ex d at e i n or d er t o  disti n g uis h 
i nci d e nt a n d pr ev al e nt A F-p ati e nts, d escri b e p ati e nt’s  c o m or bi diti es, m e dic al hist or y  a n d hist or y of tr e at m e nts . 
C o ns e q u e ntl y, t his hist oric al p eri o d will st art fr o m J a n u ar y 1 st, 2 0 1 4 . 
F oll o w -u p p eri o d   F oll o w -u p will st art o n t h e i n d ex d at e a n d e n d o n t h e d at e of occ urr e nc e of o n e of t h e f oll o wi n g 
ev e nts: d e at h or t h e e n d d at e of t h e st u d y ( D ec e m b er 3 1 t h, 2 01 9  a n d t o D ec e m b er 3 1 st, 2 0 2 0 i n s e nsiti vit y 
a n al ys es,  or t h e d at e of t h e l ast r ei m b urs e m e nt of c ar e r ec or d e d i n t h e S N D S ( p ati e nts wit h n o c o ns u m pti o n or 
r ei m b urs e m e nt of c ar e i n t h e 1 2 m o nt hs f oll o wi n g t h e d at e of l ast c o ns u m pti o n). 
D at a extr acti o n p eri o d:  T h e d at a extr acti o n p eri o d will st art o n J a n u ary 1 st, 2 0 1 4 a n d e n d o n D ec e m b er 3 1 st, 2 0 2 0. 
 
 
3. 2.  
D escri pti o n a n d j ustific ati o n of t h e st u d y p o p ul ati o n  
3. 2. 1.  St u d y p o p ul ati o n  
 
T his r etr os p ecti v e c o h ort st u dy f oc us es o n t h e A F p o p ul ati o n as d escri b e d  i n  
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
8  
 
 
Fi g ur e 1 , i n A p p e n dix 2. 
T h e i ncl usi o n crit eri a f or t h e A F p o p ul ati o n ar e:  
- 
P ati e nts wit h at l e ast o n e h os pit al st a y wit h a pri nci p al ( P D), r el at e d ( R D) or ass oci at e d ( A D) di a g n osis 
of c o d e I 4 8 ( Atri al  fi brill ati o n of t h e I nt er n ati o n al Cl assific ati o n of Dis e as e 1 0t h v ersi o n, I C D -1 0) or wit h 
a n acti v e Lo n g -T er m Dis e as e (L T D) at t h e i n d ex d at e or d uri n g t h e y e ar wit h I C D -1 0 c o d e I 4 8;  
O R  
- 
P ati e nts w h o ar e n e w us ers of O A Cs f or t h e A F tr e at m e nt wit h or wit h o ut A F di a g n osis ( P M SI -M S O or 
L T D), i d e ntifyi n g wit h a v ali d at e d a n d p u blis h e d al g orit h m  wit h a hi g h s p ecificit y (c -i n d ex 0, 9 3), usi n g a 
pr e dicti v e m o d el d ev el o p e d i n t h e N A C O R A st u d y ( 1 4, 1 6). T h e al g orit h m f or i d e ntif yi n g p ati e nts 
ex p os e d t o  O A C  i n dic at e d f or A F is b as e d o n t h e pr es e nc e of at l e ast o n e r ei m b urs e m e nt of a n O A C 
( V K A, a pix a b a n, ri v ar ox a b a n or d a bi g atr a n), wit h o ut us e of t h e s a m e O A C i n t h e 2 4 m ont hs pri or t o t h e 
first r ei m b urs e m e nt d at e. T his al g orit h m  c o nsi d ers r ei m b urs e m e nt d at a f or t h e 6 w e eks pri or t o t h e 
first O A C r ei m b urs e m e nt t o disti n g uis h p ati e nts tr e at e d f or A F fr o m t h os e tr e at e d f or d e e p v e n o us 
t hr o m b osis ( D V T) or p ul m o n ar y e m b olis m ( P E) . T his al g orit h m i ncl u d es d at a o n a g e, g e n d er, us e of 
tr e at m e nts 
as 
us e 
of 
b et a-bl oc k ers, 
a nti arr h yt h mics, 
a nti pl at el ets, 
a nti h y p ert e nsi v e 
dr u g, 
h olt er/ ec h oc ar di o gr a p h y pr oc e d ur es, c ar di ol o gist pr escri b er, D -di m er bl o o d t est r ei m b urs e m e nt . 
 
T h e excl usi o n crit eri a f or t h e A F p o p ul ati o n c orr es p o n d t o t h os e a p pli e d i n t h e N A C O R A a n d N A X O S st u di es a n d 
ar e:  
- 
P ati e nts wit h at l e ast o n e h os pit al st a ys wit h a n I C D -1 0 c o d e i n P D, R D or A D f or ass oci at e d v al v e dis e as e, 
I C D-1 0 c o d es I 0 5 t o I 0 9, I 3 4 a n d  I 3 9, or v al v e s ur g er y;  
- 
P ati e nts tr e at e d wit h a n O A C f or a n ot h er i n dic ati o n t h a n A F:  
o  
P ati e nts w h o ar e n e w us ers of O A Cs f or t h e tr e at m e nt of p ul m o n ar y e m b olis m ( P E, I C D -1 0 c o d e 
I 2 6), or d e e p v ei n t hr o m b osis ( D V T, I C D c o d es I 8 0 t o I 8 2); 
o  
P ati e nts w h o ar e n e w us e rs of O A C, n ot i n dic at e d f or A F, P E a n d D V T, h a vi n g i n t h e six w e e ks 
pr ec e di n g t h e first r ei m b urs e m e nt of O A C, a n ort h o p e dic pr oc e d ur e ( ost e o artic ul ar or m usc ul ar) 
of t h e l o w er li m b (i ncl u di n g hi p/ k n e e r e pl ac e m e nt) as c orr es p o n di n g t o t h e i n dic ati o n of pri m ar y 
pr ev e nti o n of v e n o us t hr o m b o e m b olic ev e nts (r o ot of t h e Di a g n osis R el at e d Gr o u p , D R G D 0 2)  
 
T h e f oll o wi n g t a bl e s u m m ariz es t h e crit eri a f or s el ecti n g p ati e nts fr o m t h e A F  p o p ul ati o n i n t h e S N D S  d at a .  
C o h ort  
I ncl usi o n crite ri a   
E xcl usi o n crit eri a 
A F  P o p ul ati o n  
o  
I d e ntifi e d 
p ati e nts 
wit h A F  
a g e d 1 8 y e ars a n d ol d er at 
di a g n osis of A F  
o  
- 
B e n efici ari es  
w h o  
ar e 
i ns uffici e ntl y i d e ntifi a bl e or f or 
w h o m 
t h er e 
ar e 
t ec h nic al 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
9  
 
c o nstr ai nts i n 
S N D S [ficti v e 
ps e u d o NI R ( p ati e nt i d e ntifi er), 
t wi ns]; 
o  
- B e n ef ici ari es affili at e d t o a 
s ettl e m e nt i nstit uti o n fr o m t h e 
o v ers e a 
Fr e nc h 
d e p art m e nt 
M a y ott e ; 
o  
Hist or y of v al v ul ar p at h ol o g y 
a n d c o ntr ai n dic ati o ns t o O A C 
tr e at m e nt. 
 
N ot e: Ot h er excl usi o n crit eri a will b e disc uss e d t o g et h er wit h t h e Sci e ntific C o m mitt e e  
 
3. 2. 2.  S u b p o p ul ati o ns  
T o m e et  t h e o bj ecti v es of t h e SI F N O S st u d y, diff er e nt s u b p o p ul ati o ns will b e s plit i n: 
o  
El d erl y A F p ati e nts str atifi e d o n a g e-gr o u p ( ≥ 8 0 y e ars ol d ) 
o  
A F  p ati e nts h a vi n g a h ist or y of c or o n ar y art eri al dis e as e ( CA D ), 
o  
A F f r ail p ati e nts 
o  
A F p ati e nts h a vi n g a n activ e c a nc er  
o  
A F p ati e nts r e p ort e d wit h pr e vi o us str o k e . 
 
 
3. 3.  
St u d y siz e  
 
All a n al ys es ( exc e pt t h e esti m ati o n of t h e pr ev al e nc e of A F) will b e c o n d uct e d i n p ati e nts n e wl y di a g n os e d wit h 
F A. I n 2 0 1 8, a st u d y c o n d uct e d b y S a nt é P u bli q u e Fr a nc e, s h o w e d t h at 2 2 5, 7 4 7 A F p ati e nts w er e O A C n e w  us er s 
( 6). If t h e n u m b er of n e w p ati e nts r e m ai ns c o nst a nt d uri n g t h e st u d y p eri o d of  5 y e ars fr o m 2 0 1 6  t o 2 0 2 0, w e  
ex p ect t h at a p pr oxi m at el y  1  milli o n p ati e nts will b e ex p os e d t o O A C i n t h e SI F N O S st u d y .  
 
3. 4.  
D at a s o urc es  
 
T h e st u d y will b e c o n d uct e d usi n g d at a fr o m t h e f oll o wi n g S N D S d at a b as es:  
− 
O ut p ati e nt cl ai ms d at a b as e ( D CI R - D o n n é es d e C o ns o m m ati o n I nt er -R é gi m e ): M ai n h e alt hc ar e cl ai ms 
d at a b as e, w hic h c o v ers 9 8. 8 % of t h e Fr e nc h p o p ul ati o n.  
− 
H os pit al disc h ar g e s u m m ari es d at a b as e ( P M SI 
- Pr o gr a m m e d e 
m é dic alis ati o n d es syst è m es 
d’i nf or m ati o n ): N ati o n al h os pit al disc h ar g e d at a b as e, i ncl u di n g p u blic a n d priv at e h os p it als.  
D et ails o n i nf or m ati o n c o nt ai n e d i n e ac h d at a b as e is pr es e nt e d i n  A p p e n dix 1 . 
 
3. 5.  
V ari a bl es  
3. 5. 1.  C o v ari at es  
A n i n dic ati v e list of p ar a m et ers a v ail a bl e i n t h e pr o p os e d d at a s o urc es ar e s h o w n i n  T a bl e A 1. 5 . 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
1 0  
 
3. 5. 2.  E x p os ur e  
Ex p os ur e t o a n O A C is d efi n e d b y a n i niti ati o n of V K A , a pix a b a n , d abi g atr a n  or  ri v ar ox a b a n. 
A F p ati e nts u n ex p os e d t o O A C ar e d efi n e d b y a first di a g n osis of A F wit h o ut O A C tr e at m e nt.  
3. 5. 3.  Str atific ati o n  
All a n al ys es o n A F p ati e nts will b e str atifi e d o n a g e -gr o u p:  < 8 0, 8 0 -9 0, > 9 0 y e ars ol d . 
All a n al ys es o n A F p ati e nts ex p os e d a n d u n ex p os e d t o O A C, will b e str atifi e d o n m o difi e d C H A 2D S 2V A S C sc or e 
str at a ( 1 8), lo w ris k (sc or e 0 i n m al es or 1 i n f e m al es); m o d er at e ris k (sc or e 1 i n m al es or 2 i n f e m al es); hi g h ris k 
if ≥2 f or m al es a n d ≥3 f e m al es .   
A ll an al ys es w h er e t h e e v e nt of i nt er est is str o k e, will b e str atifi e d o n isc h e mic or h e m orr h a gic str o k e.  
 
 
3. 6.  
D at a m a n a g e m e nt   
 
D at a m a n a g e m e nt f or t his st u d y will b e c o n d uct e d usi n g st a n d ar d I Q VI A pr oc ess es. F urt h er d et ails o n t h e d at a 
h a n dli n g pr oc e d ur es will b e pr o vi d e d t o Pfiz er a n d B M S  i n t h e st atistic al a n al ysis pl a n ( S A P) a n d/ or i n t h e D at a 
H a n dli n g Pl a n. T h e pr oc ess w o ul d t a k e i nt o c o nsi d er ati o n a n y d at a g o v er n a nc e i m p os e d o n t h e d at a s o urc e 
i ncl u di n g a n y pl a ns t o h a n dl e t h e d at a o utsi d e of t h e i nstit uti o n or c o u ntr y of ori gi n. I Q VI A will a d h er e t o all l oc al 
a n d r e gi o n al l a ws o n d at a pr ot ecti o n a n d pri v ac y.  
T h e i nt er n al c o d e of g o o d pr actic es gr o u pi n g all I Q VI A c o m mit m e nts r el at e d t o acc essi bilit y, circ ul ati o n, 
pr ot ecti o n a n d h a n dli n g of p ers o n al h e alt h d at a  will b e i m pl e m e nt. I n t h e c o nt ext of t his pr oj ect, t his c o d e r el at es 
t o t h e us e of S N D S d at a t hr o u g h acc essi n g t h e N ati o n al H e alt h I ns ur a nc e d at a b as e p ort al. 
I Q VI A will d ev el o p t h e q u eri es, t h e m a n a g e m e nt a n d t h e st atistic al a n al ysis of t h e ex pl oit e d d at a usi n g S A S ® 
E ntr e pris e G ui d e v ersi o n 7. 1.  
Gi v e n t h e ex h a usti v e n at ur e of t h e S N D S d at a a n d t h e v er y hi g h c o m pl et e n ess r at e of t h e v ari a bl es i n its 
d at a b as es, it d o es n ot s e e m j ustifi e d t o us e m et h o ds of i m p ut ati o n of missi n g d at a.  
 
3. 7.  
D at a tr e at m e nt a n d a n al ys es  
 
G e n er al c o nsi d er ati o ns o n st atistic al a n al yse s 
C at e g oric al or discr et e v ari a bl es will b e d escri b e d  wit h c o u nts a n d p erc e nt a g e o bs er v e d o n e ac h m o d alit y. 
Q u a ntit ati v e v ari a bl es will b e d escri b e d wit h st a n d ar d st atistics i ncl u di n g  n u m b ers ( a v ail a bl e, missi n g), m e a n, 
st a n d ar d d evi ati o n, m e di a n a n d q u artil e of or d er 1 a n d 3, mi ni m u m a n d m axi m u m.   
3. 7. 1 O utc o m es  of pri m ar y o bj ecti v es  
Esti m ati o n of i nci d e nc e r at e of str o k e, m aj or bl e e di n g, a n d d e at h i n b ot h n o n -v al v ul ar A F p ati e nts e x p os e d t o 
O A C ( V K A or D O A C) a n d u n e x p os e d t o O A C, o v er all a n d i n t h e s u b gr o u ps of i nt er est.  
I n l o n git u di n al a n al ys es , f or e ac h A F p o p ul ati o ns a n d s u b p o p ul ati o ns of i nt er est  d efi n e d i n s ecti o n 3. 2. 2 , th e 
a n n u al c u m ul ati v e i nci d e nc e will b e esti m at e d fr o m t h e occ urr e nc e of e ac h of t h e ev e nts of i nt er est, str ok e, 
m aj or bl e e di n g , a n d d e at h, d uri n g p ati e nt f oll o w-u p. T h e a n n u al c u m ul ati v e i nci d e nc e will b e d efi n e d as t h e 
n u m b er of e v e nts occ urri n g d uri n g t h e f oll o w -u p p eri o d di vi d e d b y t h e n u m b er of p ers o n -y e ars of f oll o w -u p.  
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
1 1  
 
3. 7. 2  O utc o m es  of s ec o n d ar y o bj ecti v es  
3. 7. 2. 1  T o d escri b e t h e c h ar act eristics of n o n -v al v ul ar A F p ati e nts e x p os e d a n d u n e x p os e d 
t o O A C a n d t o c o m p ar e t h e i nci d e nc e r at e of str o k e, m aj or bl e e di n g, a nd d e at h 
b et w e e n t h os e t w o p o p ul ati o ns  
I n cr oss-s ecti o n al a n al ys es a n d e v er y y e ar , w e will d escri b e f or A F s u b p o p ul ati o ns, s oci o d e m o gr a p hic 
c h ar act eristics, c o m or bi diti es, m e dic al hist or y of i nt er est a n d ass oci at e d tr e at m e nts d efi n e d i n T a bl e A 1.  
T h e m o dif i e d C H A D2D S 2V A S C sc or e f or t hr o m b o e m b olic ris k a n d H A S -BL E D ( 1 9) f or he m orr h a gic ris k will b e 
esti m at e d e v er y y e ar d uri n g t h e st u d y p eri o d usi n g a d a pt e d al g orit h ms t o S N D S.  
3. 7. 2. 2  C o m p ar is o n of t h e i nci d e nc e of str o k e, m aj or bl e e di n g, d e at h   
T o c o m p ar e t h e i nci d e nc e of cli nic al o utc o m es, str o k e, m aj or bl e e di n g a n d d e at h, i n A F p at i e nts ex p os e d a n d 
u n ex p os e d t o O A C t h er a p y, i n l o n git u di n al a n al ysis, w e will us e a c o m p aris o n of c u m ul ati v e i nci d e nc e r at e usi n g 
a C ox r e gr essi o n m o d el wit h O A C e x p os ur e c o nsi d er e d as ti m e -d e p e n d e nt v ari a bl e a dj ust e d f or c o v ari at es ( or 
I P T W if n ec ess ar y) (Fi g ur e 2 , A p p e n dix 2). T his a n al ysis will b e p erf or m e d t wic e, firstl y b y c o m p ari n g p ati e nts 
ex p os e d t o  d a bi g atr a n, a pix a b a n, ri v ar ox a b a n vs. p ati e nts ex p os e d t o V K As a n d s ec o n dl y f or A F p ati e nts wit h a 
hi g h t hr o m b o e mb olic ris k (if m o difi e d C H A 2D S 2V A S C sc or e is  ≥2 f or m al es a n d ≥3 f e m al es ) b y c o m p ari n g p a ti e nts 
ex p os e d t o D O A Cs c o m bi n e d i n o n e cl ass vs  V K As vs. u n ex p os e d p ati e nts  f or p ati e nts. B y a p pl yi n g  t h e OA C  
ex p os ur e v ari a bl e as a ti m e d e p e n d e nt v ari a bl e,  esti m at es  o f H az ar d R ati o  will acc o u nt  f or switc h es a n d 
disc o nti n u ati o ns . I n t his a n alysis, t h e r ef er e nc e will b e V K A ex p os ur e . C e ns or is d efi n e d as p ati e nt’s l ast h e alt h 
r ec or d or d at e of e n d of f oll o w-u p.  
3. 7. 2 .3  Esti m ati o n of t h e a n n u al st a n d ar diz e d i nci d e nc e r at e a n d pr e v al e nc e 
I n cr oss s ecti o n al a n al ys es p er c al e n d ar y e ar t o 2 0 1 6  to 2 0 1 9 , a n n u al st a n d ar diz e d i nci d e nc e r at e a n d a n n u al 
pr ev al e nc e, d efi n e d i n  T a bl e A 1. 1 , will b e esti m at e d ( N p er 1 0 0, 0 0 0 i n h a bit a nts).  
3. 7. 2. 3  D escri pti o n of  O A C tr e at m e nt p att er ns  
I n l o n git u di n al a n al ysis d uri n g t h e st u dy p eri o d , i n A F p ati e nts ex p os e d t o V K A, a pix a b a n, ri v ar oxa b a n, a n d 
d a bi g atr a n, w e will d escri b e t h e O A C tr e at m e nt p att er ns, usi n g a tr e at m e nt s e q u e nc e a n al ysis, t o d efi n e li n es  of 
tr e at m e nt (L O T), s witc hes  of O A C , c o nc o mit a nt tr e at m e nts  a n d t e m p or ar y or p er m a n e nt disc o nti n u ati o n. W e 
will us e a n a d a pt ati o n of S a n k e y di a gr a ms f or t h e vis u ali zati o n.  W e will d efi n e t h e d o mi n a nt t h er a p e utic 
m a n a g e m e nt  a n d c h ar act eriz e pr esc ri pti o n fills. P ati e nts m ust h av e r ec ei v e d at l e ast o n e d eli v er y  of a pix a b a n, 
d a bi g atr a n, ri v ar ox a b a n, V K A  wit hi n t h e e ntir e f oll o w -u p t o b e i ncl u d e d i n t h e tr e at m e nt p att er n a n al ys es. Ot h er 
i nf or m ati o n s uc h as pr escri b er’s c h ar act eristics at e ac h c ov er a g e p eri o d ( h os pit al or pri v at e m e dic al pr actic e a n d 
pr escri b er's s p eci alt y) a n d t h e t y p e of A F  tr e at m e nt(s) us e d will b e c o nsi d er e d. 
T h e tr e at m e nt p att er n a n al ysis will pr o vi d e  t h e f oll o wi n g i nf or m ati o n:  
- 
N u m b er a n d p erc e nt a g e of p ati e nts r ec ei vi n g e ac h  of O A C  tr e at m e nt 
- 
P erc e nt a g e  of p ati e nts w h o r ec ei v e d 1, 2 , 3 , 4  a n d 5 + L O Ts d uri n g t h e f oll o w -u p  
- 
A n al ys es of  d ur ati o n of tr e at m e nt b y L O T  
- 
Ti m e t o n ext tr e at m e nt ( T T N T) c h a n g e d b y li n e of tr e at m e nt  
 
P ersist e nc e  r at e t o O A C at 6 a n d 1 2 m o nt hs aft er t h e i niti ati o n will b e esti m at e b y K a pl a n -M ei er c ur v es   
 
3. 7. 2. 4  D escri pti o n of  t h e t h er a p e utic m a n a g e m e nt b ef or e/ aft er t h e first str o k e occ urri n g 
aft er i niti ati o n of O A C t h er a p y  
T o d escri b e t h e t h er a p e utic m a n a g e m e nt b ef or e/ aft er t h e first str o k e i n A F p ati e nts ex p os e d t o d a bi g atr a n, 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
1 2  
 
a pix a b a n, ri v ar ox a b a n , V K A  a n d u n ex p os e d t o O A C  i. e. 5  cl ass es, i n cr oss-s ecti o n al a n al ysis  at 6 a n d 1 2 m o nt hs 
b ef or e a n d aft er t h e first str o k e , w e will d escri b e H C R U  ( a m b ula to r y c ar e, h os pit al c ar e, r e h a bilit ati o n c ar e 
f aciliti es a n d m e dic ati o ns) d efi n e d i n T a bl e A 1. 2 . 
 
3. 7. 2. 5 C o m p ar is o n of H C R U  a n d ass oci at e d c osts  
I n cr oss-s ecti o n al a n a l ys es e v er y  y e ar of f oll o w u p,  H C R U  a n d ass oci at e d c osts i ncl u di n g ev e nt -r el at e d c osts (i. e. 
str o k e r el at e d a n d/ or bl e e d r el at e d) d efi n e d i n T a bl e A 1. 3 , will b e c o m p ar e d b et w e e n A F p ati e nts ex p os e d t o 
a pix a b a n, riv ar ox a b a n, d a bi g atr a n , V K A a n d u n ex p os e d t o O A C  fr o m i n d ex d at e t o e n d of f oll o w-u p, i ncl u di n g 
n u m b er a n d r at e of p ati e nts  usi n g  e ac h r es o urc e  b y y e ar of f oll o w u p , a n d t h e r at e p er p ati e nt p er m o nt h ( P P P M).  
All c osts will b e pr ovi d e d i n E ur os, a n n u aliz e d b as e d o n 2 0 1 9  pric es a n d pr es e n t e d P P P M. C ost a n al ysis will b e 
p erf or m e d fr o m t h e h e alt h i ns ur a nc e p ers p ecti v e (r ei m b urs e d c osts) . C osts a n d r es o urc e us e will b e pr es e nt e d 
P P P M , t o c o nsi d er diff er e nc es i n f oll o w-u p  d ur ati o n . M e a n of c osts of H C R U d efi n e d i n T a bl e A 1. 4 , will b e 
c o m p ar e d b et w e e n A F p ati e nts ex p os e d t o a pix a b a n, ri v ar ox a b a n, d a bi g atr a n a n d ex p os e d t o O A C vs A F p ati e nts 
ex p os e d t o V K A.  
F or t h e c o m p aris o n of a v er a g e of c osts , si g nific a nt diff er e nc es b et w e e n gr o u ps will b e d et ect e d b y m e a ns of t h e 
St u d e nt t est f or e q u alit y of m e a ns. Pri or t o t his, t h e Fisc h er t est will h a v e e n a bl e d us t o v erify t h e h y p ot h esis of 
e q u alit y of v ari a nc es a n d t h e S h a pir o Wil k t est t h e h y p ot h esis of n or m alit y. I n t h e ev e nt of n o n -v erific ati o n, a 
n o n -p ar a m etric a p pr o ac h will b e pr ef err e d; t h e Wilc ox o n or M a n n -W hit n ey t est f or c o m p aris o ns b et w e e n 2 
gr o u ps a n d t h e Kr us k al -W allis t est b ey o n d 2 gr o u ps will b e c o nsi d er e d. T h e t ests will b e t w o -si d e d wit h a 
si g nific a nc e l ev el of 5 %. 
 
3. 7. 3  O utc o m es  of e x pl or at or y o bj ec ti v es  
3. 7. 3 .3  Id e nti fic ati o n of s u b gr o u ps a m o n g p ati e nts wit h si mil ar pr ofil e wit h cl ust eri n g 
m o d els  
T o i d e ntif y s u b gr o u p of A F p ati e nts wit h si mil ar pr ofil e, w e will us e cl ust eri n g m o d els ( K-M e a ns, R a n d o m -
F or est, Asc e n di n g hi er arc hic al cl ust eri n g) wit h a d at a vis u aliz ati o n . 
3. 7. 4  Str atifi e d a n al ys es  
S ec o n d ar y o bj ecti v es a n al ys es will b e str atifi e d o n:  
o  
P ati e nts h a vi n g a  m al n utriti o n,  
o  
P ati e nts at ris k of f alls i d e ntifi e d b y a n al g orit h m a d a pt e d t o S N D S d at a,  
o  
Fr ail p ati e nts  i d e ntifi e d b y  Cl ai ms b as e d Fr ailt y I n d ex ( C FI ) a d a pt e d t o S N D S d at a, 
o  
A F  P ati e nts wit h o n e or m or e c o m or bi diti es i d e ntifi e d b y a g e -a dj ust e d C h arls o n  c o m or bi dit y i n d ex 
( A C CI) a d a pt e d t o S N D S d at a ,  
o  
P ati e nts h a vi n g a m or bi d o b esit y,  
o  
P ati e nts wit h a hist or y of isc h e mic or h e m orr h a gic str o k e,  
o  
P ati e nts wit h a hist or y of m aj or bl e e di n g,  
o  
P ati e nt wit h at l e ast o n e visit t o a n ursi n g h o m e  
o  
P ati e nts wit h a hist o r y of d e m e nti a 
 
3. 7. 5  S e nsiti v it y a n al ys es  
W e will p erf or m f oll o wi n g s e nsiti vit y a n alyse s: 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
1 3  
 
- 
All a n al ys es  will b e c o n d uct e d i ncl u di n g t h e 2 0 2 0 d at a, g i v e n t h e u nc ert ai nt y of t h e i m p act of t h e C o vi d 
1 9 h e alt h crisis o n t h e m a n a g e m e nt of A F p ati e nts  
- 
A F p ati e nts wit h o ut t h e s ec o n d i ncl usi o n crit eri a, O A C n e w us ers i d e ntifi e d b y al g orit h m us e d i n 
N A C O R A st u d y  t o esti m at e t h e st a n d ar diz e d i nci d e nc e r at e a n d pr ev al e nc e . 
 
3. 8  
Li mits of t h e st u d y 
 
Li mit ati o ns of t his st u d y i ncl u d e t h os e i n h er e nt t o t h e us e of r etr os p ecti v e a d mi nistr ati v e cl ai ms d at a a n d 
li mit ati o ns ass oci at e d wit h missi n g d at a. S ev er al li mits r el at e d t o t h e us e of S N D S d at a h a v e b e e n i d e ntifi e d i n 
t his st u d y, n o bi ol o gic al a n d cli nic al i nf or m ati o n w er e a v ail a bl e f or t his st u d y. T h e dr u g i nt a k e of p ati e nts is n ot 
m e as ur a bl e . H e alt h i ns ur a nc e sc h e m e: t h e d at es of d e at h a n d i nf or m at i o n o n l o n g t er m dis e as e (L T D) f or t h e 
s elf-e m pl o y e d a n d a gric ult ur al sc h e m es ( M S A/ R SI) as w ell as f or SL Ms ( g o v er n m e nt e m pl o y e es a n d st u d e nt 
sc h e m es) ar e p arti all y a v ail a bl e i n t h e D CI R. 
 
 
3. 9  
Mil est o n e a n d pr oj ect f e as ibilit y  
 
Mil est o n e  
Pl a n n e d d at es  
Sci e ntific c o m mitt e e m e eti n g  
J ul y 2 0 2 1 
R evi e w of pr ot oc ol b y S C m e m b ers  
J ul y-A u g ust 2 0 2 1  
R e g ul at or y s u b missi o n of t h e pr oj ect t o H D H  
S e pt e m b er  2 2 , 2 0 2 1 
C E S R E E S o pi ni o n a b o ut t h e pr oj ect  
D ec e m b er  2 0 2 1  
C NIL a p pr o v al   
F e br u ar y  2 0 2 1  
R evi e w of  st u d y st atistic al a n al ysis pl a n b y S C m e m b ers  
M arc h  2 0 2 2  
C N A M –  I Q VI A- Pfiz er/ B M S a gr e e m e nt Si g n at ur e  S  
S e pt e m b er  2 0 2 2  
D at a acc ess  b y C N A M  
Oct o b er  2 0 2 2  
D at a m a n a g e m e nt a n d a n al ysis b y I Q VI A  
Oct o b er 2 0 2 2  - J a n u ar y 2 0 2 3  
V ali d ati o n of t h e r es ults a n d st u d y r e p ort r e d acti o n  
F e br u ar y 2 0 2 3  
St u d y r e p ort d eli v er y  a n d R e vi e w of t h e r e p ort b y S C m e m b ers  
M arc h 2 0 2 3   
 
I Q VI A h a s ex p eri e nc e a n d c a p a biliti es: 
•  
Str o n g k n o wl e d g e of t h e Fr e nc h h e alt hc ar e s yst e m   
•  
A m ulti -disci pli n ar y t e a m wit h c o m pl e m e nt ar y s kills: C a p a biliti es i n e pi d e mi ol o g y, st atistics a n d m ac hi n e 
l e ar ni n g i n t h e s a m e t e a m  
•  
Ex p eri e nc e i n p erf or mi n g r etr os p ecti v e st u di es usi n g p u blic d at a (c o h orts, S N D S)  
 
 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
1 4  
 
4  
P RI V A C Y P R O T E C TI O N , D A T A S E C U RI T Y A N D C O N FI D E N TI ALI T Y   
( S ecti o n d esti n é e à l a C NIL) 
T h e tr e at m e nt of h e alt h p ers o n al d at a (i ncl u di n g S N D S d at a b as e), i n or d er t o r es p ects p ati e nts’ li b erti es a n d 
ri g hts, ar e s u bj ect t o t h e pr o visi o ns of t h e Fr e nc h I T a n d li b erti es l a w (L oi I nf or m ati q u e et li b ert és -LIL), t h e Fr e nc h 
P u blic h e alt h c o d e a n d t h e E ur o p e a n G e n er al D at a Pr ot ecti o n R e g ul ati o n ( G D P R). T h e St u d y will b e c o n d uct e d 
o n t h e l e g al b asis of a n d i n c o m pli a nc e wit h articl e 9. 2 (j) of t h e G D P R.  
 
4. 1  I nf or m ati o n of p ati e nts a n d ri g ht pr ot ecti o n 
 
4. 1. 1  In di vi d u al  i nf or m ati o n of  t h e p ati e nts  
T his st u d y is c o n d uct e d o n S N D S d at a b as es, p ati e nt i nf or m ati o n is t h e C N A M r es p o nsi bilit y as t h e d at a c o ntr oll er.  
T h er ef or e  
I n di vi d u al i nf or m ati o n is n ot r e q uir e d f or st u di es c o n d uct e d i n t h e u ni q u e S N D S d at a b as e, w e r e q u est a w ai v er 
of t h e  i n di vi d u al i nfor m ati o n . I n di vi d u als ar e i nf or m e d a b o ut S N D S exist e nc e a n d of t h e p ossi bl e r e-us e of t h eir 
d at a f or r es e arc h p ur p os es o n diff er e nt w e bsit es ( h os pit als, h e alt h i ns ur a nc e c o m p a ni es etc.), p ost ers or ev e n 
d eli v er e d d oc u m e nts.  
4. 1. 2  R es p ect of h u m a n ri g hts  
T his r es p ect of i n di vi d u al ri g hts f or t his st u d y c o n d uct e d i n S N D S d at a b as es is t h e C N A M r es p o nsi bilit y as t h e 
d at a c o ntr oll er.  
T h e pr oc e d ur es a n d m e as ur es t a k e n t o r es p ect t h e p ati e nts’ ri g hts i ncl u d e as f oll o ws:  
- 
T h e n o n -r ei d e ntific ati o n of t h e p ati e nts: S N D S dat a b as es o nl y c o nt ai n ps e u d o n y miz e d d at a. T h e 
ps e u d o n y miz ati o n pr oc ess w as b uilt t o b e n o n -r ev ersi bl e. 
- 
T h e li mit ati o n of d at a st or a g e d ur ati o n: C N A M will arc hi v e a n d st or e t h e pr oj ect fil e i ncl u di n g d at a 
extr act e d fr o m t h e a n al ys es a n d t h e r es ults’ t a bl es,  f or a p eri o d of 3 y e ars aft er t h e p u blic ati o n of t h e 
r es ults, acc or di n g t o t h e r e q u est s e nt t o t h e Fr e nc h d at a pr ot ecti o n a ut h orit y ( C NIL).  
- 
T h e i m pl e m e nt ati o n of a pr oc ess all o wi n g p ati e nts’ t o f ull y ex ercis e t h eir ri g hts: t his n ot a bl y c o nc er ns 
p ossi bilit y of b ei n g i nf or m e d a b o ut t h e o n g oi n g st u di es, t h e d at a r e us e, t h eir ri g ht t o acc ess a n d t o 
o bj ect. T h e o n g oi n g st u di es a n d t h e p ossi bl e r e us e of d at a ar e m e nti o n e d o n t h e H e alt h D at a H u b 
w e b p a g e (t h e S N D S is p art of t h e H e alt h D at a H u b). T h e ri g ht of acc e ss, t h e ri g ht of r ectific ati o n a n d t h e 
ri g ht t o o bj ect ar e ex ercis e d, u n d er t h e c o n diti o ns d efi n e d i n Articl es 9 2 t o 9 5 ( m o difi e d d ecr e e n° 2 0 0 5 -
1 3 0 9 of 2 0 Oct o b er,  2 0 0 5), t o t h e m a n a gi n g b o d y dir ect or of t h e c o m p uls or y h e alt h i ns ur a nc e sc h e m e 
t o w hic h t h e p ati e nt is affili at e d. 
- 
T h e c o nfi d e nti alit y of t h e d at a: i n acc or d a nc e wit h t h e pr o visi o ns r el ati n g t o t h e c o nfi d e nti alit y of 
i nf or m ati o n c o nc er ni n g, i n p artic ul ar, t h e st u di es, t h e p ers o ns i n v ol v e d, a n d t h e r es ults o bt ai n e d ( Articl e 
R. 5 1 2 1 -1 3 of t h e P u blic H e alt h C o d e), p ers o ns wit h acc ess t o t h e d at a will t a k e all n ec ess ar y pr ec a uti o ns 
t o e ns ur e t h e c o nfi d e nti alit y of t h e i nf or m ati o n t h ey c o nt ai n. T h es e p ers o ns are s u bj ect t o pr of essi o n al 
s ecr ec y ( acc or di n g t o t h e c o n diti o ns d efi n e d b y articl es 2 2 6 -1 3 a n d 2 2 6 -1 4 of t h e p e n al c o d e).  
 
4. 2  D a t a s u p p ort a n d s ec urit y 
4. 2. 1  M a n a gi n g t h e ris k of r e -i d e ntific ati o n 
C o m pli a nc e wit h R G P D st a n d ar ds f or a g gr e g at e d d at a t a bl es . 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
1 5  
 
4. 2. 2  D at a s u p p ort  
 
I m pl e m e nt ati o n of St a n d ar d 
O p er ati n g Pr oc e d ur e ( S O P), as 
w ell as s p ecific S N D S 
W or k I nstr ucti o n 
(S N D S _ F R WI _ 0 0 1)  gr o u pi n g all I Q VI A c o m mit m e nts r el at e d t o acc essi bilit y, circ ul ati o n, pr ot ecti o n a n d h a n dli n g 
of p ers o n al h e alt h d at a.  
I n t h e c o nt ext of t his pr oj ect, t his i nt er n al c o d e of g o o d pr actic es r el at es t o t h e acc ess a n d us e of S N D S d at a 
excl usi v el y t hr o u g h t h e N ati o n al H e alt h I ns ur a nc e f u n d p ort al ( C N A M p ort al) a n d t h e strict r es p ect of t his p ort al 
acc ess r ul es i m p os e d b y t h e C N A M a n d t h e C NIL.  
1.  Pr ot ect e d acc ess t o S N D S wit hi n t h e sc o p e of t h e st u dy  
Acc ess t o S N D S will b e li mit e d o nl y t o t h e p e o pl e d esi g n at e d b y  t h e r es p o nsi bl e f or t h e pr oj ect a n d w h o h a v e 
u n d ert a k e n t h e tr ai ni n g n ec ess ar y f or t h e us e of D CI R d at a aft er r ec ei vi n g a pri or a ut h oriz ati o n fr o m t h e D at a 
Pr ot ecti o n A ut h orit y ( C NIL). T h e r e q u ests f or q u alific ati o n will b e li mit e d t o 5 p e o pl e f or t h e pr e s e nt pr oj ect. E ac h 
p ers o n will si g n t h e d oc u m e nt r el at e d t o t h e g e n er al c o n diti o ns f or us e of h e alt h d at a s e nt b y C N A M u p o n 
r e q u est f or acc ess t o t h e S N D S p ort al, s uc h acc ess will i ncl u d e t h e S N D S d at a h er ei n. T h e p eri o d of acc ess t o 
S N D S will c o v er o nl y t h e ti m e n ec ess ar y f or t h e g o o d p erf or m a nc e of t h e pr oj ect a n d will n ot exc e e d t h e p eri o d 
s p ecifi e d i n t h e C NIL a gr e e m e nt. 
2.  H a n dli n g / S e arc h of i n di vi d u al d at a  
H a n dli n g a n d/ or s e arc h a p pli e d t o t h e i n di vi d u al d at a will b e strictl y d o n e wit hi n t h e C N A M p ort a l, i n t h e st u d y-
d e dic at e d pr oj ect s p ac e. Li k e wis e, all t a bl es of i n di vi d u al d at a r e q uir e d f or t h e a n al ys es will b e st or e d i n t his 
s p ac e. At t h e e n d of t h e st u d y, t h e d e dic at e d pr oj ect d ossi er will b e tr a nsf err e d i nt o t h e C N A M arc hi vi n g s yst e m. 
T h us, n o i n d ivi d u al d at a will b e ex p ort e d fr o m t h e C N A M s er v er. 
3.  Hi g hl y s ec ur e d acc ess t o t h e p ort al  
Q u alifi e d us ers h a v e t o c o n n ect t o t h e p ort al r es p ecti n g a t w o -st e p hi g hl y s ec ur e d pr oc ess, wit h p ers o n al i nst a nt 
p ass -w or d c o n n ecti o n e diti o n.  
4.  Acc ess t o tr ac e a bilit y a ft er c o n n ecti o ns 
O nc e c o n n ect e d, all c o n n ecti o ns a n d acti o ns of q u alifi e d p e o pl e m a d e i n t h e S N D S p ort al wit hi n t h e sc o p e of t h e 
st u d y m a y b e tr ac k e d b y t h e C N A M f or c o nf or mit y c o ntr ols.  
5.  D at a st or a g e d ur ati o n  
C N A M will arc hi v e a n d st or e t h e pr oj ect d ossi er  i ncl u di n g d at a extr act e d fr o m t h e a n al ys es a n d t h e r es ults’ 
t a bl es, st or e d f or a p eri o d of 3 y e ars aft er t h e p u blic ati o n of t h e r es ults, acc or di n g t o t h e r e q u est s e nt t o C NIL.  
6.  N o n -r e us e of d at a 
I Q VI A u n d ert o o k n ot t o r e us e t h e i n di vi d u al d at a h a n dl e d i n t h e S N D S p ort al wit hi n t h e sc o p e of t his st u d y a n d 
o ut of t h e pr es e nt pr oj ect.  
4. 2. 3  D at a circ ul ati o n a n d m atc hi n g  
 
O nl y d at a fr o m S N D S d at a b as e will b e us e d, wit h o ut a n y m atc hi n g t o a n ot h er d at a b as e. Extr act e d d at a ar e 
a v ail a bl e i n a d e dic at e d pr oj ect s p ac e o n t h e C N A M s ec ur e w e b p ort al. T h e d at a pr o visi o n is e ns ur e d b y t h e 
D E M E X t e a m, b el o n gi n g t o t h e C N A M Dir ecti o n d e l a Str at é gi e, d es ét u d es et d es st atisti q u es ( D S E S).  
I Q VI A h as d ev el o p e d a n i nt er n al c o d e of g o o d pr actic es i ncl u di n g all t h e c o m mit m e nts r e g ar di n g acc ess, 
circ ul ati o n of p ers o n al h e alt h d at a. R e g ar di n g t h e pr es e nt st u d y, t his c o d e r ef ers t o t h e us e of S N D S d at a t hr o u g h 
t h e C N A M s ec ur e w e b p ort al. T his p oi nt r el ati v e t o d at a s ec urit y is d et ail e d i n s ecti o n 4. 2.  
 
 
 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
1 6  
 
5  R E F E R E N C E S  
1.  
Hi n dric ks G, P ot p ar a T, D a gr es N, Ar b el o E, B ax JJ , Bl o mstr ö m-L u n d q vist C, et al. 2 0 2 0 E S C G ui d eli n es f or 
t h e di a g n osis a n d m a n a g e m e nt of atri al fi brill ati o n d ev el o p e d i n c oll a b or ati o n wit h t h e E ur o p e a n 
Ass oci ati o n f or C ar di o -T h or acic S ur g er y ( E A C T S). E ur H e art J. 2 0 2 1 F e b 1; 4 2( 5): 3 7 3 – 4 9 8.  
2.  
F a uc hi er L , P hili p p art R, Cl e m e nt y N, B o ur g ui g n o n T, A n g o ul v a nt D, I v a n es F, et al. H o w t o d efi n e v al v ul ar 
atri al fi brill ati o n ? Arc h C ar di o v asc Dis. 2 0 1 5 Oct 1; 1 0 8( 1 0): 5 3 0 – 9.  
3.  
C h arl e m a g n e A, Bl ac h er J, C o h e n A, C oll et J -P, Di é v art F, d e Gr o ot e P, et al. E pi d e mi o l o g y of atri al 
fi brill ati o n i n Fr a nc e: extr a p ol ati o n of i nt er n ati o n al e pi d e mi ol o gic al d at a t o Fr a nc e a n d a n al ysis of Fr e nc h 
h os pit aliz ati o n d at a. Arc h C ar di o v asc Dis. 2 0 1 1 F e b; 1 0 4( 2): 1 1 5 – 2 4.  
4.  
H A S. G ui d e p arc o urs d e s oi ns Fi brill ati o n atri al e. 2 0 1 4.  
5.  
H A S. Fic h e b o n us a g e d u m é dic a m e nt : Fi brill ati o n a uric ul air e n o n v al v ul air e. Q u ell e pl ac e p o ur l es 
a ntic o a g ul a nts or a ux  ? [I nt er n et]. 2 0 1 8 [cit e d 2 0 2 0 N o v 2 3]. A v ail a bl e fr o m: htt ps:// w w w. h as -
sa nt e.fr/ u pl o a d/ d ocs/ a p plic ati o n/ p df/ 2 0 1 8 -0 5/fic h e _ b o n _ us a g e _ a ntic o a g ul a nts _ or a ux. p df  
6.  
S a nt é P u bli q u e Fr a nc e. B ull eti n é pi d é mi ol o gi q u e h e b d o m a d air e - É pi d é mi ol o gi e d e l a fi brill ati o n atri al e 
e n Fr a nc e. I nci d e nc e d es p ati e nts n o u v ell e m e nt tr ait és p ar u n a n tic o a g ul a nt or al, év ol uti o ns t e m p or ell es 
et dis p arit és t errit ori al es [I nt er n et]. 2 0 2 1 [cit e d 2 0 2 1 M a y 2 5]. A v ail a bl e fr o m: 
htt p:// b e h.s a nt e p u bli q u efr a nc e.fr/ b e h/ 2 0 2 1/ 5/ 2 0 2 1 _ 5 _ 1. ht ml  
7.  
G a b et A, C h ati g n o ux E, Billi o n n et C, M a ur a G, Gir o u d M, B éj ot Y, et al . A n n u al r at e of n e wl y tr e at e d atri al 
fi brill ati o n b y a g e a n d g e n d er i n Fr a nc e, 2 0 1 0-2 0 1 6. E ur J E pi d e mi ol. 2 0 2 0 D ec; 3 5( 1 2): 1 1 3 9 – 4 7.  
8.  
M arti n ez B K, S o o d N A, B u nz TJ, C ol e m a n CI. Eff ecti v e n ess a n d S af et y of A pix a b a n, D a bi g atr a n, a n d 
Ri v ar ox a b a n V ers us W a rf ari n i n Fr ail P ati e nts Wit h N o n v alv ul ar Atri al Fi brill ati o n. J A m H e art Ass oc. 2 0 1 8 
A pr 1 3; 7( 8).  
9.  
Wil ki ns o n C, T o d d O, Cl e g g A, G al e C P, H all M. M a n a g e m e nt of atri al fi brill ati o n f or ol d er p e o pl e wit h 
fr ailt y: a s yst e m atic r evi e w a n d m et a-a n al ysis. A g e A g ei n g. 2 0 1 9 M ar; 4 8( 2): 1 9 6 – 2 0 3.  
1 0.  C h e n N, L uts ey PL, M acL e h os e  R F, Cl axt o n J S, N or b y FL, C h a m b erl ai n A M, et al. Ass oci ati o n of Or al 
A ntic o a g ul a nt Ty p e Wit h Ris k of D e m e nti a A m o n g P ati e nts Wit h N o n v al v ul ar Atri al Fi brill ati o n. J A m 
H e art Ass oc. 2 0 1 8 N o v 6; 7( 2 1): e 0 0 9 5 6 1.  
1 1.  H ol m es D R, R e d d y V Y, T uri Z G, D os hi S K, Si ev ert H, B uc h bi n d er M, et al. P erc ut a n e o us cl os ur e of t h e l eft 
atri al a p p e n d a g e v ers us w arf ari n t h er a p y f or pr ev e nti o n of str o k e i n p ati e nts wit h atri al fi brill ati o n: a 
r a n d o mis e d n o n-i nf eri orit y tri al. T h e L a nc et. 2 0 0 9 A u g 1 5; 3 7 4( 9 6 8 9): 5 3 4 – 4 2.  
1 2.  H a ut e  A ut orit é d e s a nt é. E v al u ati o n d e l’ occl usi o n d e l’ a p p e n dic e a uric ul air e g a uc h e p ar v oi e 
tr a nsc ut a n é e. 2 0 1 4; 1 1 3.  
1 3.  A N S M, C N A M T S. Et u d es N A C O R A -B R et N A C O R A -S witc h [I nt er n et]. 2 0 1 4. A v ail a bl e fr o m: 
htt p:// a ns m.s a nt e.fr/ D ossi ers/L es -a ntic o a g ul a nts/ Q u ell e s-s o nt-l es-i nf or m ati o ns-p u bli e es -s ur-l es-N A C O -
d e p uis -l e ur-mis e -a -dis p osit i o n-e n -Fr a nc e/( offs et)/ 2  
1 4.  B o uill o n K, B ertr a n d M, M a ur a G, Bl oti èr e P -O, Ric or d e a u P, Z ur ei k M. Ris k of bl e e di n g a n d art eri al 
t hr o m b o e m b olis m i n p ati e nts wit h n o n-v al v ul ar atri al fi brill ati o n eit h er m ai nt ai n e d o n a vit a mi n K 
a nt a g o nist or s witc h e d t o a n o n -vit a mi n K -a nt a g o nist or al a ntic o a g ul a nt: a r etr os p ecti v e, m atc h e d -c o h ort 
st u d y. L a nc et H a e m at ol. 2 0 1 5 A pr; 2( 4): e 1 5 0-1 5 9.  
1 5.  V a n G a ns e E, D a nc hi n N, M a h é I, H a n o n O, J ac o u d F, N oli n M, et al. C o m p ar ati v e S af et y a n d Eff ecti v e n ess 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
1 7  
 
of Or al A ntic o a g ul a nts i n N o nv al v ul ar Atri al Fi brill ati o n: T h e N A X O S St u d y. Str o k e. 2 0 2 0 J ul; 5 1( 7): 2 0 6 6 –
7 5.  
1 6.  Billi o n n et C, All a F, B éri g a u d É, P ari e nt e A, M a ur a G. I d e ntif yi n g atri al fi brill ati o n i n  o ut p ati e nts i niti ati n g 
or al a ntic o a g ul a nts b as e d o n m e dic o -a d mi nistr ati v e d at a: r es ults fr o m t h e Fr e nc h n ati o n al h e alt hc ar e 
d at a b as es. P h ar m ac o e pi d e mi ol Dr u g S af. 2 0 1 7 M a y; 2 6( 5): 5 3 5 – 4 3.  
1 7.  C aiss e N ati o n al e d’ Ass ur a nc e M al a di e. N o u v e a ux a nti -c o a g ul a nts or a ux : u n e ét u d e d e l’ Ass ur a nc e 
M al a di e s o uli g n e l a d y n a mi q u e f ort e d e c es n o u v e a ux m é dic a m e nts et l a n éc essit é d’ u n e vi gil a nc e accr u e 
d a ns l e ur utilis ati o n. 2 0 1 3 N o v.  
1 8.  Li p G Y H, Ni e u wl a at R, Pist ers R, L a n e D A, Crij ns HJ G M. R efi ni n g cli nic al ris k str atific ati o n f or pr e dicti n g 
str o k e a n d t hr o m b o e m b olis m i n atri al fi brill ati o n usi n g a n ov el ris k f act or -b as e d a p pr o ac h: t h e e ur o 
h e art s ur v ey o n atri al fi brill ati o n. C h est. 2 0 1 0 F e b; 1 3 7( 2): 2 6 3 – 7 2.  
1 9.  Pist ers R, L a n e D A, Ni e u wl a at R, d e V os C B, Crij ns HJ G M, Li p G Y H. A n o v el us er -fri e n dl y sc or e ( H A S-BL E D) 
t o ass ess 1-y e ar ris k of m aj or bl e e di n g i n p ati e nts wit h atri al fi brill ati o n: t h e E ur o H e art S ur v ey. C h est. 
2 0 1 0 N o v; 1 3 8( 5): 1 0 9 3 – 1 0 0.  
2 0.  B a n n a y A, C h ai g n ot C, Bl oti èr e P -O, B ass o n M, W eill A, Ric or d e a u P, et al. T h e B est Us e of t h e C h arls o n 
C o m or bi dit y I n d ex Wit h El ectr o nic H e alt h C ar e D at a b as e t o Pr e dict M ort alit y. M e d C ar e. 2 0 1 6 
F e b; 5 4( 2): 1 8 8 – 9 4.  
2 1.  Ki m D H, Sc h n e e w eiss S, Gl y n n RJ, Li psitz L A, R oc k w o o d K, Av or n J. M e as uri n g Fr ailt y i n M e dic ar e D at a:  
D ev el o p m e nt a n d V ali d ati o n of a Cl ai ms -B as e d Fr ailt y I n d ex. J G er o nt ol A Bi ol Sci M e d Sci. 2 0 1 8 J u n 
1 4; 7 3( 7): 9 8 0 – 7.  
2 2.  B eziz D, C ol as S, C olli n C, Dr a y -S pir a R, Z ur ei k M. Ass oci ati o n b et w e e n Ex p os ur e t o B e nz o di az e pi n es a n d 
R el at e d Dr u gs a n d S ur vi v ors hi p of T ot al Hi p R e pl ac e m e nt i n Art hritis: A P o p ul ati o n -B as e d C o h ort St u d y of 
2 4 6, 9 4 0 P ati e nts. Pl o S O n e. 2 0 1 6; 1 1( 5): e 0 1 5 5 7 8 3.  
 
 
 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
1 8  
 
6  S U P PL E M E N T A R Y M A T E RI AL  
A p p e n di x 1  S N D S  d at a b as es pr es e nt ati o n a n d c o nt e nts  
Pr es e nt ati o n of S N D S d at a b as es  
T h e Fr e nc h h e alt h i ns ur a nc e i nf or m ati o n s yst e m (S yst è m e n ati o n al d'i nf or m ati o n i nt err é gi m es d e l' Ass ur a nc e 
M al a di e, S NII R A M) w as cr e at e d i n 1 9 9 9 t o tr ac k h e alt h c ar e c o ns u m pti o n a n d ex p e n dit ur es. It h as b e e n i m pr o v e d 
o v er ti m e i n t er ms of ex h a ustiv e n ess a n d i nf or m ati o n a v ai l a bilit y. S NII R A M h as c o nti n u e d t o gr o w a n d ext e n d t o 
b ec o m e, i n 2 0 1 6, t h e c or n erst o n e of t h e n ati o n al h e alt h d at a s yst e m ( S yst è m e N ati o n al d es D o n n é es d e S a nt é, 
S N D S).  
T h e S N D S n o w c o v ers 9 8. 8 % of t h e Fr e nc h p o p ul ati o n, o v er 6 6 milli o n p ers o ns, fr o m birt h or i m mi gr ati o n t o 
d e at h or e mi gr ati o n. It c o nt ai ns i n di vi d u al d at a us e d f or billi n g a n d r ei m b urs e m e nt of o ut p ati e nt h e alt h c ar e 
c o ns u m pti o n ( D CI R d at a b as e –  i nt er-sc h e me c o ns u m pti o n d at a) c oll ect e d b y t h e h e alt h i ns ur a nc e, pri v at e a n d 
p u blic h os pit al d at a ( P M SI d at a b as e) a n d c a us es of d e at h ( N ati o n al d e at h r e gistr y, C é pi D C) f or s o m e y e ars. It will 
als o gr a d u all y i nt e gr at e s oci al a n d m e dic al d at a a n d d at a fr o m c o m pl e m e nt a r y h e alt h i ns ur a nc e. O ut p ati e nt a n d 
h os pit al c ar e d at a ar e c oll ect e d fr o m t h e s oci al s ec urit y c ar d, tr e at m e nt f or ms, pri v at e i nstit uti o n i n v oic es a n d 
pr oc e d ur es a n d o ut p ati e nt visits bill e d b y h os pit als.  
D CI R d at a b as e  
S oci o d e m o gr a p hic c h ar act eristics  
P at i e nt’s g e n d er, d at e of birt h, eli gi bilit y f or c o m pl e m e nt ar y u ni v ers al h e alt hc ar e i ns ur a nc e ( C M Uc), l oc aliz ati o n 
of r esi d e nc e, d at e of d e at h ( m o nt h a n d y e ar), i n dic at or of l o w i nc o m e.  
R ei m b urs e d/ m e dic al d at a  
- 
L o n g T er m Dis e as e (L T D) r e gistr ati o n wit h st art a n d e n d d at es (c ostl y c hr o nic dis e as es, wit h I C D -1 0 c o d es). 
It is r e q u est e d b y t h e p ati e nt’s pr actiti o n er a n d m e dic all y v ali d at e d b y t h e h e alt h i ns ur a nc e s yst e m. O nc e 
r e gist er e d, p ati e nts r ec ei v e f ull r ei m b urs e m e nt f or ex p e n dit ur es r el at e d t o t h e L T D.  
- 
D at es of pr of essi o n al h e alt hc ar e visits ( g e n er al pr actiti o n ers, s p eci alists, p ar a m e dics) a n d m o d e of ex ercis e 
( pri v at e of p u blic pr actic e); 
- 
D at e a n d n at ur e of r e aliz e d l a b t ests (c o d e d wit h t h e n o m e ncl at ur e c o d e of t h e m e dic al bi ol o g y acts 
[ N A B M]), 
m e dic al pr oc e d ur es (c o d e d wit h C C A M) wit h o ut 
m e dic al i n dic ati o n n or r es ults, d at es of 
pr escri pti o n a n d c o m pl eti o n, t ot al a n d r ei m b urs e d c osts;  
- 
Dr u gs pr escri b e d a n d r ei m b urs e d ( p h ar m ac y d eli v eri es), m e dic al d evic es, wit h pr escri b er a n d pr of essi o n al 
c ar e gi v er i nf or m ati o n (s p eci alt y, pri v at e/ p u blic pr actic e). N at ur e of dr u gs ( A n at o mic al T h er a p e utic 
C h e mic al [ A T C] c o d es), n at ur e of m e dic al d evic e ( List of Pr o d ucts a n d S er vic es [L P P]), n u m b er of u nits, d at e 
of pr escri pti o n, t ot al a n d r ei m b urs e d c osts ar e  als o a v ail a bl e f or t h e dr u gs/ m e dic al d evic e dis p e ns e d;  
- 
I nf or m ati o n o n occ u p ati o n al dis e as es a n d sic k l e a v es; 
 
P M SI d at a b as e  
T his n ati o n al h os pit al disc h ar g e d at a b as e is h a n dl e d b y t h e A g e nc y f or i nf or m ati o n o n h os pit al c ar e ( A TI H); it 
c o nt ai ns ex h a usti v e h os pit al h e alt h c ar e c o ns u m pti o n: h os pit aliz ati o ns i n s h ort -st ay i nstit uti o ns ( m e dici n e, 
s ur g er y, o bst etrics a n d o d o nt ol o g y: Fr e nc h acr o n y m M C O), i n aft erc ar e a n d r e h a bilit ati o n ( S S R), i n ps yc hi atr y 
( RI M-P) a n d h os pit al at h o m e ( H A D).  
P M SI -M C O i ncl u d es:  
- 
P ati e nts’ d e m o gr a p hics: d at e of birt h, g e n d er;  
- 
H os pit al n ati o n al e ntity i d e ntifi er;  
- 
I C D-1 0 c o d es f or pri m ar y di a g n osis, ass oci at e d di a g n osis, a n d li n k e d di a g n osis f or I C D -1 0 Z -c o d es ( e. g. 
c h e m oth er a p y  s essi o ns), f or all pri v at e a n d p u blic m e dic al, o bst etric a n d s ur g er y h os pit aliz ati o ns;  
- 
E ntr y a n d disc h ar g e d at es ( o nl y m o nt h b ef or e 2 0 1 0, f ull d at e si nc e), d ur ati o n of h os pit aliz ati o n;  
- 
D at e a n d n at ur e of m e dic al pr oc e d ur es p erf or m e d i ncl u di n g s ur g er y or i m a gi n g (c o n v e nti o n al i m a gi n g, 
sc a ns, r es o n a nc e i m a gi n g [ M RI], etc) c o d e d acc or di n g t o t h e Fr e nc h c o m m o n cl assific ati o n of m e dic al 
pr oc e d ur es ( C C A M); n o i n dic ati o n n or r es ults of t h es e ex a ms ar e pr o vi d e d t h o u g h;  
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
1 9  
 
- 
C ost c o di n g s yst e m ( Di a g n ostic R el at e d Gr o u p);  
- 
N at ur e of o n -t o p-of -D R G dr u gs (c ostl y i n n o v ativ e a n d list e d dr u gs o n t h e “
”) dis p e ns e d a n d 
a d mi nist er e d d uri n g h os pit al st ays (c o d e d acc or di n g t o t h e i nt er -p h ar m ac e utic al c o d e [ CI P] a n d/ or t h e 
a n at o mic t h er a p e utic a n d c h e mic al cl assific ati o n [ A T C]), d at e of a d mi nistr ati o n;  
- 
N at ur e of i m pl a nt a bl e m e dic al d evic es i m pl a nt e d d uri n g h os pit al st ays, c o d e d acc or di n g t o t h e L P P;  
T h e h os pit al disc h ar g e s u m m ar y als o i ncl u d es t h e m e di c al u nit s u m m ari es. P M SI d at a ar e a v ail a bl e y e arl y i n t h e 
S N D S, d uri n g t h e t hir d tri m est er of c urr e nt y e ar f or t h e d at a of pr evi o us y e ar.  
 
 
List of c o v ari a bl es of i nt er est  
IC D -1 0, C C A M a n d A T C c o d es t o i d e ntif y O A C e x p os ur e , cli nic al e v e nts of i nt er est, ass oci at e d tr e at m e nts, L A A 
occl usi o n,  c o m or bi diti es of i nt er est a n d m e dic al hist or y ar e pr es e nt e d i n A p p e n dic es 3 , 4 a n d 5 . 
T a bl e A 1. 5  : I n dic ati v e st u d y p ar a m et ers 
P ar a m et er  
D escri pti o n/ D efi niti o n  
S oci o d e m o gr a p hic c h ar act eristics  
A g e, 
s ex, 
c o m pli m e nt ary 
u niv ers al 
h e alt h 
c ar e  ( C M U-c), ai d f or 
c o m pl e m e nt ary h e alt h c ar e ( A C S) f or el d erly p ati e nts, d e p art m e nt of p ati e nt’s 
r esi d e nc e 
M e dic al hist or y a n d  co m or bi diti es  
I d e ntifi e d al g orit h mic ally wit h h os pit al di a g n os es, activ e l o n g-t er m dis e as e, 
dr u gs a n d m e dic al pr oc e d ur es : 
C or o n ar y art eri al dis e as es ( C A D) , 
D e m e nti a ( Alz h ei m er d e m e nti a/ v asc ul ar d e m e nti a/ ot h er d e m e nti a) , 
Isc h e mic or h e m orr h a gic str o k e (i ntr acr a ni al bl e e di n g) 
C o n g estiv e H e art f ail ur e , 
P eri p h er al art eri al dis e as e , 
Ot h er v asc ul ar dis e as es;  
Sl e e p dis or d ers;  
Activ e c a nc er ( wit hi n 6 m o nt hs i n t h e hist oric al p eri o d)  
A g e a dj ust e d C h arls o n C or m or dit y I n d ex ( A C CI) a d a pt e d  t o t h e S N D S d at a 
( 2 0) ; 
Fr ail p ati e nt i d e ntifi e d by Cl ai ms -B as e d Fr a gilit y I n d ex ( C FI) a d a pt e d t o t h e 
S N D S d at a ( 2 1) ; 
M al n utriti o n  ; 
M or bi d O b esit y;  
A n e mi a;  
C O P D  
Di a b et es  
P ati e nts at ris k of f alls  i d e ntifi e d by a n al g orit h m a d a pt e d t o S N D S d at a ( 2 2) ; 
P ati e nts p oly -m e dic at e d  
P ati e nt wit h at l e ast o n e n ursi n g h o m e e ntry a v ail a bl e  
Dr u g e x p os ur e  
A F p ati e nt s ex p os e d t o V K A, a pix a b a n, riv ar ox a b a n, d a bi g atr a n  
A F p ati e nts u n ex p os e d t o O A C  
Ass oci at e d tr e at m e nts  
B et a -bl oc k ers, a nti hy p ert e nsiv es , a nti pl at el et dr u gs, ot h er a ntic o a g ul a nts, 
N o n -st er oi d al a nti-i nfl a m m at or y dr u gs ( N S AI Ds), or al c ortic oi ds, pr ot o n p u m p 
i n hi bit ors, S el ectiv e s er ot o ni n r e u pt a k e i n hi bit or a nti d e pr ess a nts ( S S RIs) , 
syst e mic az ol e a ntif u n g als, m e dic al pr oc e d ur e of c ar di o v ersi o n, C Y P P 4 5 0 
i n hi bit ors, pr ot e as e i n hi bit ors 
L eft atri al a p p e n d a g e (L A A) o ccl usi o n  
M e dic al pr oc e d ur e of tr e at m e nt of t hr o m b o e m b olic ris k i n A F i n alt er n ativ e of 
O A C  
M o difi e d ris k sc or es  i n A F 
T hr o m b o e m b olic ris k: M o difi e d C H A
2D S 2V A S C  i d e ntifi e d by an al g orit h m 
a d a pt e d t o S N D S d at a  
H e m orr h a gic ris k : M o difi e d H A S -BL E D  i d e ntifi e d by an  al g orit h m a d a pt e d t o 
S N D S d at a  
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)
N o n- E n gli s h t e xt 

 
 
2 0  
 
P ar a m et er  
D escri pti o n/ D efi niti o n  
A n n u al s t a n d ar diz e d i nci d e nc e r at e of 
A F  
 
R ati o of n u m b er of n e wly di a g n os e d n o n v al v ul ar A F p ati e nts t o t h e n u m b er 
of i n divi d u als i n t h e Fr e nc h p o p ul ati o n  p er c al e n d ar y e ar ( N p er 1 0 0, 0 0 0 
i n h a bit a nts) st a n d ar diz e d o n a g e usi n g t h e 2 0 1 9 Fr e nc h p o p ul ati o n str uct ur e  
a n d 2 0 2 0  i n s e nsitivity a n al ys es. 
A n n u al pr e v al e nc e  of A F  
R ati o of n u m b er of di a g n os e d N V A F p ati e nts t o t h e n u m b er of i n divi d u als i n 
t h e Fr e nc h p o p ul ati o n (I N S E E d at a) p er c al e n d ar y e ar  ( N p er 1 0 0, 0 0 0 
i n h a bit a nts). 
O A C tr e at m e nt p att er ns  
Li n e of tr e at m e nt / r e gi m e n 
I d e ntifi e d al g orit h mic ally usi n g dr u g r e gi m e n, d ur ati o n of tr e at m e nt, a n d g a ps 
b et w e e n tr e at m e nts.  
N u m b er of li n es  of tr e at m e nt (L O T) , d ur ati o n of tr e at m e nt, ti m e t o n ext 
tr e at m e nt will b e esti m at e d 
H os pit aliz ati o ns a n d l e n gt h of 
h os pit aliz ati o ns p er L O T  
I d e ntifi e d wit h h os pit al di a g n os es ( pri m ar y, r el at e d, ass oci at e d ) a n d wit h t h e 
d at e of a d missi o n a n d d at e of exit fr o m t his h os pit aliz ati o n.  
Cli nic al e v e nts of i nt er est  
Str o k e (isc h e mic/ h e m orr h a gic)  
M aj or bl e e di n g  
D e at h  
 
H e alt hc ar e R es o urc e us e  ( H C R U) a n d 
c osts 
A m b ul at or y c ar e  
M e dic al c o ns ult ati o ns a n d o ut p ati e nt visits  
M e dic al a n d t ec h nic al pr oc e d ur es, i m a gi n g, bi ol o gic t ests  
H e alt hc ar e pr o vi d ers visits  
H os pit al c ar e ( M C O)  
H os pit aliz ati o ns , e m er g e nc y r o o m a d missi o ns  
M e dic al a n d t ec h nic al pr oc e d ur es, i m a gi n g …  
R e h a bilit ati o n c ar e f aciliti es ( S S R)  
M e dic ati o ns  
I ncl u di n g: A ntic o a g ul a nts, a nti pl at el ets, a nti hy p ert e nsiv e dr u gs gl uc os e-
l o w eri n g dr u gs, li pi d-l o w eri n g dr u gs, a nti arr hyt h mics, b et a-bl oc k ers  
C osts of H C R U  
H e alt h i ns ur a nc e p ers p ectiv e of dir ect c osts of H C R U  p er r es o urc e us e d 
( a m b ul at or y, h os pit al c ar e, r e h a bilit ati o n c ar e …) 
 
 
 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
2 1  
 
 
A p p e n di x 2  List of fi g ur es a n d ta bl es  
O utc o m es  
Pri m ar y 
o bj ecti v e  
S ec o n d ar y 
o bj ecti v e  
Ex pl or at or y 
o bj ecti v e  
I nci d e nc e r at e of str o k e, maj or bl e e di n g a n d d e at h i n A F 
p ati e nts ( ex p os e d/ u n ex p os e d), o v er all a n d i n s u b gr o u ps  
✓  
 
 
A n n u al st a n d ar diz e d i nci d e nc e r at e a n d a n n u al pr ev al e nc e  
 
✓  
 
C h ar act eristics of A F p ati e nts a n d ass oci at e d tr e at m e nts  
 
✓  
 
O A C tr e at m e nt p att er ns  
 
✓  
 
C o m p aris o n of  t h e i nci d e nc e r at e of str o k e, m aj or bl e e di n g, 
d e at h  
 
✓  
 
T h er a p e utic  m a n a g e m e nt b ef or e/ aft er t h e first str o k e 
occ urri n g aft er i niti ati o n of O A C t h er a p y   
 
✓  
 
Im p act of a n O A C s witc h  o n t h e o ns et of str o k e or d e at h  
 
✓  
 
C o m p aris o n of  H C R U  a n d ass oci at e d c osts  
 
✓  
 
I d e ntific ati o n of s u b gr o u ps a m o n g p ati e nts wit h si mil ar 
pr ofil e b y  cl ust eri n g m o d els  
 
 
✓  
T a bl e 1  O utc o m es b y st u d y o bj ecti v e  
 
  
 
 
Fi g ur e 1 .  A F st u d y po p ul ati o n acc or di n g t o i ncl usi o n a n d n o n -i ncl usi o n crit eri a 
 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
2 2  
 
 
Fi g ur e 2  Ti m e p eri o ds a n al yz e d  i n t h e c o m p ar ati v e a n al ysis of e v e nts of i nt er est i n p ati e nts ex p os e d a n d n ot 
ex p os e d t o O A C  
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

2 6  
 
 
A p p e n di x 3  I d e ntific ati o n of e v e nts of i nt er ests: str o k e  a n d  m aj or bl e e di n g  
 
 Titl e  
I C D-1 0 c o d e  
U ns p ecifi e d,  
isc h e mic  
str o k e  
(i ncl u di n g 
Tr a nsi e nt  
isc h e mic 
c er e br al ( TI C)) 
, I 6 3, I 6 4, G 4 6, G 8 1, G 4 5  
H e m or r h a gic 
str o k e 
(i ncl u di n g 
i ntr acr a ni al bl e e di n g) 
I 6 0, I 6 1, I 6 2. 9, S 0 6 4, S 0 6 5, 
S 0 6 6   
G astric,  
d u o d e n al  
a n d  r ect al 
bl e e di n g  
I 8 5 0, 
K 2 2 6, 
K 2 5 0, K 2 5 2, 
K 2 5 4, K 2 5 6, K 2 6 0, K 2 6 2, 
K 2 6 4, K 2 6 6, K 2 7 0, K 2 7 2, 
K 2 7 4, K 2 7 6, K 2 8 0, K 2 8 2, 
K 2 8 4, K 2 8 6, K 2 9 0, K 6 2 5, 
K 9 2 0, K 9 2 1, K 9 2 2  
Ac ut e p ost h e m orr h a gic a n e mi a  
D 6 2  
I ntr a oc ul ar bl e e di n g  
H 3 5 6, H 4 3 1 H 4 5 0  
Ot orr a gi a  
H 9 2 2  
H e m o p eric ar di u m  
I 3 1 2 
R es pir at or y bl e e di n g  
J 9 4 2, R 0 4 
H a e m o p erit o n e u m  
K 6 6 1  
I ntr a artic ul ar bl e e di n g 
M 2 5 0  
Ut eri n e a n d v a gi n al bl e e di n g  
N 0 2, 
N 9 3 8, 
N 9 3 9, 
N 9 5 0, 
R 3 1  
Ot h er bl e e di n g  
R 5 8, T 7 9 2  
 
 
 
M aj or bl e e di n g  
Str o k e  
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
2 7  
 
 
A p p e n di x 4  I d e ntific ati o n of m e dic al hist or y an d c o m or bi diti es  
Dis e as e  
 I C D-1 0 c o d es  
C or o n ar y art eri al dis e as e  ( C A D) 
I 2 1, I 2 2, I 2 4, I 2 5  
Sl e e p dis or d ers  
G 4 7  
C a nc er  
C 0 0 to  C 8 0,  
D 0 0 to  D 0 9,  
D 3 7 to  D 4 8,  
Z 5 1 0, Z 5 1 1  
M al n utriti o n  
E 4 3, E 4 4, E 4 6,  
M or bi d o b esit y ( B MI > 3 0)  
E 6 6  
H os pit alis ati o n f or a n e mi a  
D 5 0, D 5 3  
C O P D  
J 4 4. 9 
P eri p h er al art eri al dis e as e  
I 7 0. 0, I 7 0. 2, I 7 0. 9 
Di a b et es  
E 0 8, E 1 0, E 1 1, E 1 3 , E 1 4   
C o n g esti v e H e art f ail ur e  
I 5 0. 2, I 5 0. 3, I 5 0. 4  
 
 
 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
2 8  
 
A p p e n di x 5  I d e ntific ati o n of tr e at m e nts a n d l eft atri al a p p e n d a g e (L A A) occl usi o n  
Dr u g - tr e at m e nts 
A T C or C C A M c o d e  
A nti vit a mi n K  
B 0 1 A A  
a pix a b a n  
B 0 1 A F 0 2  
ri v ar ox a b a n 
B 0 1 A F 0 1  
d a bi g atr a n  
B 0 1 A E 0 7  
S el ecti v e  
s er ot o ni n  
r e u pt a k e  
i n hi bit or 
a nti d e pr ess a nts ( S S RIs)  
N 0 6 A B  
A nti ar yt h mics  
C 0 1 B A, C 0 1 B B, C 0 1 B C, C 0 1 B D, C 0 1 B G  
N o n -st er oi d al a nti-i nfl a m m at or y dr u gs ( N S AI Ds) 
M 0 1 A;  
C Y P 3 A 4 c yt  P 4 5 0 i n hi bit ors  
B 0 1 A C 2 4, C 0 5 A E 0 3, C 0 9 B B 1 0, C 0 1 B D 0 1, J 0 1 F A exc e pt é 
J 0 1 F A 0 2  
Pr ot o n p u m p i n hi bit ors  
A 0 2 B C  
S yst e mic az ol e a ntif u n g als  
J 0 2 A B et J 0 2 A C 
A nti -pl at el et a g e nts  
B 0 1 A C  
M e dic al pr oc e d ur e of c ar di o v ersi o n  
D E R P 0 0 4, D E R P 0 0 3  
Ot h er  a ntic o a g ul a nts  
B 0 1 A B, B 0 1 A E, B 0 1 A F, B 0 1 A X  
A nti h y p ert e nsi v es  
A T C: C 0 2, C 0 3, C 0 7, C 0 8, C 0 9 ( excl u di n g : C 0 2 K X 0 1 ( n ot 
a v ail a bl e i n Fr a nc e), 
C 0 3 B A 0 8 ( n ot a v ail a bl e f or 
o ut p ati e nt), C 0 3 C A 0 1, C 0 7 A A 0 7, C 0 7 A A 1 2 ( n ot a v ail a bl e 
i n Fr a nc e), C 0 7 A G 0 2 
gl uc os e -l o w eri n g dr u gs 
A 1 0 B A M etf or mi n, A 1 0 B H D P P -I V i n hi bit ors, A 1 0 BJ GL P-
1 r ec e pt or a g o nists, A 1 0 B X 
Gli ni d e, A 1 0 B F Al p h a 
Gl uc osi d as e i n hi bit ors, A 1 0 B B S ulf o n yl ur e a a n d t h e 
c o m bi n ati o ns A 1 0 B D 0 7, 0 8, 1 0 D P P -I V + M etf or mi n a n d 
A 1 0 B D 0 2 S ulf o n yl ur e a + M etf or m i n a n d A 1 0 A i ns uli ns  
li pi d-l o w eri n g dr u gs 
St ati ns: C 1 0 A A, C 1 0 B A, C 1 0 B X; fi br at es: C 1 0 A B; o m e g a 3 
C 1 0 A X 0 6;  
M o n ocl o n al  
a nti -P C S K -9 C 1 0 A X 1 3  
a n d 
C 1 0 A X 1 4  
B et a -bl oc k ers  
C 0 7 A, C 0 7 B, C 0 7 C, C 0 7 D, C 0 7 E, C 0 7 F  
A nti vir als, pr ot e as e i n hi bit ors  
J 0 5 A E 
 
 
C C A M c o d e 
L A A occl usi o n 
D A S F 0 7 4  
 
 
 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)
N o n- E n gli s h t e xt 

 
 
2 9  
 
A p p e n di x 6  D e t ails o n H C R U a n al ysis  
 
D escri pti o n of H C R U a n d c ost t o b e d escri b e d i n t h e a n al ysis  
T his list of H C R U will b e d escri b e d a n d ass oci at e d c ost will b e c alc ul at e d.  
List of H C R U a n d c ost c at e g ori es t h at will b e extr act e d  
H os pit al st ay(s) ( pri v at e a n d p u blic), i ncl u di n g:  
- 
H os pit al a d missi o n  
- 
H os pit al at h o m e  
- 
R e h a bilit ati o n a n d r ec u p er ati v e c ar e f aciliti es  
- 
P alli ati v e c ar e  
- 
E m er g e nc y visit  
N o n -h os pit al / a m b ul at or y c ar e:  
- 
O ut p ati e nt p h ysici a n’s visits  ( pri v at e pr actic e, h o m e or o ut p ati e nt) 
- 
O ut p ati e nt p ar a m e dic visits  
- 
Dis p e nsi n g of o bs er v a bl e dr u gs ( A F  dr u gs a n d ot h er)  
N u m b er a n d fr e q u e nc y of sic k n ess b e n efits  
N u m b er a n d fr e q u e nc y of r ei m b urs e d tr a ns p orts  
H C R U a n d  C osts r el at e d t o A F   
- 
H os pit al  c ar e wit h a di a g n osis of A F  
- 
Tr e at m e nt r el at e d t o A F  
- 
L a b t ests 
- 
M e dic al pr oc e d ur es  
- 
M e dic al d evic es (L P P)  
- 
Tr a ns p ort ati o n f oll o wi n g a n A F  h os pit aliz ati o n  
- 
Sic k l e a v e a n d i n v ali dit y u p t o 7 d a ys aft er A F  h os pit aliz ati o n
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)

 
 
3 0  
 
A p p e n di x 7  
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)
N o n- E n gli s h t e xt 
N o n- E n gli s h t e xt 

3 1  
 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)
N o n- E n gli s h t e xt 

3 2  
 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)
N o n- E n gli s h t e xt 

3 3  
 
0 9 0 1 7 7 e 1 9 d 8 4 b 8 d 3\ Fi n al\ Fi n al O n: 2 2- M a y- 2 0 2 3 1 2: 2 9 ( G M T)
N o n- E n gli s h t e xt