Christiansen, S.C.
Citation
Christiansen, S. C. (2010, September 28). Clinical and biochemical risk factors for first and recurrent episodes of venous thrombosis. Retrieved from https://hdl.handle.net/1887/15992
Version: Corrected Publisher’s Version License:
Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
Downloaded from: https://hdl.handle.net/1887/15992
Note: To cite this publication please use the final published version (if applicable).
(OHYDWHGHQGRJHQRXVWKURPELQSRWHQWLDOLVDVVRFLDWHG
ZLWKDQLQFUHDVHGULVNRID¿UVWGHHSYHQRXV
WKURPERVLVEXWQRWZLWKWKHULVNRIUHFXUUHQFH
$YDQ+\OFNDPD9OLHJ6&&KULVWLDQVHQ5/XGGLQJWRQ6&&DQQHJLHWHU
)55RVHQGDDO73%DJOLQ
%ULWLVK-RXUQDORI+DHPDWRORJ\6HS
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
6XPPDU\
0HDVXUHPHQWRIWKHWKURPELQJHQHUDWLQJSRWHQWLDOFRXOGSURYLGHDPHWKRGIRUTXDQWLI\LQJ
WKHFRPSRVLWHHIIHFWRIPXOWLSOHULVNIDFWRUV7KLVVWXG\DVVHVVHGWKHULVNRID¿UVWDVZHOO
DVDUHFXUUHQWYHQRXVWKURPERWLFHYHQWDVVRFLDWHGZLWKDQLQFUHDVHGHQGRJHQRXVWKURPELQ
SRWHQWLDO(73$QDO\VHVZHUHSHUIRUPHGLQSDWLHQWVDQGFRQWUROVXEMHFWVRIWKH
/HLGHQ 7KURPERSKLOLD 6WXG\ 7KH (73 ZDV PHDVXUHG GLUHFWO\ XVLQJ D ÀXRURJHQLF DVVD\
7KURPELQRVFRSH,QGLYLGXDOVZLWKDQLQFUHDVHG(73LHDERYHWKSHUFHQWLOHPHDVXUHG
LQFRQWUROVXEMHFWV!Q0×PLQKDGDIROG>FRQ¿GHQFHLQWHUYDO&,±@
LQFUHDVHGULVNRID¿UVWGHHSYHQRXVWKURPERVLV7KHULVNZDVPRUHSURQRXQFHGDIWHUWKH
DQDO\VLVZDVUHVWULFWHGWRLGLRSDWKLFWKURPERVHVLHIROG&,±
2YHUDOOWKHKD]DUGUDWLRRIDUHFXUUHQWWKURPERWLFHYHQWDVVRFLDWHGZLWKDKLJK(73DGMXVWHG
IRUDJHVH[DQGRUDODQWLFRDJXODQWXVHZDV&,±7KXVDKLJK(73ZDV
QRWDVVRFLDWHGZLWKDQLQFUHDVHGUHODWLYHULVNRIUHFXUUHQWYHQRXVWKURPERVLV$WSUHVHQW
FOLQLFDOUHOHYDQFHRIWKHWKURPELQJHQHUDWLRQDVVD\LQSUHGLFWLQJUHFXUUHQWYHQRXVWKURPERVLV
UHPDLQVXQFHUWDLQ
55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55
,QWURGXFWLRQ
'XULQJWKHODVWGHFDGHQXPHURXVULVNIDFWRUVIRUD¿UVWGHHSYHQRXVWKURPERWLFHYHQWKDYH
EHHQGHVFULEHGERWKHQYLURQPHQWDODVZHOODVJHQHWLF5RVHQGDDO0RUHUHFHQWO\
TXHVWLRQVKDYHEHHQUDLVHGRQZKHWKHUWKHVHULVNIDFWRUVDUHDOVRDVVRFLDWHGZLWKDQLQFUHDVHG
ULVNRIUHFXUUHQWWKURPERVLV,WZDVVKRZQWKDWIRULQGLYLGXDOVZLWKDWUDQVLHQWHQYLURQPHQWDO
ULVNIDFWRUVXFKDVSUHJQDQF\VXUJHU\LPPRELOL]DWLRQRUKRUPRQHXVHWKHULVNRIUHFXUUHQW
WKURPERVLV LV ORZ ZKHUHDV WKH ULVN RI UHFXUUHQFH LV KLJK LQ SDWLHQWV ZLWK SHUVLVWHQW ULVN
IDFWRUVVXFKDVPDOLJQDQFLHVRUOXSXVDQWLFRDJXODQW+DQVVRQHWDO7KURPERSKLOLF
FRQGLWLRQVVXFKDVSURWHLQ&SURWHLQ6DQGDQWLWKURPELQGH¿FLHQF\'H6WHIDQRHWDO
DVZHOODVKRPR]\JRXVRUGRXEOHKHWHUR]\JRXVFDUULHUVKLSRIWKHIDFWRU9/HLGHQ)9/ DQGSURWKURPELQ$PXWDWLRQKDYHEHHQRQO\ZHDNO\DVVRFLDWHGZLWKLQFUHDVHGULVNRI
UHFXUUHQWYHQRXVWKURPERVLV(PPHULFKHWDO*RQ]DOH]3RUUDVHWDO
2WKHUULVNIDFWRUVIRUD¿UVWWKURPERWLFHYHQWWKDWKDYHDOVREHHQDVVRFLDWHGZLWKWKHULVNRI
UHFXUUHQWYHQRXVWKURPERVLVDUHKHWHUR]\JRXVFDUULHUVKLSRIWKH)9/RUSURWKURPELQ$
PXWDWLRQUHYLHZHGE\+RHWDOHOHYDWHG7$),OHYHOV(LFKLQJHUHWDOORZ
YLWDPLQ % (LFKLQJHU ORZ IUHH7)3, +RNH HW DO K\SHUKRPRF\VWHLQHPLD
.HLM]HUHWDO(LFKLQJHUDQGHOHYDWHGOHYHOVRIIDFWRU9,,,DQG,;.\UOHHW
DO:HOWHUPDQQHWDO%REURZ+RZHYHURQO\VLQJOHVWXGLHVKDYHEHHQ
SHUIRUPHGRUUHVXOWVZHUHFRQWUDGLFWHGLQRWKHUVWXGLHV
2YHUDOOLWFDQEHHQFRQFOXGHGWKDWPRVWRIWKHFXUUHQWO\NQRZQULVNIDFWRUVGRQRWDSSHDUWR
SOD\DQLPSRUWDQWUROHLQWKHULVNRIUHFXUUHQWWKURPERVLV&KULVWLDQVHQHWDO7KHUHIRUH
WHVWLQJ IRU WKHVH GHIHFWV KDV OLWWOH FRQVHTXHQFH ZLWK UHVSHFW WR SURSK\ODFWLF VWUDWHJLHV
&OLQLFDO IDFWRUV DSSHDU PRUH LPSRUWDQW WKDQ ODERUDWRU\ DEQRUPDOLWLHV LQ GHWHUPLQLQJ WKH
GXUDWLRQRIDQWLFRDJXODWLRQWKHUDS\+DQVVRQHWDO%DJOLQHWDO&KULVWLDQVHQHW
DO,WLVVWLOOLPSRUWDQWWRLGHQWLI\WKHJURXSRISDWLHQWVWKDWPD\EHQH¿WIURPSURORQJHG
WUHDWPHQW ZLWK RUDO DQWLFRDJXODWLRQ WKHUDS\ LH WKRVH SDWLHQWV ZLWK DQ LQFUHDVHG ULVN RI
UHFXUUHQWYHQRXVWKURPERVLV,QSDWLHQWVZLWKDORZULVNRIUHFXUUHQFHSURORQJHGWUHDWPHQW
LVDVVRFLDWHGZLWKDQLQFUHDVHGULVNRIEOHHGLQJZKLFKRXWZHLJKVWKHEHQH¿WVRIWKHWUHDWPHQW
3ULQV 0DUFKLRUL 7HVWLQJ IRU LQGLYLGXDO KHULWDEOH WKURPERSKLOLF GHIHFWV UHÀHFWV
QHLWKHUJHQHHQYLURQPHQWLQWHUDFWLRQQRUWKHFRQQHFWLYLW\RIFRPSRQHQWVRIWKHFRDJXODWLRQ
QHWZRUNLHLWGRHVQRWPHDVXUHWKHFRPSRVLWHSKHQRW\SH,QWKLVSHUVSHFWLYHPHDVXUHPHQW
RIODERUDWRU\SKHQRW\SHVIRUWKHVWUDWL¿FDWLRQRIWKURPERWLFULVNPLJKWEHFUXFLDO3DODUHWLHW
DOGHPRQVWUDWHGWKDW'GLPHUWHVWLQJFRXOGEHXVHGLQWKHLGHQWL¿FDWLRQRILQGLYLGXDOV
OHVVSURQHWRUHFXUUHQWYHQRXVWKURPERVLV
%ORRGFRDJXODELOLW\LVGHWHUPLQHGE\LWVFDSDFLW\WRJHQHUDWHWKURPELQ0HDVXUHPHQWRIWKH
WKURPELQJHQHUDWLQJSRWHQWLDOWKHUHIRUHFRXOGSURYLGHDPHWKRGIRUTXDQWLI\LQJWKHFRPSRVLWH
HIIHFWRIPXOWLSOHULVNIDFWRUV7KLVVWXG\DVVHVVHGWKHULVNRID¿UVWDVZHOODVDUHFXUUHQW
YHQRXVWKURPERWLFHYHQWDVVRFLDWHGZLWKDQLQFUHDVHGHQGRJHQRXVWKURPELQSRWHQWLDO(73
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
0DWHULDODQG0HWKRGV
6WXG\GHVLJQ
$QDO\VHV ZHUH SHUIRUPHG LQ WKH /HLGHQ WKURPERSKLOLD VWXG\ /(767KH GHVLJQ RI WKLV
VWXG\KDVEHHQGHVFULEHGLQGHWDLOSUHYLRXVO\.RVWHUHWDOYDQGHU0HHUHWDO
,QEULHIFRQVHFXWLYHSDWLHQWV\RXQJHUWKDQ\HDUVZLWKD¿UVWREMHFWLYHO\FRQ¿UPHG
HSLVRGHRIGHHSYHQRXVWKURPERVLV'97ZHUHLQFOXGHGLQWKLVVWXG\)RXUKXQGUHGDQG
VHYHQW\IRXUFRQWUROVXEMHFWVZHUHLQFOXGHGZKRZHUHIULHQGVRUSDUWQHUVRISDWLHQWVZLWK
WKH VDPH VH[ DQG DSSUR[LPDWHO\ WKH VDPH DJH ZLWKLQ \HDUV ,QGLYLGXDOV ZLWK NQRZQ
PDOLJQDQWGLVRUGHUVZHUHH[FOXGHG
3DWLHQWVDQGFRQWUROVXEMHFWVZHUHLQLWLDOO\VHHQDWOHDVWPRQWKVDIWHUGLVFRQWLQXDWLRQRIRUDO
DQWLFRDJXODWLRQWKHUDS\H[FHSWLQFDVHVZKHQWKLVWUHDWPHQWFRXOGQRWEHVWRSSHGQ
%ORRGZDVFROOHFWHGIURPWKHDQWHFXELWDOYHLQLQWR6DUVWHGW0RQRYHWWHWXEHVLQYROXPH
PROOWULVRGLXPFLWUDWH3ODVPDZDVSUHSDUHGE\FHQWULIXJDWLRQIRUPLQDWJDW
URRPWHPSHUDWXUHDQGVWRUHGDW°&XQWLOXVHG+LJKPROHFXODUZHLJKW'1$ZDVLVRODWHG
IURPOHXFRF\WHVDQGVWRUHGDW°&
3DWLHQWVZHUHVXEVHTXHQWO\IROORZHGXSWRDVVHVVWKHULVNRIUHFXUUHQW'97$OOSDWLHQWV
JDYHLQIRUPHGFRQVHQWIRUIROORZXS7KH/(76IROORZXSKDVDOVREHHQGHVFULEHGLQGHWDLO
&KULVWLDQVHQ HW DO )ROORZXS VWDUWHG G DIWHU WKH GDWH RI WKH LQLWLDO WKURPERWLF
HYHQW ZKLFK RFFXUUHG EHWZHHQ DQG DQG HQGHG RQ -DQXDU\ 5HFXUUHQW
WKURPERWLF HYHQWV ZHUH DGMXGLFDWHG ZKHQ WKH\ ZHUH REMHFWLYHO\ FRQ¿UPHG ZLWK 'RSSOHU
XOWUDVRXQG YHQRJUDSK\ RU LPSHGDQFH SOHWK\VPRJUDSK\ 5HFXUUHQW SXOPRQDU\ HPEROXV
ZDV FRQ¿UPHG E\ D SRVLWLYH SHUIXVLRQ OXQJ VFDQ D YHQWLODWLRQSHUIXVLRQ OXQJ VFDQ RU D
FRPSXWHUL]HGWRPRJUDSKLFVFDQ
0HDVXUHPHQWRIWKH(73EHFRPHVXQUHOLDEOHLQSODVPDRISDWLHQWVXVLQJRUDODQWLFRDJXODQW
WKHUDS\WKHUHIRUHSDWLHQWVDQGRQHFRQWUROVXEMHFWZHUHH[FOXGHGIURPDQDO\VHV3ODVPD
ZDVDYDLODEOHIRUSDWLHQWVQRWXVLQJRUDODQWLFRDJXODWLRQWKHUDS\DQGFRQWUROVXEMHFWV
0HDVXUHPHQWRIWKH(73FDOLEUDWHGDXWRPDWHGWKURPERJUDSK\
7KH(73ZDVPHDVXUHGGLUHFWO\XVLQJDÀXRURJHQLFDVVD\7KURPELQRVFRSH6\QDSVH%9
0DDVWULFKWWKH1HWKHUODQGVZKLFKPHDVXUHVFORWERXQGDVZHOODVIUHHWKURPELQWKDWLV
IRUPHGGXULQJFRDJXODWLRQ
$PRGL¿HGYHUVLRQRIWKHRULJLQDOWHVWDVGHVFULEHGE\+HPNHUHWDOZDVXVHG,Q
GXSOLFDWH μ/ +(3(6 EXIIHU > PPROO +(3(6 PPROO 1D&O PJPO ERYLQH
VHUXPDOEXPLQ%6$S+@ZLWKSPROOWLVVXHIDFWRU7)$PHULFDQ'LDJQRVWLFD
6WDPIRUG&786$DQGQPROOWKURPERPRGXOLQ70$PHULFDQ'LDJQRVWLFDZDVDGGHG
WRμORIRQHLQIRXUGLOXWHGSODVPDμOSODVPDLQμO+(3(6EXIIHUHGVDOLQHPPROO
+(3(6PPROO1D&OPJPO%6$S+@LQDSRO\SURS\OHQHURXQGERWWRPHG
PLFURWLWUHSODWH*UHLQHU%LRRQH/WG6WRQHKRXVH8.3KRVSKROLSLGVZHUHDGGHGDWD¿QDO
FRQFHQWUDWLRQRIμPROODQGZHUHREWDLQHGIURP$YDQWL3RODU/LSLGV$ODEDVWHU$/86$ DQGFRQVLVWHGRIPROSKRVSKDWLG\OVHULQHPROSKRVSKDWLG\OHWKDQRODPLQHDQG
PROSKRVSKDWLG\OFKROLQHSUHSDUHGE\H[WUXVLRQ$IWHUDGGLWLRQRIμORIVXEVWUDWHUHDJHQW
QPROO *O\*O\$UJ$0& PROO &D&O PPROO +(3(6 PJPO %6$ S+
WKHUHDFWLRQZDVPRQLWRUHGLQD)OXRURVFDQ$VFHQWSODWHUHDGHU7KHUPR/DEV\VWHPV
55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 +HOVLQNL)LQODQGZLWKDQH[FLWDWLRQ¿OWHUDWQPDQGDQHPLVVLRQ¿OWHUDWQP7KH
ÀXRUHVFHQW VLJQDO ZDV FRQYHUWHG WR D WKURPELQ FRQFHQWUDWLRQ E\ FRQWLQXRXV FRPSDULVRQ
ZLWKWKHVLJQDOJHQHUDWHGE\WKHWKURPELQFDOLEUDWRUDGGHGWRDVHSDUDWHVDPSOHRIWKHWHVW
SODVPDXVLQJ7KURPELQRVFRSHVRIWZDUH$WKURPELQFDOLEUDWRUZDVDGGHGWRDWKLUGSODVPD
VDPSOHWRVXEVHTXHQWO\HOLPLQDWHGLIIHUHQFHVLQWKHVLJQDOIURPWKHÀXRURSKRUHGXHWRWKH
YDULDELOLW\LQWKHOLJKWDEVRUSWLRQFKDUDFWHULVWLFVRIGLIIHUHQWSODVPDVDQGWRWKHLQQHUHIIHFW
ZKLFKUHVXOWVLQDQRQOLQHDUUHODWLRQVKLSEHWZHHQWKHFRQFHQWUDWLRQRIFOHDYHGÀXRURSKRUH
DQGWKHHPLVVLRQVLJQDO7KH(73ZDVFDOFXODWHGIURPWKHDUHDXQGHUWKHWKURPELQJHQHUDWLRQ
FXUYHDGMXVWHGIRUαPDFURJOREXOLQWKURPELQDFWLYLW\
7KHLQWUDDQGLQWHULQGLYLGXDOFRHI¿FLHQWRIYDULDWLRQ&9ZDVDQGQ UHVSHFWLYHO\
7KH GHWHUPLQDWLRQ RI WKH )9/ DQG WKH SURWKURPELQ $ PXWDWLRQ ZDV SHUIRUPHG E\
VWDQGDUGSRO\PHUDVHFKDLQUHDFWLRQZKLFKKDVEHHQGHVFULEHGSUHYLRXVO\5RVHQGDDOHWDO
3RRUWHWDO
6WDWLVWLFDODQDO\VLV&DVHFRQWUROVWXG\
3XWDWLYHGHWHUPLQDQWVRIWKH(73ZHUHVWXGLHGLQWKHKHDOWK\FRQWUROJURXSDVUHÀHFWLQJWKH
JHQHUDOSRSXODWLRQ'HWHUPLQDQWVZHUHHVWDEOLVKHGPDLQO\E\FRPSDULQJPHDQV
7KHULVNRID¿UVWGHHSYHQRXVWKURPERWLFHYHQWRYHUDOODQGDQLGLRSDWKLFHYHQWVHSDUDWHO\ DVVRFLDWHGZLWKDQLQFUHDVHG(73ZDVDVVHVVHGE\FDOFXODWLQJRGGVUDWLRVZLWKWKHLU
FRQ¿GHQFHLQWHUYDOV&,$VDFXWRIISRLQWZHXVHGWKHWKSHUFHQWLOHRI(73OHYHOV
PHDVXUHGLQWKHFRQWUROVXEMHFWV5LVNVZHUHFDOFXODWHGLQVXEJURXSVGH¿QHGE\VH[DJHDQG
KRUPRQDOVWDWXVLHSUHDQGSRVWPHQRSDXVDOZRPHQZLWKDQGZLWKRXWRUDOFRQWUDFHSWLYH
XVH$Q LGLRSDWKLF WKURPERWLF HYHQW ZDV GH¿QHG DV DQ LQLWLDO HYHQW WKDW RFFXUUHG LQ WKH
DEVHQFH RI SUHJQDQF\ SXHUSHULXP RUDO FRQWUDFHSWLYH XVH ZLWKLQ G WUDXPD VXUJHU\
LPPRELOL]DWLRQRUWKHXVHRIDSODVWHUFDVWZLWKLQPRQWKVEHIRUHWKHHYHQW&KULVWLDQVHQ
HWDO
6WDWLVWLFDODQDO\VLVIROORZXSVWXG\
7KHFXPXODWLYHLQFLGHQFHRIUHFXUUHQWWKURPERVLVZDVFDOFXODWHGE\.DSODQ0HLHUVXUYLYDO
DQDO\VLV7KH&R[SURSRUWLRQDOKD]DUGVPRGHOZDVXVHGWRHYDOXDWHULVNVRIWKHJURXSZLWK
DQ HOHYDWHG (73 LH DERYH WKH SHUFHQWLOH DV PHDVXUHG LQ WKH KHDOWK\ FRQWUROV RI WKH
FDVHFRQWUROVWXG\FRPSDUHGZLWKWKHJURXSZLWKDORZ(73WKSHUFHQWLOH7KHULVN
RIUHFXUUHQWWKURPERVLVZDVFDOFXODWHGIRUDOOSDWLHQWVDQGIRUSDWLHQWVZKRKDGDQLQLWLDO
LGLRSDWKLFWKURPERWLFHYHQW+D]DUGUDWLRVZHUHDGMXVWHGIRUVH[DJHDQGRUDODQWLFRDJXODWLRQ
WKHUDS\GXULQJIROORZXSDGGHGWRWKHPRGHODVDWLPHGHSHQGHQWYDULDEOH
5HVXOWV
7DEOH,GHVFULEHVWKHPHDQ(73&,LQGLIIHUHQWVXEJURXSV7KHUHZDVQRGLIIHUHQFH
LQ(73OHYHOEHWZHHQPHQDQGZRPHQ(73OHYHOVLQFUHDVHGVOLJKWO\ZLWKDJHDQG(73
OHYHOVZHUHKLJKHULQZRPHQXVLQJRUDOFRQWUDFHSWLYHVFRPSDUHGZLWKZRPHQQRWXVLQJRUDO
FRQWUDFHSWLYHV)XUWKHUPRUH(73OHYHOVZHUHDVVRFLDWHGZLWKWKH)9/DQGWKHSURWKURPELQ
$PXWDWLRQZKHUHFDUULHUVKDGKLJKHU(73OHYHOVWKDQQRQFDUULHUV
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
7DEOH,(QGRJHQRXVWKURPELQSRWHQWLDO(73OHYHOVLQGLIIHUHQWVXEJURXSV
Q 0HDQ(73&,
&RQWUROVXEMHFWV
$OO ±
6XEJURXSV
6H[
0HQ ±
:RPHQ ±
$JH
±
±
±
! ±
2&
<HV ±
1R ±
)9/
<HV KHWHUR] ±
1R ±
37$
<HV KHWHUR] ±
1R ±
3DWLHQWV
$OO ±
6XEJURXSV
)LUVWHYHQW
,GLRSDWKLF ±
3URYRNHG ±
,GLRSDWKLF WKURPERWLF HYHQW DEVHQFH RI SUHJQDQF\ SXHUSHULXP RUDO FRQWUDFHSWLYH XVH ZLWKLQ
G WUDXPD VXUJHU\ LPPRELOL]DWLRQ RU WKH XVH RI D SODVWHU FDVW ZLWKLQ PRQWKV EHIRUH WKH HYHQW
(73HQGRJHQRXVWKURPELQSRWHQWLDO)9/IDFWRU9/HLGHQ
$WWKHWLPHRIWKHYHQHSXQFWXUHZRPHQZKRZHUHQRWSUHJQDQWQRWZLWKLQGSRVWSDUWXPGLGQRW
KDYHDUHFHQWPLVFDUULDJHDQGGLGQRWXVHGHSRWFRQWUDFHSWLYHV 7KURPERWLFULVNRID¿UVW'97DVVRFLDWHGZLWKDQLQFUHDVHG(73
,QGLYLGXDOVZLWKDQLQFUHDVHG(73LHDERYHWKSHUFHQWLOHPHDVXUHGLQFRQWUROVXEMHFWV
!Q0⋅PLQKDGDIROG&,±LQFUHDVHGULVNRID¿UVWGHHSYHQRXV
WKURPERWLFHYHQW7DEOH,,7KHULVNRID¿UVWGHHSYHQRXVWKURPERWLFHYHQWZDVLQFUHDVHG
LQDOOVXEJURXSVRIPHQZRPHQDQGPHQRSDXVDOVWDWXV7KHULVNZDVPRUHSURQRXQFHGDIWHU
WKH DQDO\VLV ZDV UHVWULFWHG WR LGLRSDWKLF WKURPERVHV LH RYHUDOO WKH ULVN RI DQ LGLRSDWKLF
¿UVWHYHQWZDVIROG&,±LQFUHDVHGLQLQGLYLGXDOVZLWKDKLJKFRPSDUHG
ZLWKDORZ(737KHULVNRID¿UVW'97DVVRFLDWHGZLWKDKLJK(73DSSHDUHGKLJKHVWLQ
SRVWPHQRSDXVDOZRPHQZKRZHUHQRWXVLQJRUDOFRQWUDFHSWLYHVDOOWKURPERVHV25
&,±LGLRSDWKLFWKURPERVHV25 &,±$GMXVWPHQWIRUDJH
VH[DQGFDUULHUVWDWXVRIWKH)9/RUWKHSURWKURPELQ$PXWDWLRQGLGQRWDIIHFWWKH
UHVXOWV
55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55
$FOHDUGRVHUHVSRQVHUHODWLRQFRXOGQRWEHGHPRQVWUDWHGZKHQGLYLGLQJWKH(73OHYHOVLQWR
TXDUWLOHV8VLQJLQGLYLGXDOVZLWKDQ(73OHYHOLQWKH¿UVWORZHVWTXDUWLOHQ0⋅PLQ DVDUHIHUHQFHFDWHJRU\ZHIRXQGQRLQFUHDVHLQWKHULVNRIYHQRXVWKURPERVLVIRULQGLYLGXDOV
ZLWKDQ(73OHYHOLQWKHRWKHUTXDUWLOHV25QGTXDUWLOH&,±25UGTXDUWLOH
&,±25UGTXDUWLOH&,7KHLQFUHDVHGULVNRID¿UVWGHHSYHQRXV
WKURPERWLFHYHQWVHHPHGSUHVHQWRQO\LQLQGLYLGXDOVZLWKDSURQRXQFHG(73LHDERYHWKH
WKSHUFHQWLOH
7KHWLPHEHWZHHQWKHYHQRXVWKURPERWLFHYHQWDQGWKHYHQHSXQFWXUHGLGQRWDIIHFWWKH(73
OHYHOVLQWKHSDWLHQWV$IWHUGLYLGLQJWKHLQWHUYHQLQJWLPHLQIRXUSHULRGVWKH(73OHYHOV
UHPDLQHGDSSUR[LPDWHO\WKHVDPH7KH(73OHYHOVUDQJHGIURPQ0⋅PLQLQLQGLYLGXDOV
ZLWKDYHQHSXQFWXUHZLWKLQ\HDUDIWHUWKHWKURPERWLFHYHQWWRQ0⋅PLQLQLQGLYLGXDOV
ZLWKDYHQHSXQFWXUHPRUHWKDQ\HDUVDIWHUWKHLQLWLDOHYHQW
7KURPERWLFULVNRIUHFXUUHQW'97DVVRFLDWHGZLWKLQFUHDVHG(73
,QWKHWRWDOJURXSRISDWLHQWVSDWLHQWVKDGDUHFXUUHQWHYHQWRYHUDPHDQRI
\HDUVRIIROORZXS7KHRYHUDOOLQFLGHQFHUDWHRIUHFXUUHQWWKURPERVLVZDVSHU
SDWLHQW\HDUVLQWKHJURXSRISDWLHQWVZLWKDKLJK(73DQGSHUSDWLHQW\HDUVLQ
WKHJURXSRISDWLHQWVZLWKDORZ(737KHDQQXDOULVNRIUHFXUUHQWWKURPERVLVZDVLQ
SDWLHQWVZLWKDKLJK(73FRPSDUHGZLWKLQSDWLHQWVZLWKDORZ(73)LJ
2YHUDOOWKHKD]DUGUDWLRRIDUHFXUUHQWWKURPERWLFHYHQWDVVRFLDWHGZLWKDKLJK(73DGMXVWHG
IRUDJHVH[DQGRUDODQWLFRDJXODQWXVHDGGHGWRWKHPRGHODVDWLPHGHSHQGHQWYDULDEOHZDV
&,±8VLQJWKHVDPHDGMXVWPHQWVWKHKD]DUGUDWLRRIDUHFXUUHQWWKURPERWLF
HYHQWDVVRFLDWHGZLWKDKLJK(73DIWHUDQLQLWLDOLGLRSDWKLFWKURPERWLFHYHQWZDV
&,±
:HDOVRDVVHVVHGWKHUHODWLYHULVNRIUHFXUUHQWWKURPERVLVLQWKH¿UVW\HDUDIWHUYHQHSXQFWXUH
6L[SDWLHQWVKDGDUHFXUUHQWWKURPERWLFHYHQWZLWKLQ\HDUDIWHUYHQHSXQFWXUH7KHUHZDVQR
GLIIHUHQFHLQWKH(73OHYHORIWKHSDWLHQWVZKRKDGDUHFXUUHQWHYHQWZLWKLQ\HDUDIWHUWKH
LQLWLDOHYHQWDQGWKRVHZKRKDGDUHFXUUHQWHYHQWODWHU(73OHYHOVDQGQ0⋅PLQ
UHVSHFWLYHO\PHDQGLIIHUHQFH&,WR
7KURPERWLFULVNDVVRFLDWHGZLWKRWKHUWHVWRXWFRPHV
2WKHUVHFRQGDU\FRPSRQHQWVRIWKURPELQJHQHUDWLRQWHVWDUHWKHODJWLPHLHFORWWLQJWLPH
WKHPD[LPXPDPRXQWRIWKURPELQIRUPHGDWDFHUWDLQSRLQWLQWLPHLHWKHSHDNWKHWLPH
IURPLQLWLDWLRQRIFRDJXODWLRQWRSHDNDQGWKHPD[LPXPUDWHRIWKURPELQIRUPDWLRQ1RQH
RIWKHVHFRPSRQHQWVZDVDVVRFLDWHGZLWKHLWKHUD¿UVWRUDUHFXUUHQWYHQRXVWKURPERWLFHYHQW
GDWDQRWVKRZQ
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
7DEOH,,5LVNRID¿UVWGHHSYHQRXVWKURPERVLVDVVRFLDWHGZLWKDKLJKHQGRJHQRXVWKURPELQ
SRWHQWLDO(73
6XEMHFWV $OO ,GLRSDWKLFWKURPERVLV
$OO ± ±
6H[0HQ ± ±
:RPHQ ± ±
2UDOFRQWUDFHSWLYHV
3UHPHQRSDXVDOQR2& ± ±
3UHPHQRSDXVDOZLWK2& ±
3RVWPHQRSDXVDOQR2& ± ±
$+LJK(73LVGH¿QHGDVDQ(73OHYHODERYHWKSHUFHQWLOHDVPHDVXUHGLQWKHFRQWUROVXEMHFWV3 Q0⋅PLQ
$W WKH WLPH RI WKURPERVLV RU VLPLODU LQGH[ GDWH IRU FRQWURO VXEMHFWV DV ZHOO DV DW WLPH RI WKH
YHQHSXQFWXUHLHZRPHQZKRGLGQRWFKDQJHWKHLURUDOFRQWUDFHSWLYHXVHVLQFHWKHWKURPERWLFHYHQW
)LJXUH&XPXODWLYH,QFLGHQFHRIUHFXUUHQWWKURPERVLV
3DWLHQWVZLWKDKLJKHQGRJHQRXVWKURPELQSRWHQWLDO(73LHDERYHWKHWKSHUFHQWLOHDVPHDVXUHG
LQFRQWUROVXEMHFWVDQGSDWLHQWVZLWKDORZ(73GXULQJWKHSHULRGIURPGDIWHUWKH¿UVWWKURPERWLF
HYHQWXQWLO-DQXDU\
0 2 4 6 8 10 12
Y ears of follow-up 0
5 10 15 20 25 30 35 40
Cumulative incidence, %
E T P
< P 90
> P 90
1RDWULVN
(73!3
(733
55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55
'LVFXVVLRQ
)URPDFOLQLFDOSHUVSHFWLYHLWZRXOGEHKLJKO\GHVLUDEOHWRKDYHDWHVWWKDWSUHGLFWVWKHULVNRI
GHYHORSLQJDUHFXUUHQWYHQRXVWKURPERWLFHYHQW7KURPELQLVWKHNH\HQ]\PHLQFRDJXODWLRQ
0HDVXUHPHQW RI WKH WKURPELQ JHQHUDWLQJ SRWHQWLDO WKHUHIRUH FRXOG SURYLGH D PHWKRG IRU
TXDQWLI\LQJWKHFRPSRVLWHHIIHFWRIPXOWLSOHULVNIDFWRUV$QHOHYDWHGHQGRJHQRXVWKURPELQ
SRWHQWLDOZDVDVVRFLDWHGZLWKDQLQFUHDVHGULVNRID¿UVWYHQRXVWKURPERWLFHYHQW$VLWZDV
VKRZQSUHYLRXVO\WKDWWKHULVNRIDUHFXUUHQWYHQRXVWKURPERWLFHYHQWZDVORZLQLQGLYLGXDOV
ZLWKDWUDQVLHQWULVNIDFWRUIRUYHQRXVWKURPERVLVVXFKDVVXUJHU\RULPPRELOL]DWLRQ+DQVVRQ
HWDOZHLQYHVWLJDWHGWKHDVVRFLDWLRQEHWZHHQDQHOHYDWHG(73DQGWKHULVNRIDQ
LGLRSDWKLF YHQRXV WKURPERWLF HYHQW GH¿QLWLRQ VHH 0DWHULDOV DQG PHWKRGV$Q HOHYDWHG
(73ZDVDVVRFLDWHGZLWKDPLOGO\LQFUHDVHGULVNRIDQLGLRSDWKLFWKURPERWLFHYHQWZLWKULVN
HVWLPDWHVEHLQJLQFUHDVHGE\WRIROG7KHUHZDVQRDVVRFLDWLRQEHWZHHQWKHRYHUDOO
ULVNRIDUHFXUUHQWWKURPERWLFHYHQWDQGDQHOHYDWHG(737KHVHUHVXOWVDUHDSSOLFDEOHIRU
SDWLHQWVDJHGOHVVWKDW\HDUVDWWKHWLPHRIWKHLULQLWLDOHYHQW
7KHPHGLDQWLPHEHWZHHQWKHLQLWLDOWKURPERVLVDQGWKHYHQHSXQFWXUHZDVPRQWKV
3DWLHQWIROORZXSVWDUWHGGDIWHUWKHLQLWLDOWKURPERWLFHYHQW$OWKRXJKWKHOHYHOVRIWKH
(73UHPDLQHGVWDEOHDVGHPRQVWUDWHGE\WKHODFNRIDQHIIHFWRIWKHWLPHHODSVHGEHWZHHQWKH
WKURPERWLFHYHQWDQGWKHYHQHSXQFWXUHZHDOVRFDOFXODWHGWKHKD]DUGUDWLRLQWKH¿UVW\HDU
DIWHUWKHYHQHSXQFWXUH&RQVLVWHQWZLWKWKHDQDO\VLVZKHUHIROORZXSVWDUWHGGDIWHUWKH
LQLWLDOHYHQWQRLQFUHDVHLQWKHUHODWLYHULVNRIDUHFXUUHQWWKURPERVLVLQWKH¿UVW\HDUDIWHUWKH
YHQHSXQFWXUHFRXOGEHGHPRQVWUDWHG
5HFHQWO\+URQHWDOUHSRUWHGRQWKHUHODWLRQVKLSEHWZHHQUHFXUUHQWYHQRXVWKURPERVLV
DQGSHDNWKURPELQJHQHUDWLRQ7KH\FRQFOXGHGWKDWSDWLHQWVZLWKDSHDNWKURPELQJHQHUDWLRQ
OHVV WKDQ QPROO KDG D ORZHU ULVN RI UHFXUUHQFH FRPSDUHG ZLWK SDWLHQWV ZLWK D SHDN
WKURPELQJHQHUDWLRQDERYHJUHDWHUWKDQQPROO55+URQHWDOD¿QGLQJ
WKDWFRXOGQRWEHFRQ¿UPHGLQWKHFXUUHQWVWXG\
$PDMRUSUREOHPZLWKWKURPELQJHQHUDWLRQDVVD\VLVWKHLQWHUIHUHQFHIURPFRQWDFWDFWLYDWLRQ
HVSHFLDOO\ZLWKDVVD\VXVLQJDORZ7)WULJJHUFRQFHQWUDWLRQ/XGGLQJWRQ %DJOLQ
&RQWDFWDFWLYDWLRQFDQEHDYRLGHGE\VDPSOLQJEORRGGLUHFWO\LQWRDQWLFRDJXODQWFRQWDLQLQJ
FRUQ WU\SVLQ LQKLELWRU &7, DQ LQKLELWRU RI DFWLYDWHG IDFWRU ;,, +RZHYHU DGGLWLRQ RI
&7, DIWHU SODVPD VHSDUDWLRQ ZDV VKRZQ QRW WR EH VXI¿FLHQW WR DEROLVK FRQWDFW DFWLYDWLRQ
/XGGLQJWRQ %DJOLQDQGDVWKHSODVPDVDPSOHVRIWKH/(76KDYHEHHQVWRUHGIRU
PDQ\\HDUVFRQWDFWDFWLYDWLRQFRXOGQRWEHUXOHGRXW:KHQXVLQJD7)WULJJHUFRQFHQWUDWLRQ
EHORZ SPROO IDFWRU ;,,DGULYHQ WKURPELQ JHQHUDWLRQ FDQ HTXDO RU H[FHHG WKDW GXH
WR7)$WD7)WULJJHUFRQFHQWUDWLRQRISPROOWKHUHLVOLWWOHHIIHFWIURPFRQWDFWIDFWRU
DFWLYDWLRQ /XGGLQJWRQ %DJOLQ DQG VR WKLV FRQFHQWUDWLRQ ZDV XVHG WR WULJJHU
WKURPELQJHQHUDWLRQDVVDPSOHVKDGQRWEHHQFROOHFWHGLQ&7,+RZHYHUZHFDQQRWH[FOXGH
WKHSRVVLELOLW\WKDWGLIIHUHQWUHVXOWVZRXOGKDYHEHHQREWDLQHGLIVDPSOHVKDGEHHQWDNHQ
LQWR&7,DQGWKH(73WULJJHUHGZLWKDORZHU7)FRQFHQWUDWLRQ7KURPELQJHQHUDWLRQDIWHU
7) LQLWLDWLRQ FDQ EH GLYLGHG LQWR WKH SURSDJDWLRQ DQG LQLWLDWLRQ SKDVH 8VLQJ D ORZ 7)
WULJJHUFRQFHQWUDWLRQLQWKURPELQJHQHUDWLRQWHVWVUHVXOWVLQDPRUHSK\VLRORJLFDOVLWXDWLRQ
7KHUHIRUHSUHIHUDEO\WRJHWDPRUHJOREDOLPSUHVVLRQRIWKHFRDJXODWLRQV\VWHPLQFOXGLQJ
ERWKWKHLQLWLDWLRQDVZHOODVWKHSURSDJDWLRQSKDVHDORZHU7)WULJJHUFRQFHQWUDWLRQVKRXOG
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
EHXVHG7KHUHODWLYHO\KLJK7)WULJJHUFRQFHQWUDWLRQWKDWZDVQHFHVVDULO\XVHGLQWKLVVWXG\
PLJKWH[SODLQWKHDEVHQFHRIDQLQFUHDVHGULVNLQUHFXUUHQWYHQRXVWKURPERVLVDVVRFLDWHG
ZLWKHOHYDWHG(73%UXPPHO=LHGLQVHWDOFDOFXODWHGWKURPELQJHQHUDWLRQDVZHOODV
VHYHUDORWKHUGHWHUPLQDQWVHJUDWHRIWKURPELQJHQHUDWLRQPD[LPXPDPRXQWRIWKURPELQ
IRUPHG DOVR LQ WKH /HLGHQ 7KURPERSKLOLD FDVHFRQWURO VWXG\ &RQVLVWHQW ZLWK WKH UHVXOWV
SUHVHQWHGLQWKHFXUUHQWVWXG\DQLQFUHDVHGULVNRID¿UVWYHQRXVWKURPERVLVDVVRFLDWHGZLWK
DQHOHYDWHGHQGRJHQRXVWKURPELQSRWHQWLDOZDVGHPRQVWUDWHGXVLQJDFRPSXWHUVLPXODWLRQRI
WKURPELQJHQHUDWLRQ+RZHYHUIRUWKHPDQDJHPHQWRISDWLHQWVZLWKYHQRXVWKURPERVLVWKLV
PRGHOLVOHVVXVHIXODVDOOFRDJXODWLRQIDFWRUVLQYROYHGQHHGWREHPHDVXUHGLQHDFKSDWLHQW
7KHULVNVUHSRUWHGLQWKHVWXG\E\%UXPPHO=LHGLQVHWDODUHVOLJKWO\KLJKHUWKDQWKRVH
UHSRUWHGKHUH,QWKHGHVFULEHGFRPSXWHUPRGHOFRDJXODWLRQZDVDFWLYDWHGZLWKSPROO7)
LHORZHUWKDQWKH7)WULJJHUFRQFHQWUDWLRQXVHGLQWKHSUHVHQWVWXG\7KLVDJDLQHPSKDVL]HV
WKDWDWKURPELQJHQHUDWLRQDVVD\WKDWXVHVDORZ7)WULJJHUFRQFHQWUDWLRQPD\EHEHWWHULQ
SUHGLFWLQJWKHULVNRID¿UVWDQGUHFXUUHQWGHHSYHQRXVWKURPERWLFHYHQW
:H DGGHG WKURPERPRGXOLQ WR RXU DVVD\ DV GHVFULEHG LQ WKH 0DWHULDOV DQG PHWKRGV7KH
FRQFHQWUDWLRQRIWKURPERPRGXOLQFKRVHQZDVEDVHGRQDSUHYLRXVVWXG\RIVHOHFWHGSDWLHQWV
LQZKLFKWKLVFRPELQDWLRQRI7)70JDYHPD[LPXPGLVFULPLQDWLRQEHWZHHQQRUPDOVXEMHFWV
DQGSDWLHQWVZLWKDVWURQJSHUVRQDODQGIDPLO\KLVWRU\RIYHQRXVWKURPERVLV5/XGGLQJWRQDQG
73%DJOLQXQSXEOLVKHGREVHUYDWLRQV7KHWUDQVPHPEUDQHJO\FRSURWHLQWKURPERPRGXOLQLV
WKHFRIDFWRURIWKURPELQDQGLVQHFHVVDU\IRUHIIHFWLYHDFWLYDWLRQRISURWHLQ&E\WKURPELQ
7KURPERPRGXOLQDPSOL¿HVWKHSURWHLQ&DFWLYDWLRQPRUHWKDQDIROG9DQGH:RXZHU
HWDO7KHDGGLWLRQRIWKURPERPRGXOLQWKHUHIRUHLQFRUSRUDWHVWKHSURWHLQ&SDWKZD\
LQWKHDVVD\WKHUHE\SRVVLEO\SURYLGLQJDPRUHJOREDOWHVWRIERWKWKHSURDVZHOODVWKH
DQWLFRDJXODQWV\VWHP7KHHIIHFWRIWKLVDGGLWLRQWRWKHWHVWQHHGVWREHVWXGLHGLQPRUHGHWDLO
,QWHUHVWLVFXUUHQWO\IRFXVVHGRQWKHXVHRIDVLQJOHODERUDWRU\WHVWLQWKHGLDJQRVLVRIYHQRXV
WKURPERVLV +RZHYHU DW SUHVHQW WKH FOLQLFDO UHOHYDQFH RI WKH WKURPELQ JHQHUDWLRQ DVVD\
LQ SUHGLFWLQJ UHFXUUHQW YHQRXV WKURPERVLV UHPDLQV XQFHUWDLQ ,W LV WKHUHIRUH QRW XVHIXO WR
SHUIRUPWKHVHWHVWVURXWLQHO\LQSDWLHQWVZKRH[SHULHQFHGD¿UVWWKURPERWLFHYHQW1R¿UP
FRQFOXVLRQVFDQEHGUDZQIURPWKHRXWFRPHRIWKLVWHVWXQWLOLWKDVEHHQVWXGLHGLQPRUHGHWDLO
DQGDSRVLWLYHSUHGLFWLYHYDOXHKDVEHHQFRQ¿UPHGE\VHYHUDOVWXGLHV
$FNQRZOHGJHPHQWV
:HDUHJUDWHIXOWRWKHSHUVRQQHORIWKH$QWLFRDJXODWLRQFOLQLFVRI/HLGHQ5RWWHUGDPDQG
$PVWHUGDPZKRIDFLOLWDWHGWKHLQFOXVLRQRIWKHSDWLHQWV:HWKDQN7HG.RVWHUIRUFROOHFWLQJ
EORRGVDPSOHVRISDWLHQWVDQGFRQWUROVXEMHFWV$QN6FKUHLMHU,QJHERUJGH-RQJHDQG,QJH
1RRUGHUPHHUIRUGDWDPDQDJHPHQWDQGDOOSDUWLFLSDWLQJSDWLHQWVDQGFRQWUROVXEMHFWVIRU
WKHLUFRRSHUDWLRQ
55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55
5HIHUHQFHV
%DJOLQ7 /XGGLQJWRQ 5 %URZQ . %DJOLQ & ,QFLGHQFH RI UHFXUUHQW YHQRXV
WKURPERHPEROLVP LQ UHODWLRQ WR FOLQLFDO DQG WKURPERSKLOLF ULVN IDFWRUV SURVSHFWLYH FRKRUW
VWXG\/DQFHW
%REURZ56([FHVVIDFWRU9,,,DFRPPRQFDXVHRIK\SHUFRDJXODELOLW\-RXUQDORIWKH
$PHULFDQ%RDUGRI)DPLO\3UDFWLFH
%UXPPHO=LHGLQV .( 9RVVHQ &< %XWHQDV 6 0DQQ .* 5RVHQGDDO )5 7KURPELQ JHQHUDWLRQ SUR¿OHV LQ GHHS YHQRXV WKURPERVLV -RXUQDO RI 7KURPERVLV DQG
+DHPRVWDVLV
&KULVWLDQVHQ 6& &DQQHJLHWHU 6& .RVWHU 7 9DQGHQEURXFNH -3 5RVHQGDDO )5
7KURPERSKLOLDFOLQLFDOIDFWRUVDQGUHFXUUHQWYHQRXVWKURPERWLFHYHQWV-RXUQDORIWKH
$PHULFDQ0HGLFDO$VVRFLDWLRQ
'H6WHIDQR96LPLRQL35RVVL(7RUPHQH'=D73DJQDQ$ /HRQH*7KH
ULVN RI UHFXUUHQW YHQRXV WKURPERHPEROLVP LQ SDWLHQWV ZLWK LQKHULWHG GH¿FLHQF\ RI QDWXUDO
DQWLFRDJXODQWVDQWLWKURPELQSURWHLQ&DQGSURWHLQ6+DHPDWRORJLFD
(LFKLQJHU 6 +RPRF\VWHLQH YLWDPLQ % DQG WKH ULVN RI UHFXUUHQW YHQRXV
WKURPERHPEROLVP3DWKRSK\VLRORJ\RI+DHPRVWDVLVDQG7KURPERVLV
(LFKLQJHU6$UH%YLWDPLQVDULVNIDFWRUIRUYHQRXVWKURPERHPEROLVP"<HV-RXUQDORI
7KURPERVLVDQG+DHPRVWDVLV
(LFKLQJHU66FKRQDXHU9:HOWHUPDQQ$0LQDU(%LDORQF]\N&+LUVFKO06FKQHLGHU
%4XHKHQEHUJHU3 .\UOH3$7KURPELQDFWLYDWDEOH¿EULQRO\VLVLQKLELWRUDQGWKH
ULVNIRUUHFXUUHQWYHQRXVWKURPERHPEROLVP%ORRG
(PPHULFK - 5RVHQGDDO )5 &DWWDQHR 0 0DUJDJOLRQH 0 'H 6WHIDQR 9 &XPPLQJ
7 $UUXGD 9 +LOODUS $ 5HQ\ -/ &RPELQHG HIIHFW RI IDFWRU 9 /HLGHQ DQG
SURWKURPELQ$RQWKHULVNRIYHQRXVWKURPERHPEROLVPSRROHGDQDO\VLVRIFDVHFRQWURO
VWXGLHVLQFOXGLQJFDVHVDQGFRQWUROV6WXG\*URXSIRU3RROHG$QDO\VLVLQ9HQRXV
7KURPERHPEROLVP7KURPERVLVDQG+DHPRVWDVLV
*RQ]DOH]3RUUDV-5*DUFLD6DQ]5$OEHUFD,/RSH]0/%DODQ]DWHJXL$*XWLHUUH]
2 /R]DQR ) 0LJXHO -6 5LVN RI UHFXUUHQW YHQRXV WKURPERVLV LQ SDWLHQWV ZLWK
*$PXWDWLRQLQWKHSURWKURPELQJHQHRUIDFWRU9/HLGHQPXWDWLRQ%ORRG&RDJXODWLRQ
DQG)LEULQRO\VLV
+DQVVRQ326RUER- (ULNVVRQ+5HFXUUHQWYHQRXVWKURPERHPEROLVPDIWHUGHHS
YHLQWKURPERVLVLQFLGHQFHDQGULVNIDFWRUV$UFKLYHVRI,QWHUQDO0HGLFLQH
+HPNHU+&:LHOGHUV6.HVVHOV+ %HJXLQ6&RQWLQXRXVUHJLVWUDWLRQRIWKURPELQ
JHQHUDWLRQLQSODVPDLWVXVHIRUWKHGHWHUPLQDWLRQRIWKHWKURPELQSRWHQWLDO7KURPERVLVDQG
+DHPRVWDVLV
+R:. +DQNH\ *- 4XLQODQ '- (LNHOERRP -: 5LVN RI UHFXUUHQW YHQRXV
WKURPERHPEROLVPLQSDWLHQWVZLWKFRPPRQWKURPERSKLOLDDV\VWHPDWLFUHYLHZ$UFKLYHVRI
,QWHUQDO0HGLFLQH
+RNH 0 .\UOH 3$ 0LQDU ( %LDORQ]F\N & +LUVFKO 0 6FKQHLGHU % .ROODUV 0
:HOWHUPDQQ$ (LFKLQJHU67LVVXHIDFWRUSDWKZD\LQKLELWRUDQGWKHULVNRIUHFXUUHQW
YHQRXVWKURPERHPEROLVP7KURPERVLVDQG+DHPRVWDVLV
+URQ*.ROODUV0%LQGHU%5(LFKLQJHU6 .\UOH3$,GHQWL¿FDWLRQRISDWLHQWV
DWORZULVNIRUUHFXUUHQWYHQRXVWKURPERHPEROLVPE\PHDVXULQJWKURPELQJHQHUDWLRQ-RXUQDO
RIWKH$PHULFDQ0HGLFDO$VVRFLDWLRQ
.HLM]HU 0% GHQ +HLMHU 0 %ORP +- %RV *0 :LOOHPV +3 *HUULWV :%
5RVHQGDDO )5 ,QWHUDFWLRQ EHWZHHQ K\SHUKRPRF\VWHLQHPLD PXWDWHG
PHWK\OHQHWHWUDK\GURIRODWHUHGXFWDVH07+)5DQGLQKHULWHGWKURPERSKLOLFIDFWRUVLQUHFXUUHQW
YHQRXVWKURPERVLV7KURPERVLVDQG+DHPRVWDVLV
.RVWHU 7 5RVHQGDDO )5 GH 5RQGH + %ULsW ( 9DQGHQEURXFNH -3 %HUWLQD 50
9HQRXVWKURPERVLVGXHWRSRRUDQWLFRDJXODQWUHVSRQVHWRDFWLYDWHGSURWHLQ&/HLGHQ
7KURPERSKLOLD6WXG\/DQFHW
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
.\UOH3$0LQDU(+LUVFKO0%LDORQF]\N&6WDLQ06FKQHLGHU%:HOWHUPDQQ$
6SHLVHU:/HFKQHU. (LFKLQJHU6+LJKSODVPDOHYHOVRIIDFWRU9,,,DQGWKHULVN
RIUHFXUUHQWYHQRXVWKURPERHPEROLVP1HZ(QJODQG-RXUQDORI0HGLFLQH
/XGGLQJWRQ5 %DJOLQ7&OLQLFDOPHDVXUHPHQWRIWKURPELQJHQHUDWLRQE\FDOLEUDWHG
DXWRPDWHG WKURPERJUDSK\ UHTXLUHV FRQWDFW IDFWRU LQKLELWLRQ -RXUQDO RI 7KURPERVLV DQG
+DHPRVWDVLV
YDQ GHU 0HHU )- .RVWHU 79DQGHQEURXFNH -3 %ULsW ( 5RVHQGDDO )5 7KH
/HLGHQ7KURPERSKLOLD6WXG\/(767KURPERVLVDQG+DHPRVWDVLV
3DODUHWL*&RVPL%/HJQDQL&7RVHWWR$%UXVL&,RULR$3HQJR9*KLUDUGX]]L$
3DWWDFLQL&7HVWD6/HQVLQJ$: 7ULSRGL$'GLPHUWHVWLQJWRGHWHUPLQHWKH
GXUDWLRQRIDQWLFRDJXODWLRQWKHUDS\1HZ(QJODQG-RXUQDORI0HGLFLQH
3RRUW655RVHQGDDO)55HLWVPD3+ %HUWLQD50$FRPPRQJHQHWLFYDULDWLRQ
LQ WKH ¶XQWUDQVODWHG UHJLRQ RI WKH SURWKURPELQ JHQH LV DVVRFLDWHG ZLWK HOHYDWHG SODVPD
SURWKURPELQOHYHOVDQGDQLQFUHDVHLQYHQRXVWKURPERVLV%ORRG
3ULQV0+ 0DUFKLRUL$5LVNRIUHFXUUHQWYHQRXVWKURPERHPEROLVPH[SDQGLQJWKH
IURQWLHU7KURPERVLVDQG+DHPRVWDVLV
5RVHQGDDO)55LVNIDFWRUVIRUYHQRXVWKURPERVLVSUHYDOHQFHULVNDQGLQWHUDFWLRQ
6HPLQDUVLQ+HPDWRORJ\
5RVHQGDDO)5.RVWHU79DQGHQEURXFNH-3 5HLWVPD3++LJKULVNRIWKURPERVLV
LQSDWLHQWVKRPR]\JRXVIRUIDFWRU9/HLGHQDFWLYDWHGSURWHLQ&UHVLVWDQFH%ORRG
9DQGH:RXZHU0&ROOHQ' &RQZD\(07KURPERPRGXOLQSURWHLQ&(3&5
V\VWHPLQWHJUDWHGWRUHJXODWHFRDJXODWLRQDQGLQÀDPPDWLRQ$UWHULRVFOHURVLV7KURPERVLVDQG
9DVFXODU%LRORJ\
:HOWHUPDQQ $ (LFKLQJHU 6 %LDORQF]\N & 0LQDU ( +LUVFKO 0 4XHKHQEHUJHU 3
6FKRQDXHU9 .\UOH 3$ 7KH ULVN RI UHFXUUHQW YHQRXV WKURPERHPEROLVP DPRQJ
SDWLHQWVZLWKKLJKIDFWRU,;OHYHOV-RXUQDORI7KURPERVLVDQG+DHPRVWDVLV