B Y T

TRNG I HC DC H NI

MAI TH LAN ANH

KHO ST TNH HNH S DNG

THUC CHNG NG MU KHNG

VITAMIN K TI KHOA C6 VIN TIM

MCH QUC GIA

KHA LUN TT NGHIP DC S

H NI 2014

B Y T

TRNG I HC DC H NI

MAI TH LAN ANH

KHO ST TNH HNH S DNG

THUC CHNG NG MU KHNG

VITAMIN K TI KHOA C6 VIN TIM

MCH QUC GIA

KHA LUN TT NGHIP DC S

Ngi hng dn:

1. ThS. Nguyn Th Hin

2. TS. Trn Song Giang

Ni thc hin:

1. B mn Y hc c s

2. Khoa C6 Vin Tim mch quc gia

(bnh vin Bch Mai)

H NI - 2014

LI CM N

Vi lng knh trng, ti xin by t lng bit n chn thnh v su sc nht ti

ThS. Nguyn Th Hin ging vin b mn Y hc c s, TS. Trn Song Giang

bc s khoa C6 Vin Tim mch quc gia l nhng ngi thy trc tip hng

dn, ht lng ch bo v tn tnh gip ti trong sut thi gian thc hin ti

ny!

Ti xin chn thnh cm n:

Cc thy c gio trng i hc Dc H Ni, c bit l cc thy c

b mn Y hc c s - Dc l Dc lm sng trc tip dy d, truyn t

nhng kin thc qu gi trong qu trnh hc tp cng nh trong khong thi gian

lm kha lun.

Tp th y bc s, cn b, nhn vin khoa C6 vin Tim Mch quc gia,

cc thy c trong ban gim hiu, phng Hnh chnh Tng hp trng i hc

Dc H Ni ta mi iu kin tt, gip ti trong qu trnh thu s liu v

thc hin kha lun.

Cc anh ch em trong facebook Nhm ti bo rt nhit tnh gip

, download cc bi bo, ti liu tham kho qu bu ti hon thnh kha lun.

Cui cng, ti xin gi li cm n v hn ti gia nh, bn b v nhng ngi

thn yu lun cnh, ng vin, khch l, chia s nhng kh khn trong cuc

sng cng nh trong qu trnh thc hin kha lun ny!

H Ni, thng 5 nm 2014

Sinh vin

Mai Th Lan Anh./

Mc lc

T VN ............................................................................................................ 1

CHNG 1: TNG QUAN ..................................................................................... 2

1.1 Qu trnh ng mu ........................................................................................ 2

1.1.1. Khi qut v c ch ng mu ................................................................... 2

1.1.2. Cc giai on ca qu trnh ng mu huyt tng ................................... 2

1.1.3. Khi qut v qu trnh tng ng v huyt khi ........................................ 4

1.2. Cc xt nghim ng mu thng dng trn lm sng .............................. 7

1.2.1. Thi gian chy mu .................................................................................... 7

1.2.2. m s lng tiu cu ................................................................................ 7

1.2.4. Thi gian Prothrombin ............................................................................... 7

1.2.5. Thi gian thromboplastin hot ha tng phn (aPTT) ............................... 8

1.2.6. Thi gian thrombin ..................................................................................... 9

1.3. Tng quan v thuc chng ng mu khng vitamin K ............................. 9

1.3.1. Dc l v c ch tc dng ...................................................................... 10

1.3.2. Dc ng hc ......................................................................................... 11

1.3.3. Ch nh .................................................................................................... 13

1.3.4. Liu dng cch dng ............................................................................. 14

1.3.5. Theo di iu tr ....................................................................................... 15

1.3.6. X tr khi qu liu .................................................................................... 16

1.3.7. Tc dng ph ca thuc chng ng khng vitamin K ............................ 17

1.3.8. Chng ch nh ......................................................................................... 18

1.3.9. Tng tc thuc ........................................................................................ 18

CHNG 2: I TNG V PHNG PHP NGHIN CU ................... 20

2.1. i tng nghin cu ................................................................................... 20

2.2. Phng php nghin cu ............................................................................. 20

2.2.1. Thit k nghin cu .................................................................................. 20

2.2.2. Phng php ly mu ............................................................................... 20

2.2.3. Thu thp thng tin .................................................................................... 20

2.3. Ni dung nghin cu ..................................................................................... 20

2.3.1. c im bnh nhn trong mu nghin cu ............................................. 20

2.3.2. Thc trng s dng thuc chng ng khng vitamin K ......................... 21

2.4. X l s liu ................................................................................................... 22

CHNG 3: KT QU NHN XT V BN LUN ...................................... 23

3.1. c im bnh nhn trong mu nghin cu .............................................. 23

3.1.1. Tui/Gii .................................................................................................. 23

3.1.2. Thi gian s dng AVK ........................................................................... 24

3.1.3. c im bnh l ca cc bnh nhn trong mu nghin cu ................... 24

3.1.4. c im chc nng gan thn ca bnh nhn trong mu nghin cu ...... 25

3.2. Thc trng s dng thuc ca bnh nhn.................................................. 26

3.2.1. Danh mc cc AVK c s dng ........................................................... 26

3.2.2. ng dng, cch dng ........................................................................... 28

3.2.3. Liu dng .................................................................................................. 29

3.2.4. Gim st iu tr ....................................................................................... 32

3.2.5. Tc dng ph ca thuc chng ng khng vitamin K ............................ 36

3.2.6. Tng tc ca thuc chng ng khng vitamin K ................................. 39

3.2.7. Kt qu iu tr ......................................................................................... 43

KT LUN .................................................................................................... 46

XUT ....................................................................................................... 47

TI LIU THAM KHO ...................................................................................... 48

CC CH VIT TT

ACCP : American College of Chest Physicians

(Hip hi cc bc s Lng ngc Hoa K)

ADR : Adverse Drug Reaction

(Phn ng c hi ca thuc)

APC : Activated protein C

(Protein C hot ha)

APTT : Activated partial thrombopastin

(Thi gian thrompoplastin tng phn hot ha)

ATIII : Antithrombin III

AVK :Anti vitamin K

(Thuc khng vitamin K) BN : Bnh nhn

DIC : Disseminated intravascular clotting

(Hi chng ng mu ri rc/lan ta)

EHRA : European Heart Rythme Association

(Hip hi nhp tim Chu u)

FDA : Food and Drug Administration

(Cc qun l Thc phm v Dc phm Hoa K)

INR : International Normallized Ratio

(Ch s bnh thng ha quc t)

ISI : International Sensitivity Index

OR : Odd Ratio

(T s Odd)

PPI : Proton-pump inhibitor

(Thuc c ch bm proton)

PT : Prothrombin time

(Thi gian Prothrombin)

PTr : Prothrombin ratio

(T s Prothrombin)

RR : Relative Risk

(Nguy c tng i)

TFPI : Tissue factor pathway inhibitor

(Cht c ch con ng yu t m)

TB : Trung bnh

TT : Thrombin time

(Thi gian thrombin)

VKOR : Vitamin K epoxid reductase

(Enzym kh Vitamin K epoxid)

DANH MC CC BNG, HNH

S th t Tn bng/hnh Trang

Bng 1.1. Nhng tnh trng tng ng tin pht 5

Bng 1.2. Nhng tnh trng tng ng th pht 5

Bng 1.3 Cc thng s dc ng hc ca cc AVK 12

Bng 1.4 Cc ch nh chng ng lu di bnh nhn hp van

hai l.

14

Bng 2.1. Phn loi mc suy thn 21

Bng 3.1. Phn b bnh nhn theo tui, gii. 23

Bng 3.2. c im bnh l ca cc bnh nhn 25

Bng 3.3. c im chc nng gan ca bnh nhn 26

Bng 3.4. c im chc nng thn ca cc bnh nhn 26

Bng 3.5. Danh mc cc AVK c s dng 27

Bng 3.6. T l hai cch dng acenocoumarol 28

Bng 3.7. Liu dng ban u ca cc AVK 29

Bng 3.8. Liu dng trung bnh ca cc bnh nhn trong mu nghin cu

30

Bng 3.9. T l kim tra INR trc liu u tin 33

Bng 3.10. T l hiu chnh liu ca cc bnh nhn 33

Bng 3.11. T l hiu chnh liu phn b theo cc khong INR 34

Bng 3.12. Kt qu hiu sau hiu chnh 35

Bng 3.13. T l chy mu khi s dng AVK 36

Bng 3.14. Phn loi mc tng tc 39

Bng 3.15. T l cc cp tng tc theo mc tng tc 39

Bng 3.16. T l bnh nhn c tng tc thuc 42

Bng 3.17. Phn b INR trong mu nghin cu 43

Bng 3.18. Kt qu INR ca bnh nhn trc khi ra vin 44

S 1.1. Cc giai on ca qu trnh ng mu 3

1

T VN

Cc thuc chng ng khng vitamin K (AVK) bao gm dn cht coumarin

c tm thy nm 1948 v sau l dn cht indandion c tc dng chng ng

thng qua c ch tng hp cc yu t ng mu ph thuc vitamin K [44]. T

n nay, cc AVK v ang c s dng rng ri nhm mc ch d phng v

iu tr bnh l huyt khi gy tc mch trong cc bnh nh: rung nh, huyt khi

tnh mch v thuyn tc phi, hay cc bnh van tim [16].

Ti Vin Tim Mch Quc gia, thuc chng ng khng vitamin K c

a vo s dng hn 25 nm nay vi bit dc chnh l Sintrom (Acenocoumarol)

v gn y l Warfarin [8]. Hiu qu trong phng v iu tr huyt khi l r rng,

tuy nhin, cc AVK c tnh n nh thp, t l gp bin chng l kh cao

[7][11][14].

Hn na, do khong iu tr hp [18][44], tc dng ca thuc b nh hng

nhiu bi ch n ung v nht l mt s thuc nh: h st gim au, cc khng

sinh cephalosporin th h hai v ba, aspirin v thuc chng vim khng steroid

(NSAIDs)[18][44]. S bin i gen tng c th bnh nhn cng nh hng

khng t n hiu qu iu tr ca cc AVK [10]. Ti Vit Nam, hin nay, cc

nghin cu v vn ny cha nhiu, chnh v vy chng ti thc hin ti:

Kho st tnh hnh s dng thuc chng ng mu khng vitamin K ti khoa C6

Vin Tim mch Quc gia nhm hai mc tiu:

1. Kho st cc c im ca cc bnh nhn c s dng thuc chng

ng mu khng vitamin K ti khoa C6.

2. Kho st thc trng s dng thuc chng ng mu khng vitamin K trn

cc i bnh nhn trong mu nghin cu.

Nghin cu nhm cung cp t liu v tnh hnh s dng thuc chng ng

khng vitamin K ti khoa C6 Vin Tim mch Quc gia, t rt ra cc kin ng

gp vic s dng thuc an ton v hiu qu hn.

2

CHNG 1: TNG QUAN

1.1 Qu trnh ng mu

1.1.1. Khi qut v c ch ng mu

Bnh thng, mu lu thng trong lng mch trng thi lng, khng b

ng nh c s cn bng gia h thng ng mu v c ch ng mu. Khi xy ra

tn thng mch mu, h thng ng cm mu c khi ng nhm to cc ng

khu tr ti ch tn thng, lm ngng chy mu. Sau khi hon thnh chc nng

cm mu, cc mu ng s c tiu i, tr li s lu thng bnh thng cho lng

mch. Ton b qu trnh ny cn c s tham gia ca cc thnh phn: thnh mch,

tiu cu, cc yu t ng mu, cc cht c ch ng mu v h thng tiu si huyt.

Qu trnh ng cm mu bao gm cc giai on:

- Cm mu nguyn pht (to nt cm mu tm thi).

- ng mu huyt tng (to nt cm mu vnh vin).

- Tiu cc mu ng.

Cm mu nguyn pht (cm mu ban u), din ra ngay tc khc, c hai yu

t quan trng l tiu cu (kt hp thnh nt chn tiu cu) v thnh mch (hin

tng co mch). Tiu cu kt dnh vo ni thnh mch b tn thng trc tip hay

thng qua yu t von Willebrand.

Cm mu th pht (ng mu huyt tng) din ra chm (vi pht ti gi),

dn ti vic hnh thnh cc mu ng). Sau khi ra khi lng mch 2 4 pht, mu

bt u ng li. ng mu ngha l chuyn mu t th lng sang th c nh

chuyn fibrinogen ha tan trong huyt tng thnh fibrin khng ha tan di xc tc

ca thrombin. Cc fibrin kt dnh li vi nhau thnh mng li giam gi cc t bo

mu v huyt tng to thnh cc mu ng [2][15].

1.1.2. Cc giai on ca qu trnh ng mu huyt tng

Qu trnh ng mu gm 3 giai on chnh:

- Giai on 1: Hnh thnh prothrombinase.

- Giai on 2: Hnh thnh thrombin.

- Giai on 3: Hnh thnh fibrin t fibrinogen.

3

S 1.1. Cc giai on ca qu trnh ng mu

Giai on 1: L giai on hnh thnh phc hp prothrombinase (cng c

gi l giai on thromboplastin hot ng hoc yu t chuyn prothrombin), l qu

trnh phc tp v ko di nht thng qua hai c ch ni sinh (nu mu b tn

thng) v ngoi sinh (nu c chn thng ca thnh mch hoc cc m b tn

thng).

- ng mu ngoi sinh: Khi m b tn thng, gii phng thromboplastin (yu t

III) v phospholipid ca m. Hai yu t trn kt hp vi Ca2+ hot ha yu t

VII. Yu t VII hot ha kt hp vi Ca2+ hot ha yu t IX. Yu t IX kt hp

vi Ca2+ hot ha yu t V. Yu t V hot ha to thrombokinase ngoi sinh

- ng mu ni sinh (cht hot ha mu), khi thnh mch b tn thng, cc si

collagen hot ha yu t XII trong mu. Yu t XII hot ha IX. Yu t IX hot

ha VIII; phospholipid tiu cu hot ha XI, yu t IX hot ha X. Yu t X

hot ha V. Yu t V hot ha kt hp vi Ca2+ to thrombokinase ni sinh.

Giai on 2: Giai on chuyn prothrombin (yu t II) thnh thrombin.

Yu t ni sinh Yu t ngoi sinh

Cc yu t ng mu c hot ha kt hp vi Ca2+

Thrombokinase

Thrombin Prothrombin

Fibrin Fibrinogen

4

Vi s c mt ion Ca2+, prothrombinkinase s chuyn prothrombin thnh

thrombin. Lc u, s chuyn prothrombin xy ra rt chm to ra mt lng

thrombin cn thit cho mu ng. Sau , thrombin s lm tng tc ca qu trnh

to ra bn thn n bng cch hot ha yu t V v yu t VIII. Yu t VIII hot ha

l thnh phn ca phc hp enzyme hot ha yu t X. Yu t V hot ha l thnh

phn ca prothrombinase. C hai yu t trn gp phn lm tng qu trnh chuyn

prothrombin thnh thrombin. Thrombin cng hot ha yu t XIII n nh mng

li fibrin.

Giai on 3: Giai on chuyn fibrinogen thnh fibrin

Di tc dng ca Thrombin, fibrinogen chuyn thnh fibrin n phn. Sau

cc fibrin t trng hp to thnh mng li fibrin khng ha tan. Thrombin cng

hot ha yu t VIII. Yu t VIII hot ha vi s c mt ca ion Ca lm mng li

firin tr nn n nh nh cc dy ni ng ha tr gia cc si fibrin [2][15].

1.1.3. Khi qut v qu trnh tng ng v huyt khi

1.1.3.1 Sinh bnh hc tng ng mu

Tnh trng tng ng mu xy ra khi mt cn bng gia h thng hot ha v

c ch ng mu do tng hot ha ng mau hoc do gim c ch ng mu, tiu

si huyt dn n cc mu ng lan rng qu gii hn cn thit, gy tc nghn

mch. Tng ng mu c chia thnh hai nhm: Tng ng tin pht v tng ng

th pht [12][15].

Tng ng tin pht

Tnh trng tng ng tin pht thng gy nn bi nhng bt thng v s

lng hoc cht lng cc yu t tham gia vo qu trnh c ch ng mu. Hu ht

nhng bt thng ny l do qu trnh t bin gen gy nn. Tnh trng tng ng

tin pht rt d gy huyt khi khi cn tr tui, ti pht nhiu ln. Bnh nhn c tnh

trng tng ng tin pht s d dng b huyt khi, huyt khi nng ln khi c mt

yu t gy nn tnh trng tng ng mc phi kt hp nh: c thau, nhim trng, bt

ng lu.

5

Bng 1.1. Nhng tnh trng tng ng tin pht

+ Thiu ht AT III

+ Thiu ht heparin cofactor II

+ Thiu ht protein C

+ Thit ht protein S

+ Bt thng chc nng fibrinogen

+ Thiu ht yu t XII

+ Bt thng chc nng plasminogen

+ Thiu ht cht hot ha plasminogen

+ Tng cht c ch hot ha plasminogen

Tng ng th pht

Tng ng th pht l tnh trng tng ng gy nn bi s kt hp nhiu yu t

mc phi, c xu hng hnh thnh huyt khi bi nhng c ch phc tp v thng

l a yu t nh tiu cu, thnh mch, hot tnh cc yu t ng mu, h thng tiu

si huyt. c chi lm ba nhm chnh, da vo nguyn nhn gy nn tnh trng

tng ng theo tam chng Virchow gm c:

- Bt thng dng chy: Mi tnh trng gy trn dng chy ca mu nh bt

ng lu ngy, chn p do khi u, shocks tr s lm tng nng tiu cu v

cc yu t ng mu.

- Bt thng thnh mch: hin din ca mt b mt bt thng tip xc vi mu

do tn thng hoc c vt liu l nh van tim nhn to.

- Tng nng hoc mc hot ha cc yu t tham gia ng cm mu.

6

Bng 1.2. Nhng tnh trng tng ng th pht

Bt thng dng chy/thnh mch:

+ Bt ng

+ Sau phu thut

+ Tng homocystein mu

+ a hng cu

+ Tng nht mu

+ Xut huyt gim tiu cu tc mch

+ Cc b mt nhn to (van tim nhn to)

Bt thng tiu cu:

+ Tng tiu cu tin pht hoc ri lon tng sinh ty khc.

+ Tng lipid mu

+ i tho ng

+ Gim tiu cu do heparin

Nhng bt thng ng mu/tiu si huyt:

+ Bnh c tnh

+ Mang thai

+ S dng thuc trnh thai

+ Cht khng ng lupus (LA)

+ Tng fibrinogen, yu t VII, yu t vonWillebrand

1.1.3.2 Bnh sinh huyt khi

Huyt khi ng mch

Thnh phn ch yu trong cc mu ng ca huyt khi ng mch l tiu

cu, fibrin v cc thnh phn khc. Nhng tiu cu vn l thnh phn chnh.

Yu t nguy c: tng huyt p, i tho ng.

Huyt khi tnh mch

Thnh phn chnh ca cc mu ng l fibrin.

7

Nguyn nhn: Do gim cht c ch sinh l ng mu (ATIII, protein C hoc

tng hot ha cc yu t ng mu)

Yu t nguy c: sau phu thut, tai bin sn khoa [12].

1.2. Cc xt nghim ng mu thng dng trn lm sng

1.2.1. Thi gian chy mu

Phn nh chc nng cm mu mao mch v tiu cu.

Thi gian mu chy bnh thng: 2-4 pht

Thi gian chy mu > 6 pht ko di trong trng hp:

+ Bnh nhn mch mu km bn vng

+ Gim tiu cu hoc ri lon chc nng tiu cu.

1.2.2. m s lng tiu cu

m s lng tiu cu nhm nh gi s b giai on cm mu ban u.

C th m th cng bng my hin vi quang hc hoc m bng my m t

bo t ng.

S lng tiu cu bnh thng: 150 350 x 109/L. Di 100 x 109/L l gim

tiu cu.

S lng tiu cu gim trong cc bnh: gim tiu cu v cn, suy ty xng,

bch cu cp, st xut huyt hoc sau ha tr liu.

Tng tiu cu trong cc bnh: tng tiu cu tin pht, x ty v cn, bch cu

cp dng ht hoc a hng cu tin pht[1][13].

1.2.4. Thi gian Prothrombin

Thi gian prothrombin (PT) hay cn gi l thi gian Quick: l thi gian ng

ca huyt tng c chng ng bng natri oxalat hoc citrate khi c phc

hi calci v thm yu t ca t chc (thromboplastin).

Xt nghim ny c s dng nh gi hot tnh ca con ng ng

mu ngoi sinh (bao gm yu t m v yu t VII) v cc yu t ph thuc vitamin

K (yu t II, X)

Kt qu ca PT thng c th hin cc dng [48]:

8

+ Thi gian: gi tr bnh thng khong 11 13 giy, ko di khi PT bnh

di hn chng 3 giy.

+ T s Prothrombin (PTr): c tnh bng PT bnh nhn/PT chng; PTr

>1,2 c chng minh l lm tng ng k nguy c ri lon ng mu do chn

thng cp tnh.

+ Phn trm prothrombin%: gi tr bnh thng trong khong 70 140%,

gim khi < 70%.

V cc mu thromboplastin mi t xt nghim l khng ng nht nn

kt qu thng nht T chc y t th gii pht trin ch s INR v khuyn co s

dng ch s ny theo di hiu qu chng ng ca Warfarin cng nh cc thuc

chng ng khng vitamin K khc.

INR l ly tha ISI (International Sensitivity Index) ca t l gia thi gian

PT ca bnh nhn trn thi gian PT ca ngi bnh thng i chng.

Do :

INR=(

)ISI

ISI = 1, i vi mu thromboplastin chun ha theo quy c quc

t, mi phng th nghim c gi tr ISI ring sau khi so snh vi mu.

INR l ch s quan trng, gim st s dng vitamin K. Bnh thng, khi

khng dng AVK, INR ngi bnh thng l 1. Khi dng thuc, a s cc trng

hp ch INR cn t c l 2,5, dao ng trong khong 2 3. INR di 2 phn

nh dng thuc chng ng cha , INR trn 3 l dng tha thuc. INR trn 5 l

c nguy c chy mu [3].

Ngoi s dng coumarin, PT cng c th ko di do nhng nguyn nhn sau:

thiu ht vitamin K, bnh gan, bnh ng mu lan ta ni mch, bnh nhn c

khng th khng lupus hoc antithrombin hot ng, a hng cu [1][46].

1.2.5. Thi gian thromboplastin hot ha tng phn (aPTT)

Thromboplastin hot ng nh mt cht thay th cho phospholipid tiu cu,

c thm vo mt cht hot ha nh silicon hoc kaolin hot ha. Hn hp

9

thromboplastin v cht hot ha c trn ln vi huyt tng c chng ng

bng citrate v thm calci tr li. Thi gian huyt tng ng l aPTT.

aPTT c s dng nh gi tnh ton vn ca con ng ng mu ni

sinh (prekallikrein, kininogen trng lng phn t cao, yu t XII, XI, IX, VIII) v

con ng ng mu chung (yu t II, V, X, v fibrinogen) ng thi cng l ch s

theo di ph bin nht khi iu tr bng heparin.

Thi gian APTT ca huyt tng bnh thng thay i trong khong 30 35.

Khi kt qu ko di trn 8s so vi mu chng c gi l aPTT ko di.

aPTT ko di thng gp trong tnh trng ri lon ng mu ni sinh do thiu ht

cc yu t ng mu (hemophilia) hoc do cht khng ng lu hnh (bnh

leukemia cp, iu tr bng heparin)

aPTT thch hp nht khi iu tr bng heparin l khong 1,5 n 2,5 ln gi

tr bnh thng [1][13][48].

1.2.6. Thi gian thrombin

Thi gian thrombin (TT) o thi gian ng ca huyt tng khi cho

thrombin vo. Xt nghim ny nh gi giai on chuyn fibrinogen thnh fibrin

[13].

TT ca mu kim tra c coi l ko di khi hn TT ca mu chng trn 5

giy. TT ko di trong cc trng hp sau:

+ C s hin din ca cc cht chng ng nh: heparin, cht c ch

thrombin trc tip (bivalirudin hoc argatroban), hoc cc cht ging heparin

(danaparoid).

+ C s hin din ca cc sn phm thoi ha fibrin/fibrinogen.

+ Gim fibrinogen huyt (< 100mg/dL), ri lon chc nng fibrinogen, tng

fibrinogen huyt (> 400mg/dL).

+ Nng cao protein huyt thanh (xut hin trong bnh a u ty xng).

1.3. Tng quan v thuc chng ng mu khng vitamin K

Cc thuc chng ng khng vitamin K bao gm [2]:

10

Dn xut 4 hydroxyl coumarin: dicoumarol, warfarin, ethyl bicoumacetat,

phenprocoumaron.

Cc dn xut indandion: phenyl indandion, flourophenyl indandion,

clophenindion.

1.3.1. Dc l v c ch tc dng

Cc thuc chng ng khng vitamin K tc ng bng cch gim chc nng

carboxyl ha ca vitamin K nhm bin i cc tin cht thnh cc yu t ng mu

gm: yu t prothrombin (yu t II), proconvertin (yu t VII), yu t anti

hemophilia B (yu t IX), v yu t Stuart Prower (yu t X), sau cng thnh yu

t ng mu bt hot. Trong qu trnh chuyn i, vitamin K b oxy ha thnh

epoxid vitamin K khng hot ng. cc bnh nhn khng s dng thuc chng

ng, epoxid vitamin K cn bng thun nghch vi vitamin K. Cc AVK gy tr

ngi cho vic kh vitamin K ti gan do c ch c ch vitamin K epoxid reductase

(VKOR) enzyme c th chuyn i epoxid vitamin K thnh vitamin K. S tch

ly ca epoxid vitamin K lm gim nng ca vitamin K v gim tng hp cc

yu t ng mu. Nng cc yu t II, VII, IX, X gim dn tng ng vi thi

gian bn thi [3][18][44].

Nh vy, cc khng vitamin K c tc dng chng ng mu gin tip bng

cch ngn cn s tng hp cc dng hot ng ca nhiu yu t ng mu k trn

[3][10].

Cc VKAs khng c bt k nh hng ln cc yu t ng mu carboxyl

ha, tim khi u tc dng chng ng ca cc thuc ny ph thuc vo tc

thi tr ca cc yu t ng mu carboxyl ha ra khi h tun hon (na i thi

tr ca yu t VII: 6h; yu t IX: 24h; yu t X: 36h; v yu t II: 50h). Do , cn

khong 5-7 ngy t c mt trng thi chng ng n nh sau khi bt u

iu tr vi AVK hoc thay i liu [3][10].

Ngoi ra, cc AVK cn cn tr s chuyn i acid glutamic thnh acid

gama-carboxylglutamic ca hai cht c ch chng ng t nhin (protein C v S),

do khi mi bt u iu tr vi AVK, nng hai protein ny c th gim dn

11

n tc ng ng mu thong qua. Tuy nhin, tc ng chng ng vn l ni bt

[33][44].

1.3.2. Dc ng hc

Cc AVK c hp thu nhanh qua ng tiu ha vi sinh kh dng cao. S

hp thu ch yu xy ra phn u rut non [44]. Nng nh ca thuc trong

huyt tng t c trong vng 1 3 gi sau khi ung [3]. Cc AVK u gn

mnh vi protein huyt tng (ch yu l albumin) (bng 1.1). Ch phn t do l c

hot tnh v b chuyn ha. Tuy nhin, chng c th tch phn b trong c th khc

nhau [42]. Chuyn ha ch yu gan bi h enzyme chuyn ha thuc CYP450

thnh cc dn cht chuyn ha mt hot tnh, c chu k gan rut. Tc dng ca

thuc ko di 2 5 ngy. Cc AVK thi tr qua thn, v mt phn c thi qua

phn [33].

Cc AVK qua c nhau thai v sa m. Nu dng trong ba thng u ca

thai k c th gy d tt mt, mi, xng. Do , cc AVK chng ch nh vi ph

n c thai, c bit l trong ba thng u tin [3].

Warfarin l AVK c s dng ph bin nht hin nay. Dng ng ung

hin nay l hn hp hai enatiomer l (S) v (R) warfarin vi t l 50 : 50. Chng c

hiu lc chng ng v chuyn ha khc nhau. Racemic warfarin c thi gian bn

thi 36 42 gi (R-warfarin: 45h; S-warfarin: 29h), v c hai ng phn ny u

c chuyn ha gan bi cc con ng khc nhau. S-warfarin c tc dng chng

ng mnh hn 2,7 3,8 ln so vi ng phn R, v ch yu c chuyn ha ch

yu bi men cytochrome P450 CYP2C9. Dng R(+) warfarin li c chuyn ha

ch yu bi CYP1A2 v CYP3A4. Biu hin di truyn ca CYP2C9 nh hng n

chuyn ha ca warfarin v do nh hng n liu lng cn thit cho p

ng thi im kt thc iu tr. S bin thin a dng trong biu hin gen ca

VKORC1 (cc tiu n v C1 v cc gen m ha cho VKOR) cng nh hng n

liu warfarin cn thit [10][44].

Cng nh warfarin, acenocoumarol v phenprocoumarol cng tn ti hai

dng isomer nhng c nhng c im dc ng hc khc nhau. R-acenocoumarol

12

c thi gian bn thi 9h v c chuyn ha ch yu bi CYP2C9 v CYP2C19,

ng phn ny c tc dng chng ng mnh hn dng S(+) acecocoumarol c

thi gian bn thi ngn (0,5 gi) v chuyn ha ch yu bi CYP2C9 [44][45].

Phenprocoumarol l mt AVK tc dng ko di vi c 2 dng ng phn R

v S u c thi gian bn thi di (5,5 ngy) v u c chuyn ha bi enzyme

CYP2C9. Dng S-phenprocoumarol c hiu lc chng ng gp 1,5 2,5 ln dng

R-phenprocoumarol.

Bng 1.3. Cc thng s dc ng hc ca cc AVK[44]

Thng s Warfarin Phenprocoumarol Acenocoumarol

Liu duy tr

(mg/ngy)

1,5 12 0.75 9 1 - 9

Th tch phn b

(L/kg)

0,08 0,12 0,11 0,14 0,22 0,52

T l gn protein

huyt tng

> 99% > 99% > 98%

Thi gian bn thi

(gi)

S-WAR: 24 33

R-WAR: 35 58

S-PPC: 110- 130

R-PPC: 110 125

S-AC: 1,8

R-AC: 6,6

thanh thi

huyt tng (L/h)

S-WAR: 0,10

1,00

R-WAR: 0,07

0,35

S-PPC: 0,045

0,055

R-PPC: 0,055

0,08

S-AC: 28,5

R-AC: 1,9

ng hc thi tr First-order First-order biphasic

H enzyme

chuyn ha thuc

S-WAR: P450

CYP2C9

R-WAR: P450

CYP1A2, CYP3A4

P450 2C9 S-AC: P450

CYP2C9,

CYP2C19

R-AC: CYP2C9

WAR: warfarin; PPC = phenprocoumarol; AC = acenocoumarol

13

1.3.3. Ch nh

Phng v iu tr cc trng hp huyt khi gy tc mch. Do c nguy c

xut huyt cao nn cc dn xut indandion ch s dng khi ngi bnh khng dng

c coumarin. Trong cc coumarin th warfarin c s dng nhiu nht hin nay

[2].

Cc ch nh ca AVK bao gm:

- D phng t qu do huyt khi tt c cc bnh nhn rung nh, tr trng

hp rung nh n c c nguy c t qu thp (c nh gi bng thang im

CHADS2 = 0) hoc chng ch nh vi cc VKAs. Nu bnh nhn ch c mt trong

s cc yu t nguy c C, H, A, D th c th chn la gia aspirin 75325 mg/ngy

hoc thuc khng vitamin K (INR = 23). Cn nu bnh nhn c nhiu hn mt yu

t nguy c (trong s cc yu t nguy c C, H, A, D) hoc c tin s t qu/cn

thiu mu no thong qua (S2) th nn dng thuc khng vitamin K (INR = 23)

[5][9].

- iu tr huyt khi tnh mch v nghn mch phi: dng ngay ngy u tin

cng vi heparin khng phn on/ heparin trng lng phn t thp, phi hp

trong t nht nm ngy cho n khi INR duy tr n nh 2,0 3,0 trong hai ngy lin

tc. Sau c th ngng heparin hu ht bnh nhn [10]. iu tr t nht ba thng,

trong trng hp nguyn nhn gy huyt khi c th o ngc, dng di hn hoc

sut i trn bnh nhn ung th c huyt khi tnh mch hoc bt thng ng mu

[9][10].

- Bnh van tim: Vit Nam, hp hai l (hu thp) thng l ch nh chnh ca

chng ng di hn. Theo khuyn co ca hi Tim mch Vit Nam 2008, ch nh

dng chng ng lu di cc bnh nhn ny nh sau[4][9]:

14

Bng 1.4. Cc ch nh chng ng bnh nhn hp hai l

Nhm Ch nh dng chng ng lu di

I 1. Bnh nhn hp hai l c rung nh (cn kch pht, dai

dng, vnh vin).

2. Bnh nhn hp van hai l c tin s tc mch, k c nhp

xoang.

3. Bnh nhn hp hai l c huyt khi nh tri.

II 1. Bnh nhn hp hai l kht cha c triu chng c nng,

c ng knh nh tri 55 mm (o trn siu m tim).

2. Bnh nhn hp van hai l kht, nh tri gim, m cun t

nhin khi siu m.

+ Trong h van hai l nguy c thuyn tc mch do huyt khi thp hn so

vi trong hp van hai l. Tuy nhin nu bnh nhn h van hai l c rung nh th

cng nn iu tr chng ng di hn bng thuc khng vitamin K. iu tr ny l

bt buc nu bnh nhn tng b thuyn tc mch do huyt khi [9]

- Thay th van tim: bao gm van c hc v van sinh hc.

- Ngoi ra, cc AVK cn c dng trong cc trng hp sau [3]:

+ D phng bin chng huyt khi tc mch trong nhi mu c tim nh huyt

khi thnh tim, ri lon chc nng tht tri nng, lon ng tht tri gy tc mch

khi iu tr tip thay cho heparin. D phng ti pht nhi mu c tim khi khng

dng c aspirin.

+ D phng huyt khi tnh mch, nghn mch phi trong phu thut khp

hng hoc bnh nhn nm bt ng lu ngy.

+ D phng huyt khi trong ng thng.

1.3.4. Liu dng cch dng

Vic dng liu VKAs phi c iu chnh nhm mc ch ngn cn c ch

ng mu ti mc khng xy ra huyt khi nhng trnh c chy mu t pht.

Liu dng ph thuc vo p ng iu tr ca tng bnh nhn [3].

15

1.3.4.1. Warfarin

Liu u tin: ph thuc vo tng bnh nhn, liu u tin thng thng

khong 5 10 mg trong 1 2 ngy u tin, sau hiu chnh liu da vo kt qu

INR ca bnh nhn.

+ Mc liu thp hn: 2 5 mg c khuyn co cho cc bnh nhn c tn

thng gan, thn nng, suy dinh dng, suy tim, ngi gi, hoc c nguy c chy

mu cao hoc ang s dng thuc lm tng tc dng ca Warfarin [18][45].

+ Mc liu 10 mg c th c s dng trn cc bnh nhn n nh c nguy

c chy mu thp hoc nhng bnh nhn khe mnh iu tr ngoi tr nh khuyn

co ca ACCP nm 2012 [45].

+ Mc liu cao hn 10 mg khng c khuyn co.

Liu duy tr: ph thuc vo p ng INR ca bnh nhn, phn ln bnh nhn

c duy tr vi liu 2 - 10 mg/ngy [3].

1.3.4.2. Acenocoumarol [3][34]

Liu cho ngi ln: trong hai ngy u l 4mg, ung vo cc bui ti. T

ngy th ba, vic kim tra INR s cho php xc nh liu iu tr. Liu thng

thng khong 1 8 mg/ngy. Vic chnh liu thng tin hnh tng nc 1 mg.

ngi cao tui, liu khi u thp hn, thng ch bng n ngi

ln.

1.3.5. Theo di iu tr

Thi gian Prothrombin (PT) hay INR l test ph bin nht c dng nh

gi hiu qu chng ng ca cc thuc khng vitamin K [45].

Thi gian PT ko di ch yu do s suy gim cc yu t tin ng mu II,

VII, X. Cc yu t tin ng mu ny c hot ha bi vitamin K. Khi dng AVK

ng ung s gy ko di PT. Chnh v vy, PT l xt nghim c s dng

gim st iu tr bng AVK.

ACCP 2012 khuyn co [18]:

+ Kim tra INR nn c thc hin sau hai n ba liu VKAs u tin v lp

li cho n khi t INR iu tr.

16

+ Bnh nhn iu tr vi liu VKAs n nh lp li kim tra INR nh k mi

bn tun.

+ Khong INR t mc tiu iu tr vi hu ht cc ch nh c khuyn

co l 2,0 3,0 bao gm iu tr huyt khi tnh mch nh: nghn mch phi, rung

nh, bnh van tim, hoc van sinh hc.

+ Bnh nhn c INR t mc tiu iu tr (2,0 3,0) nhng vn xut hin

huyt khi ti pht hoc c cc yu t nguy c huyt khi c khuyn co INR cao

hn, khong 3,0 (2,5 3,5). Mc INR ny cng c khuyn co vi bnh nhn sau

nhi mu c tim, ngi bnh c van tim c hc hoc hi chng khng

phosphorlipid.

1.3.6. X tr khi qu liu

X tr qu liu thng cn c vo INR v cc du hiu chy mu, cc bin

php iu chnh phi tun t trnh gy nguy c huyt khi [3].

Theo khuyn co ACCP 2008 [18]:

+ Nu INR trn ngng iu tr nhng < 5,0 v khng c biu hin chy

mu, nn gim liu VKAs v theo di iu tr thng xuyn hn. Ti iu tr vi

mc liu VKAs ph hp khi INR t ch.

+ INR 5,0 v 9,0 v khng c biu hin chy mu khc ngoi chy mu

li hoc chy mu cam: b qua mt hoc hai liu sau , theo di thng xuyn

hn, ti iu tr mc liu ph hp khi INR t ch. Cng c th b qua mt liu

AVK v dng vitamin K ng ung (1 2,5 mg) c bit nhng bnh nhn c

nguy c chy mu cao. Nu cn o ngc tc dng chng ng phc v cho phu

thut cp, tng liu vitamin K ng ung vi hy vng INR s gim trong 24 gi

tip theo. Nu INR vn gi nguyn mc cao, cn b sung thm vitamin K ng

ung (1 2 mg).

+ INR 9,0 v khng c biu hin chy mu cn b sung liu cao hn

vitamin K ng ung (2,5 5,0 mg) vi hy vng INR s gim trong 24 48 gi

tip theo. Theo di INR thng xuyn v b sung thm vitamin K nu cn thit, lp

li iu tr vi mc liu ph hp khi INR t ch.

17

+ INR tng kt hp vi biu hin chy mu nghim trng, chy mu e da

tnh mng (xut huyt ni s) bt k mc tng INR th no, b sung vitamin K

(10mg) truyn tnh mch chm cng vi huyt tng ti ng lnh, phc hp

prothrombin, hoc yu t VIIa ti t hp. Cn lp li liu dng vitamin K mi 12

gi nu INR tng cao dai dng.

1.3.7. Tc dng ph ca thuc chng ng khng vitamin K

1.3.7.1. Xut huyt

Chy mu l tc dng ph hay gp nht (ADR > 1/100) c th xy ra trn

khp c th: h thn kinh trung ng, cc chi, ph tng, trong bng, nhn cu [3].

Cc yu t d on mc xut huyt [18][33][39]:

+ Cng iu tr: l yu t quan trng nht nh hng n nguy c chy

mu. INR > 5 c bo co l c nguy c chy mu do tha thuc chng ng [3].

+ Cc c im khc ca bnh nhn bao gm: tin s chy mu (c bit l

xut huyt tiu ha), tin s t qu, hoc cc bnh nng mc km khc nh suy

thn nng, thiu mu, ung th hoc tng huyt p.

Tn sut v mc nghim trng ca xut huyt c th c gim thiu

bng cch gim st cht ch PT/INR. Biu hin sm ca qu liu chng ng c th

c xem xt bi tng phn tch t bo mu, phn en, chy mu kinh nguyt qu

mc hoc rong kinh, chm xut huyt, bm mu, chy mu li, nim mc khc [3].

1.3.7.2. Cc tc dng ph khc

Tc dng ph him gp nhng quan trng khc bao gm hoi t da v hoi t

chi. C ch bnh sinh ca tnh trng ny cha c bit n mt cch y , tuy

nhin, c s lin quan gia hoi t da do s dng thuc chng ng khng vitamin

K v thiu ht protein C hay ng yu t l protein S [3].

Ngoi ra, cc bnh nhn dng AVK c th gp cc triu chng: ri lon tiu

ha (nn, bun nn, au bng, tiu chy) hay vim da, ni m ay, pht ban, mn

nga. Tng men gan, phosphatse kim, v bilirubin cng c bo co nhng him

xy ra [3][33].

18

1.3.8. Chng ch nh

- Mn cm vi cc dn cht coumarin hay cc thnh phn c trong thuc

- Suy gan nng

- Nguy c chy mu, mi can thip ngoi khoa v thn kinh hoc mt hay c

kh nng phi m li.

- Tai bin mch no (tr trng hp nghn mch ni khc)

- Suy thn nng ( thanh thi creatinine < 20 ml/pht)

- Gin tnh mch thc qun

- Lot d dy t trng ang tin trin

- Phi hp vi cc thuc aspirin liu cao, thuc chng vim khng steroid

nhn pyrazol, mionazol dng ng ton thn, m o, phenylbutazon,

chloramphenicol [2][3].

1.3.9. Tng tc thuc

1.3.9.1 Tng tc vi thc n v ung

Ung ru: ng c ru cp tnh lm gim chuyn ha thuc khng vitamin

K gy tng tc dng chng ng c th lm d chy mu. Ngc li, nghin ru s

lm tng chuyn ha thuc dn n gim tc dng ca thuc [6][18].

Cc loi thuc b cha vitamin K hay thc n c nhiu vitamin K nh: Bng

ci xanh, gan b hay heo, tr xanh, mt s loi tho dc nh Linh Lng, mng ty,

cc loi ci lm gim tc dng ca thuc. Mc khuyn co hm lng vitamin K

trong mi ba n l 70 140 mcg/ngy.

1.3.9.2. Tng tc vi cc loi thuc khc [2][3][45].

Cc thuc i khng tc dng ca thuc khng vitamin K

+ Gim hp thu: cholestyramine.

+ Tng o thi: barbiturate, rifampicin, carbamazepine, ru

+ C ch cha r: nafcillin, sucralfate

Cc thuc tng cng tc dng ca khng vitamin K

+ c ch o thi: phenylbutazone, sulfinpyrazon, disulfiram,

metronidazole, cotrimoxazol, cimetidine, amiodarone.

19

+ Tng cng tc dng chng ng (khng nh hng n nng

khng vitamin K huyt tng): cephalosporin th h 2 3, clofibrate,

heparin, ancrod.

+ C ch cha r: erythromycin, phenytoin, ketoconazole,

fluconazole, isoniazid, quinidine, vitamin E liu cao, propafenone.

Cc thuc tng nguy c chy mu khi phi hp vi khng vitamin K (d

khng c tc dng chng ng): aspirin, thuc khng vim khng steroid,

clopidogrel, ticlopidine.

20

CHNG 2: I TNG V PHNG PHP NGHIN CU

2.1. i tng nghin cu

i tng nghin cu bao gm tt c cc bnh nhn c ch nh v c s

dng AVK nm iu tr ni tr ti khoa C6 Vin Tim Mch Quc gia. Tt c cc

bnh nhn ny c ly theo trnh t thi gian t ngy 20/12/2013 n ngy

31/03/2014.

Tiu chun la chn

Tt c cc bnh nhn c s dng AVK nm iu tr ni tr ti khoa C6 Vin

Tim mch Quc gia t 20/12/2013 n 31/03/2014.

Tiu chun loi tr

Bnh nhn ang iu tr ti khoa C6 nhng trong qu trnh iu tr li chuyn

vin hay chuyn khoa khc.

Bnh nhn s dng AVK t hn 3 ngy.

2.2. Phng php nghin cu

2.2.1. Thit k nghin cu

Tin cu m t ct ngang, khng can thip.

2.2.2. Phng php ly mu

Cn c vo danh sch bnh nhn ca khoa v bnh n nm vin ca cc bnh

nhn, ly mu theo tiu chun la chn v tiu chun loi tr ni trn.

2.2.3. Thu thp thng tin

Trong thi gian bnh nhn iu tr ni tr, thu thp thng tin da trn bnh

n ca bnh nhn theo phiu thu thp s liu c sn (ph lc).

2.3. Ni dung nghin cu

2.3.1. c im bnh nhn trong mu nghin cu

- T l bnh nhn phn theo nhm tui: nhm tui < 20, nhm tui nm

trong khong 20 40, nhm tui nm trong khong 40 60, nhm tui > 60.

- T l bnh nhn theo gii: nam/n.

- Thi gian s dng AVK

- c im bnh l ca cc bnh nhn trong mu nghin cu.

21

- c im chc nng gan thn ca bnh nhn.

+ Chc nng gan: Phn loi tn thng gan ca bnh nhn theo mc tng

nng men gan ASAT/ALAT.

+ Chc nng thn:

Da vo nng Creatinin ca bnh nhn, theo cng thc ca

Cockroft v Gault tnh h s thanh thi Creatinin, phn loi mc

tn thng da vo h s thanh thi Creatinin [1]:

Clcr = ( )

(x 0,85 nu l n)

Trong : Tui tnh bng nm

Th trng: cn nng ca bnh nhn (kg)

Cretinin huyt tng bng mg/dL.

Bng 2.1. Phn loi mc suy thn

Mc suy thn Mc lc cu thn

(mL/pht)

Creatinin mu

(mol/L)

Creatinin mu

(mg/dl)

I 60 41 < 130 1,5

II 40 21 130 299 1,5 3,4

IIIa 20 -11 300 499 3,5 5,9

IIIb 10 5 500 900 6,0 10,0

IV < 5 > 900 >10,0

2.3.2. Thc trng s dng thuc chng ng khng vitamin K

Kho st s b cho thy ti khoa C6 Vin Tim Mch Vit Nam c s dng

hai loi thuc chng ng khng vitamin K l: Warfarin, Acenocoumarol (Sintrom).

- Liu dng, cch dng, ng dng ca tng thuc nghin cu: warfarin,

aceocoumarol.

- Gim st iu tr trong qu trnh s dng thuc

+ T l bnh nhn c lm xt nghim INR trc khi dng AVK.

+ Khong cch gia hai ln xt nghim INR.

+ T l INR t ch so vi tng s xt nghim.

22

+ Hiu chnh liu theo INR

- Tc dng khng mong mun: bao gm chy mu v cc tc dng ph khc.

Cn c vo ti liu [18][40][41] phn loi mc chy mu trn bnh nhn

dng thuc ng khng vitamin K.

+ Chy mu nng: khi bnh nhn gp mt trong nhng tiu ch sau:

1. Chy mu gy t vong v/hoc

2. Chy mu c triu chng ti mt trong nhng v tr sau: ni s, kt

mc, sau phc mc, ngoi mng tim v/hoc.

3. Chy mu c xc nh bi s gim nng hemoglobin di

20g/L (1,24 mmol/l), hoc cn phi truyn hai hoc nhiu hn n v mu

ton phn hay hng cu.

+ Chy mu nh: nhng chy mu khng yu cu kim tra hay nhp vin

(chy mu cam hoc chy mu chn rng)

- Cc tng tc bt li trong qu trnh s dng thuc. Cn c vo ti liu Tng

tc thuc v ch khi ch nh, phn loi cc tng tc thuc theo tng mc

:

Mc 1: Tng tc cn theo di

Mc 2: Tng tc cn thn trng

Mc 3: Cn nhc nguy c/li ch

Mc 4: Phi hp nguy him

- Kt qu iu tr chng ng ca cc bnh nhn trong nghin cu c nh gi

theo hai tiu ch sau:

+T l INR t ch trong qu trnh iu tr.

+T l bnh nhn c INR t ch trc khi ra vin.

2.4. X l s liu: Phn mm Excel 2010.

23

CHNG 3: KT QU NHN XT V BN LUN

3.1. c im bnh nhn trong mu nghin cu

3.1.1. Tui/Gii

Trong thi gian theo di, 86 bnh nhn trong mu nghin cu c phn

chia theo cc nhm tui: nhm tui < 20, t 20 40 tui, 40 60 tui v nhm tui

> 60. Kt qu phn b bnh nhn theo tui, gii c th hin trong bng sau:

Bng 3.1. Phn b bnh nhn theo tui, gii.

Tui Nam N Tng

S BN T l (%) S BN T l (%) S BN T l

< 20 2 6,3 0 0 02 2,3

20 40 5 15,6 6 11,1 11 12,8

40 60 16 50,0 29 53,7 45 52,3

> 60 9 28,1 19 35,2 28 32,6

Tng 32 100 54 100 86 100

Tui TB 54,9315,43

Nhn xt:

- Nhn chung, t l bnh nhn s dng AVK tng theo tui. N gii c t

l cao hn nam gii.

- Trong bn nhm tui, nhm tui 40 60 chim t l cao nht c hai gii

(nam: 50% v n: 53,7%). Cc bnh nhn ln hn 60 tui chim t l tng i cao

(nam: 28,1%; n: 35,2%). tui nh hn 20, t l bnh nhn c dng AVK

u thp nht vi c hai gii (nam 6,3%; n 0%).

- Tui trung bnh ca bnh nhn trong mu nghin cu l 54,93 15,43;

trong bnh nhn cao tui nht l 85 tui; v bnh nhn nh tui nht l 18 tui.

Bn lun:

T l bnh nhn c s dng AVK nhn chung tng theo tui. T l cc

bnh nhn s dng AVK nhiu nht tui trn 40. Hu ht cc bnh tim mch

24

ngi gi u c mi lin quan n huyt khi nh l bnh c tim thiu mu cc b,

rung nh, bnh van tim v huyt khi tnh mch su. Nghin cu ca Anderson v

cng s cho thy t l mc huyt khi tnh mch tng theo cp s nhn vi t l

t 30/100000 40 tui ln 90/100000 60 tui, v 80 tui l 260/100000 [17].

Theo tc gi Richard H White, t l huyt khi tnh mch l di 5/100.000 dn

ngi di 15 tui, tng ln n 100/100.000 dn ngi trn 40 tui, 400/100.000

dn ngi 70 tui v ngi trn 80 tui t l l 500/100.000 dn [37]. C nhiu

kin gii thch ti sao nguy c huyt khi li ph thuc vo tui. C kin cho

rng l do tnh trng a bnh l phi hp ngi cao tui, km theo s gim

trng lc c, tnh trng km vn ng v nhng thay i thoi ha h mch [38].

Kt qu nghin cu ECHOES cng cho thy t l mc rung nh tng theo tui t 0,2

% nhm tui 45 54 ln 8,0% i tng trn 75 tui [25]. Trong nghin cu

ca chng ti, cc bnh nhn tui trn 40 chim t l cao. Kt qu tng t

cng c ghi nhn nghin cu ca Nguyn Thu Hng v Lng Th Minh Hin

trc [9]. Nh vy, c th thy rng, tui trn 40 l mt yu t nguy c vi cc

bnh tim mch cn s dng thuc chng ng khng vitamin K.

N gii c t l s dng AVK cao hn nam gii. tui 40 60 c hai

gii u chim t l cao nht, c bit l n. y l tui hu thai sn v mn

kinh. Nguy c huyt khi tng cao trong thi k hu thai sn. Ngoi ra, ph n

mn kinh, s dng liu php hormone thay th lm tng nguy c huyt khi tnh

mch ln t 2 n 4 ln [28].

3.1.2. Thi gian s dng AVK

Thi gian dng thuc trung bnh ca mi bnh nhn trong mu nghin cu

l: 12,6 7,5 ngy. Trong , bnh nhn c thi gian dng di nht l 41 ngy,

bnh nhn c thi gian s dng ngn nht l 3 ngy.

3.1.3. c im bnh l ca cc bnh nhn trong mu nghin cu

25

Bng 3.2. c im bnh l ca cc bnh nhn

STT Bnh l S BN T l (%)

1 Huyt khi tnh mch su 26 30,3

2 Rung nh 7 8,2

3 Rung nh + THA + Suy tim 5 5,8

4 Rung nh + bnh van tim 10 11,6

6 Van tim nhn to 21 24,4

5 Bnh van tim 7 8,2

7 Cc bnh l khc 10 11,5

Tng 86 100,0

Nhn xt:

Kt qu bng 3.2 cho thy: nhm bnh l hay gp phi s dng AVK l

huyt khi tnh mch su (30,3%), rung nh bao gm rung nh n thun v rung

nh km cc bnh tim mch khc chim 25,6%, van tim nhn to (24,4%). Nhm

bnh nhn c bnh van tim chim t l nh (8,2%), cc bnh nhn c cc bnh tim

mch khc (nhi mu c tim, bnh mch vnh, suy tim) chim t l t (11,6%).

Nh vy, cc nhm bnh l hay s dng AVK nht l huyt khi tnh mch

su, van tim nhn to v rung nh. Li ch ca AVK trong phng v iu tr huyt

khi cc bnh nhn trn c khng nh qua nhiu nghin cu, iu tr v d

phng huyt khi vi cc bnh l trn l cn thit.

3.1.4. c im chc nng gan thn ca bnh nhn trong mu nghin cu

3.1.4.1. Chc nng gan ca cc bnh nhn

Mc tn thng gan ca cc bnh nhn c nh gi bng mc tng

nng men gan ASAT, ALAT. Kt qu kho st chc nng gan ca cc bnh

nhn trong mu nghin cu c th hin trong bng sau:

26

Bng 3.3. c im chc nng gan ca bnh nhn

Mc tng men gan

(ASAT, ALAT)

S BN T l (%)

Men gan bnh thng 59 68,6

Men gan tng nh 24 27,9

Men gan tng 3 ln 3 3,5

Tng 86 100

Nhn xt:

T l bnh nhn c men gan nm trong gii hn bnh thng cao nht vi

68,6%. Cc bnh nhn c men gan (ASAT, ALAT) tng nh chim t l t hn

(27,9%). Trong mu nghin cu c 3 bnh nhn c men gan tng 3 ln (3,5%).

3.1.4.2. c im chc nng thn

Bng 3.4. c im chc nng thn ca cc bnh nhn

Mc suy thn S BN T l (%)

Chc nng thn bnh thng 60 69,8

I 15 17,4

II 11 12,8

IIIa 0 0

IIIb 0 0

IV 0 0

Tng 86 100,0

Nhn xt:

69,8% cc bnh nhn trong mu nghin cu c chc nng thn bnh thng.

17,4% bnh nhn c suy thn I v 12,8% cc bnh nhn c suy thn II. Khng

c bnh nhn no trong nghin cu suy thn giai III v IV.

3.2. Thc trng s dng thuc ca bnh nhn.

3.2.1. Danh mc cc AVK c s dng

27

Bng 3.5. Danh mc cc AVK c s dng

Hot cht

(Bit dc)

Dng bo ch -

Hm lng

S BN T l (%)

Acenocoumarol

(Sintrom)

Vin nn 4mg 82 95,35

Warfarin

(Coumadin)

Vin nn 5mg 4 4,65

Tng 86 100,0

Nhn xt:

C hai bit dc c s dng l: Sintrom (Acenocoumarol) v Coumadin

(Warfarin), y u l cc dng bo ch vin nn rt tin li cho bnh nhn khi s

dng. Trong , Sintrom c s dng nhiu nht vi 82 trng hp (95,35%),

Warfarin rt t c s dng vi 4 trng hp (4,65%).

Ti Vin Tim Mch Quc gia, thuc chng ng mu khng vitamin K

c s dng hn 25 nm nay phng v iu tr cc bnh huyt khi gy tc

mch. Thuc c dng ch yu l acenocoumarol vi bit dc Sintrom v gn

y l warfarin [7]. iu ny c khc vi vic s dng thuc chng ng hin nay

trn th gii khi m acenocoumarol c s dng rt hn ch do thi gian bn thi

ngn, tc ng chng ng mu km n nh. Ti H Lan, 75% s ngi dng

thuc chng ng ng ung l phenprocoumarol, s cn li l warfarin. Warfarin

l thuc chng ng c s dng rng ri nht ti M [44]. Ngi ta thng nht

rng, n nh ca thuc chng ng khng vitamin K ph thuc ch yu vo thi

gian bn thi ca thuc. Do thi gian bn thi di (36 42 gi), Warfarin c tc

dng chng ng n nh hn acenocoumarol thuc c thi gian bn thi ngn (8

11 gi) [44].

Ti khoa C6, Sintrom vn c s dng rng ri nht. iu ny c th do

thi quen v kinh nghim k n ca bc s. Ngoi ra, bit dc Coumadin

(warfarin) c gi thnh t, hin nay cha c nhiu trn th trng Vit Nam,

28

thun tin cho bnh nhn khi tm mua v s dng, Sintrom c u tin la chn

hn.

Nghin cu ca T Mnh Cng tin hnh so snh s n nh v tc dng

chng ng mu ca acenocoumarol v warfarin ngi mang van tim c hc ti

Vin Tim mch quc gia cho thy Warfarin kim sot tnh trng chng ng mu

n nh hn, ch s INR t dao ng v s dao ng cng phm vi hp hn, tn

sut thp hn so vi acenocoumarol. Bnh nhn dng chng ng loi warfarin t

phi iu chnh liu lng thuc hn so vi acenocoumarol [7]. Kt qu tng t

cng c ghi nhn nghin cu ca V Thy Lin [11]. Tuy nhin, vic nn la

chn chng ng warfarin hay acenocoumarol cn phi c nhiu nghin cu so snh

n nh ca hai thuc ny.

3.2.2. ng dng, cch dng

ng dng: Tt c 86 bnh nhn u dng theo ng ung.

Cch dng:

- Acenocoumarol: c 2 cch dng: ung 1 ln/ngy vo bui ti v ung 2

ln/ngy (8h sng v 20h ti)

Bng 3.6. T l 2 cch dng acenocoumarol

Cch dng S lng BN T l (%)

Ung 1 ln/ngy 80 97,6

Ung 2 ln/ngy 02 2,4

Tng 82 100,0

- Warfarin: tt c 4 bnh nhn u c dng 1 ln/ngy vo bui ti.

Nhn xt:

- 100% bnh nhn dng thuc chng ng warfarin 1 ln/ngy, vo bui ti.

Nhm dng acenocoumarol c 97,6% bnh nhn dng 1 ln/ngy, ch c 2 bnh

nhn dng 2 ln/ngy (sng-ti). Nh vy, hu ht cc bnh nhn u dng thuc

chng ng theo cch ung 1 ln/ngy vo bui ti.

29

ACCP 2008[18] khuyn co nn s dng cc thuc chng ng khng

vitamin K vo mt gi nht nh trong ngy m bo tnh tun th iu tr cho

bnh nhn. Vi acenocoumarol, Dc th quc gia Vit Nam v nh sn xut u

a ra hng dn l s dng mt ln/ngy vo mt thi im c nh. Vic chia

thuc ung hai ln/ngy, ung vo hai thi im sng, ti hin cha c nhc

nhiu trong cc ti liu.

Hai trng hp s dng acenocoumarol 2 ln/ngy u l nhng bnh nhn

c s dng acenocoumarol theo phc ny t trc . Acenocoumarol c

thi gian bn thi ngn (8 - 11 gi), do , khong cch a thuc l 12 gi c th

gip to ra di nng thuc n nh trong mu. Tuy nhin, bit dc Sintrom c

hm lng 4mg, vi nhng bnh nhn dng liu thp 1 1,5 mg/ngy, vic dng 2

ln/ngy s gy kh khn cho bnh nhn trong vic tun th iu tr. Hin nay, cch

dng ny cha ph bin v cng cha c y nghin cu nh gi hiu qu ca

phc dng nh trn.

3.2.3. Liu dng

3.2.3.1 Liu bt u

Bng 3.7. Liu dng ban u ca cc AVK

Acenocoumarol Warfarin

Liu ban u

(mg)

S BN T l

(%)

Liu ban u

(mg)

S BN

1 60 73,2 2,5 3

1 xen k 1,5 4 4,9 5 1

1 xen k 2 5 6,1

1,5 4 4,9

2 8 9,8

2 xen k 3 1 1,3

Tng 82 100,0 4

30

3.2.3.2. Liu duy tr v thi gian dng thuc

Da vo liu dng tng ngy ca bnh nhn v s ngy dng thuc tnh

liu duy tr trung bnh ca cc bnh nhn trong mu nghin cu. ng thi cng

da vo s ngy dng thuc ca tng bnh nhn tnh thi gian dng thuc trung

bnh.

Bng 3.8. Liu dng trung bnh ca cc bnh nhn trong mu nghin cu

Nhn xt:

Vi Acenocoumarol:

Liu bt u bng 1mg chim t l cao nht (73,2%), cc phc dng liu

bt u vi 1,5 mg; 2mg; 1,5 xen k 2; 1 xen k 1,5 v 2 xen k 3 chim t l rt t

(26,8%).

Nh vy, liu u tin 1 mg c s dng nhiu nht trong iu tr chng

ng ti Khoa C6.

Liu trung bnh ca acenocoumarol l 1,47 mg. Liu dng ban u ca AVK

ph thuc vo tnh trng ca tng bnh nhn.

+ Liu bt u thng thng ngi ln l 2 4 mg trong hai ngy u tin.

Sau kt qu INR s cho php hiu chnh liu ph hp.

+ Bnh nhn cao tui, suy gan, thn nng, suy tim hoc suy dinh dng liu

bt u thng thp hn (1- 3 mg) [3][18].

Liu bt u ca cc bnh nhn trong mu nghin cu thp hn hng dn

c ghi trong cc ti liu. y c th l kinh nghim k n ca cc bc s

trnh nguy c xut huyt cho cc bnh nhn, sau vic hiu chnh liu s da trn

kt qu INR.

Vi Warfarin:

Thuc Liu trung bnh (mg) Thi gian dng trung bnh

(ngy)

Warfarin 2,95 1,02 13 5,03

Acenocoumarol 1,47 0,65 9,55 6,28

31

Trong tng s 4 bnh nhn c k n warfarin, 3 bnh nhn c dng

liu bt u vi 2,5mg; 1 bnh nhn dng liu 5mg. Khng c bnh nhn no dng

liu bt u 10 mg.

Liu warfarin dng trung bnh ca cc bnh nhn l 2,95mg, thi gian dng

trung bnh l 13 5,03 ngy.

Liu ban u v liu duy tr ca warfarin cng ph thuc vo c im ca

tng bnh nhn. ACCP 2008 [18] khuyn co:

+ Liu thng thng 5 10 mg c s dng trong hai ngy u tin, sau

hiu chnh liu theo INR.

+ Liu 2 5 mg c khuyn co vi nhng bnh nhn suy gan, thn,

suy dinh dng, c suy tim hoc s dng cc thuc lm tng nhy cm

vi warfarin.

+ Liu bt u 2 3 mg ph hp cho nhng bnh nhn mi tri qua thay

van tim nhn to.

C 4 bnh nhn trong mu nghin cu u bt u vi mc liu warfarin

thp (< 5mg) v liu duy tr sau < 5mg. Hin nay vic s dng liu ban u 5mg

hoc 10mg vn cn nhiu tranh ci. Nhiu d liu ng h vic s dng warfarin

mc liu thp 5mg. Nghin cu ca Harrison v cng s, Crowther v cng s

[22][29] cho thy mc liu 5mg cho kt qu kim sot INR tt hn mc liu 10mg

nhng bnh nhn nhp vin dng warfarin. Tuy nhin, kt qu nghin cu ca

Kovaces v cng s trn bnh nhn c huyt khi tnh mch iu tr ngoi tr cho

thy, s dng warfarin 10mg c thi gian t ch INR nhanh hn (1,4 ngy) so vi

mc liu 5mg, m khng khc nhau v t l qu liu chng ng [30].

3.2.3.3. Hiu chnh liu

a. Hiu chnh liu theo chc nng gan

Suy gan dn n gim tng hp cc yu t ng mu, gim chuyn ha cc

AVK dn n tng nguy c xut huyt. Do , iu tr chng ng nhng bnh

nhn ny phi tht thn trng. ACCP 2008 khuyn co nn gim liu dng ban u

v liu duy tr nhng bnh nhn suy gan nng [18].

32

Trong mu nghin cu, ch c ba bnh nhn c tng men gan 3 ln gi tr

bnh thng. C ba bnh nhn ny u c dng vi mc liu 1mg/ngy trong

sut thi gian iu tr. Vic p dng mc liu thp acenocoumarol trn nhng bnh

nhn ny l hp l, sau da vo p ng INR ca bnh nhn hiu chnh liu

tip theo.

b. Hiu chnh liu theo chc nng thn

Cc AVK khng yu cu hiu chnh liu trn bnh nhn suy thn nh v va.

Gim thanh thi thuc; hot ng ca CYP2C9 enzyme chnh chu trch nhim

chuyn ha cc thuc chng ng gan gim 50% cc bnh nhn suy thn giai

on cui [24] dn n tng nng cc AVK, tng c tnh cng nh nguy c

xut hin tc dng ph. Do , cc AVK chng ch nh bnh nhn suy thn giai

on cui [1][16].

Kt qu kho st ca chng ti cho thy, khng c bnh nhn no suy thn

nng do , vic s dng cc AVK trong mu nghin cu l hon ton ph hp vi

khuyn co v hng dn ca nh sn xut.

3.2.4. Gim st iu tr

3.2.4.1. Gim st INR

Gim st INR trc liu u tin

Bng 3.9. T l kim tra INR trc liu u tin

S lng BN T l (%)

C kim tra 86 100

Khng kim tra 0 0

Tng 86 100

Nhn xt:

Tt c cc bnh nhn trong nghin cu u c kim tra INR trc khi

c s dng AVK. Vic kim tra INR trc khi dng AVK c vai tr quan trng

trong vic nh gi tnh trng ng mu ca bnh nhn v nh hng cho bc s

a ra mc liu dng ph hp trn tng bnh nhn.

Gim st INR trong qu trnh iu tr

- S ln xt nghim INR trung bnh: 4,01 2,50.

33

- Khong cch trung bnh gia hai ln xt nghim INR: 3,3 2,5 ngy

Theo khuyn co ca ACCP 2008, nhng bnh nhn nhp vin nn c lm

xt nghim INR hng ngy sau 2 3 liu dng u tin cho n khi INR n nh t

nht hai ngy lin tip; sau thc hin 2 3 ln/tun hoc t hn ph thuc vo

mc n nh INR ca bnh nhn [18]. Trong trng hp hiu chnh liu, cn

kim tra INR hng ngy sau cho n khi t INR n nh. Tn sut kim tra INR

cn ph thuc vo c im ca tng bnh nhn, cc bnh mc km, s thay i

trong ch n ung v liu dng thuc. Thi gian trung bnh gia cc ln o INR

lin tip ca cc bnh nhn trong mu nghin cu l 3,3 2,5 ngy, tng ng 2

3 ln/tun, khong cch ny p dng cho cc bnh nhn c INR n nh. Trong

qu trnh nghin cu chng ti cng ghi nhn c 31/86 bnh nhn (36,1%) c

thc hin xt nghim INR vo hai hoc ba ngy lin tip, nhng ln xt nghim ny

c thc hin khi c INR tng cao (> 4). Cc lt xt nghim INR cn li c

thc hin vi khong cch xa hn. Nh vy, vi tn sut 2 3 ln/tun, vic kim

tra INR trong mu nghin cu c tin hnh thng xuyn, ph hp vi cc

hng dn trc .

3.2.4.2. Hiu chnh liu theo INR

a. T l bnh nhn c hiu chnh liu

Liu dng cc AVK khng c nh m c hiu chnh liu theo p ng INR

ca tng bnh nhn.

Bng 3.10. T l hiu chnh liu ca cc bnh nhn

S ln hiu chnh S lng BN T l (%)

0 38 44,2

1 35 40,7

2 10 11,7

3 2 2,3

5 1 1,1

Tng 86 100

34

Tng s lt hiu chnh thuc: 66

Nhn xt:

S bnh nhn c hiu chnh liu thuc chng ng chim t l ln, trong

phn ln cc bnh nhn c mt ln iu chnh liu AVK (40,7%), 11,7% s bnh

nhn tri qua hai ln iu chnh liu chng ng. T l bnh nhn c ba ln iu

chnh liu chng ng l 2,3%. Trong mu nghin cu, ch c mt bnh nhn phi

nm ln hiu chnh liu dng chng ng.

b. T l hiu chnh liu theo INR

Bng 3.11. T l hiu chnh liu phn b theo cc khong INR

Khong

INR

INR < 2 3 < INR < 5 INR 5

S lt

INR

T l

(%)

S lt

INR

T l

(%)

S lt

INR

T l

(%)

Hiu

chnh liu

42 18,4 13 38,2 11 100

Khng

hiu chnh

186 81,6 21 61,8 0 0

Tng 228 100,0 34 100,0 11 100,0

Nhn xt:

T l hiu chnh liu vi INR < 2 thp; 81,6% s lt INR < 2 khng c

hiu chnh. Theo khuyn co ACCP 2008, vi INR di mc tiu iu tr nhng

nh hn khng qu 0,5 so vi gi tr INR mc tiu c th khng cn hiu chnh liu

m cn c vo p ng INR sau ca bnh nhn x tr tip[18]. Bn cnh ,

lo ngi v nguy c xut huyt cng c th l nguyn nhn khng tng liu i vi

cc lt INR ny.

Vi khong 3 < INR < 5, 38,2% lt INR c hiu chnh, 61,8% t l INR

khng c hiu chnh.

Vi INR > 5, 100% lt bnh nhn c tin hnh hiu chnh liu.

35

Nh vy, vic hiu chnh liu i vi cc lt INR > 5 c thc hin tt.

Tuy nhin, vi khong INR < 2 v 3 < INR < 5, hiu chnh liu cha c thc hin

y .

c. Kt qu hiu chnh

Bng 3.12. Kt qu INR sau hiu chnh

Trc hiu chnh Sau hiu chnh

Khong INR

S lt

INR

INR < 2 2 INR 3 3 INR 5

S lt T l

(%)

S lt T l

(%)

S lt T l

(%)

INR < 2 42 19 45,2 18 42,9 5 11,9

3 < INR 5, t l INR sau hiu chnh t mc tiu iu tr cao (72,7%),

27,3% INR vn trn khong mc tiu iu tr.

36

3.2.5. Tc dng ph ca thuc chng ng khng vitamin K

Chy mu l tc dng ph nghim trng v thng gp nht ca cc AVK.

Kt qu theo di t l chy mu ca cc bnh nhn trong mu nghin cu nh sau:

Bng 3.13. T l chy mu khi s dng AVK

Mc chy mu S lng T l (%)

Chy mu nh (chy mu

chn rng)

2 2,3

Chy mu nng 4 4,7

Chy mu tiu ha 2

Chy mu ng niu 1

Rong kinh 1

Khng chy mu 80 93,0

Tng 86 100

Trong mu nghin cu, 6/86 bnh nhn (7,0%) gp chy mu trong qu trnh

s dng AVK trong , hai bnh nhn c chy mu nh (2,3%), cc trng hp

chy mu nng bao gm: rong kinh, xut huyt tiu ha, xut huyt ng niu

chim 4,7%. Chng ti nhn thy, chy mu khi s dng AVK xy ra nhiu v tr

khc nhau, t l xut huyt trong qu trnh iu tr chng ng cao, cn theo di v

x tr kp thi.

Bn lun:

Chy mu l tc dng ph thng gp v nguy him nht ca AVK [3][18].

warfarin nm trong top 10 thuc c s lng tc dng ph nghim trng c bo

co ti FDA trong 10 nm t 1990 2000. Thuc chng ng cng xp hng u

trong nm 2003 2004 v s ca t vong do tc dng ph ca thuc trong nng

iu tr [47]. Chy mu do thuc chng ng khng vitamin K c chia thnh hai

loi: chy mu nh (l nhng chy mu cn c bo co nhng khng cn kim tra

hay yu cu nhp vin), chy mu nng (chy mu e da tnh mng nh chy mu

no, xut huyt tiu ha hoc c yu cu truyn mu hay nm vin theo di). T l

chy mu nng l 1,2 7,0%, chy mu nh 2 24% trong cc nghin cu trc

37

[40]. Theo thng k ca EHRA t l chy mu nng nhng bnh nhn rung nh c

s dng AVK dao ng trong khong 1,3 7,2% /nm [32]. Trong nghin cu ca

chng ti, t l bnh nhn chy mu nng l 4,7%; chy mu nh l 2,3%. T l ny

ph hp vi kt qu ca cc nghin cu trn.

Cng iu tr chng ng (INR) l yu t nguy c quan trng ca xut

huyt khi dng AVK [17][37][43]. Theo ACCP, kt qu ca nhiu th nghim lm

sng cho thy mi quan h mt thit gia INR v nguy c chy mu, vi t l

xut huyt nhng bnh nhn dng warfarin c INR duy tr 2- 3 t hn mt na so

vi nhm bnh nhn c INR > 3,0 [37]. Nghin cu ISCOAT tin hnh phn tch a

bin cc yu t nguy c chy mu cho thy, INR 4,5 l yu t nguy c c lp

mnh m vi RR = 5,96; CI 95% = 3,68 9,67; p = 0,0001[35]. Theo mt nghin

cu khc, kt qu INR trung bnh ti thi im xy ra xut huyt nhm xy ra

bin chng v nhm khng xy ra bin chng ln lt l 5,9 5,9 v 2,3 0,7 (p <

0,001) [35]. Thc t trong nghin cu ca chng ti, 5/6 bnh nhn c chy mu c

INR > 4,0 ti thi im xy ra bin chng vi INR trung bnh l 5,6 2,1. Nh vy,

INR l yu t d bo mnh m nguy c xut huyt bnh nhn dng chng ng

bng AVK. Nguy c ny tng nhanh hn khi INR > 4,0 5,0 [35][39]. Tuy nhin,

vi cc trng hp chy mu nng trong mu nghin cu, tnh trng chy mu ca

bnh nhn xut hin trc khi nhp vin. iu ny cho thy, vic kim sot cht

lng chng ng ti nh cha c thc hin tt. Do , cn tng cng gio dc

bnh nhn, theo di v gim st INR, hiu chnh liu thuc chng ng ph hp

t INR trong khong mc tiu iu tr.

Cc yu t nguy c xut huyt khc l c im ca tng bnh nhn bao

gm: tui, tin s xut huyt, cc bnh mc km (suy thn, thiu mu hay tng

huyt p) [43][18][32]. Mi quan h gia tui v nguy c chy mu c xem

xt trong nhiu nghin cu. Tin hnh so snh t l xut huyt bnh nhn rung nh

bnh nhn iu tr bng warfarin v nhm khng iu tr cho thy; t l xut

huyt tng theo tui; chy mu ni s cao hn ng k nhm bnh nhn trn 80

(OR= 1,8; CI 95% = 1,1 3,1) nhm bnh nhn dng warfarin, nhm khng iu

38

tr l (OR =4,7; CI 95% = 2,4 9,2) [25].Tin hnh nh gi 4200 bnh nhn khc,

Torn v cng s cho thy mi quan h tng t gia tui v t l chy mu tng t

1,5/100 nm ngi tui 60 ln 4,2/100 nm ngi tui 80[43]. Kt

qu mt phn tch meta nh gi su th nghim vi hn 1900 bnh nhn rung nh

s dng AVK cho thy, t l chy mu nng l 1,8/100 ngi nm nhm tui

75, v 3,2/100 ngi nm tui 75 [47]. Do , i vi nhng bnh nhn

cao tui ( 60), ACCP khuyn co nn theo di cn trng, v thng xuyn hn

gim thiu cc tc dng ph ca thuc chng ng [18]. Trong nghin cu ca

chng ti, tui trung bnh ca cc bnh nhn c chy mu nng l 50 5,7, v

khng c bnh nhn no 60 tui.

Vic chn on v nh gi xut huyt cc bnh nhn c chy mu nng

khi dng thuc chng ng khng vitamin K phi ht sc cn thn. Khi c xut

huyt (c bit l xut huyt d dy, ng niu), cn xem xt n kh nng c

nhng bnh tim n khc [18]. Kt qu nghin cu ca Coon v Willis cho thy

nhng bnh tim n khc l nguyn nhn gy chy mu 11% trong 292 bnh nhn

xut huyt [21]. Thc t kho st ca chng ti cho thy, ba trong bn bnh nhn c

xut huyt nng u c nhng bnh tn thng tim n khc, c th, hai bnh nhn

xut huyt tiu ha c vim lot d dy t trng; mt bnh nhn rong kinh c u x

t cung. Vic nh gi ng tnh trng nhng tn thng tim n trn nhng bnh

nhn c xut huyt s gip thy thuc nh hng x tr v iu chnh chin lc

chng ng ph hp.

Ngoi ra, trong qu trnh theo di chng ti cng ghi nhn thm nhng bnh

nhn gp phi d ng nh (ni ban), ri lon tiu ha (bun nn, nn, au bng, tiu

chy) hay au u, chng mt. Tuy nhin, rt kh xc nh nguyn nhn chnh

xc gy ra nhng tc dng ph ny v thc t trong qu trnh iu tr ti bnh vin,

cc bnh nhn c dng phi hp rt nhiu thuc. Do , chng ti ch xem xt

nh gi n nhng trng hp c chy mu tc dng ph thng gp v nghim

trng ca thuc chng ng khng vitamin K.

39

3.2.6. Tng tc ca thuc chng ng khng vitamin K

3.2.6.1. Phn loi mc tng tc

Do qu trnh iu tr ni tr, cc bnh nhn c th c s dng ng thi

nhiu thuc. Tuy nhin, trong qu trnh theo di, chng ti ch kho st cc tng

tc thuc c lin quan n thuc chng ng khng vitamin K.

Bng 3.14. Phn loi mc tng tc

Mc tng tc S lng tng tc T l (%)

Mc 1 2 1,9

Mc 2 88 83,0

Mc 3 16 15,1

Mc 4 0 0

Tng 106 100,0

Kt qu kho st cc cp tng tc c th theo tng mc tng tc nh sau:

Bng 3.15. T l cc cp tng tc thuc

Mc tng tc Cp tng tc thuc S lng T l (%)

Mc 1 Ace glicazid 2 1,9

Mc 2 AVK paracetamol 35 33,0

AVK PPI 24 22,6

AVK Amiodaron 6 5,7

AVK allopurinol 3 2,8

AVK - KS 13 12,7

AVK metronidazol 3 2,8

AVK glucocorticoid 4 3,8

Mc 3 AVK aspirin 5 4,7

AVK ceftriaxone 11 10,0

Tng 106 100,0

Ace = Acenocoumarol; PPI = Proton-pump inhibitor; KS = Khng sinh (Quinolon;

Aminosid ng ung; Macrolid)

40

Nhn xt:

T l tng tc thuc mc 2 ln nht (80,5%), tng tc thuc mc 3

tng i cao 16,9%. y l hai tng tc cn thn trng v cn nhc khi phi hp

thuc. Tng tc thuc mc 1 chim 2,6% v trong mu nghin cu khng c

tng tc no thuc mc 4 (phi hp nguy him).

Bn lun:

Trong tng s tng tc ca thuc khng vitamin K, s lng tng tc

mc 2 chim t l ln nht (83%). Cc cp tng tc chim t l ln l: AVK

paracetamol; AVK PPI (esomeprazol; pantoprazol). Cc tng tc ca AVK vi

amiodaron, allopurinol, metronidazol, khng sinh quinolone, macrolid, aminosid

ng ung chim t l t hn.

Cp tng tc AVK paracetamol chim t l cao nht (33,0%) trong s

nhng cp tng tc thuc mc 2 ni ring v ton b tng tc ni chung. Kt

qu ny cng c ghi nhn trong nghin cu ca Nguyn Thu Hng trc [14].

Paracetamol c ch nh gim au do huyt khi tnh mch su v cc trng hp

au bi cc nguyn nhn khc. C ch tng tc gia paracetamol AVK cha

c bit n mt cch y [6][19]. C th do paracetamol v cc cht chuyn

ha ca n c ch enzyme VKOR, nh hng n chuyn ha vitamin K trong c

th [19]. Theo Tng tc thuc v ch khi ch nh, paracetamol lm tng tc

dng chng ng ca cc AVK, ph thuc vo liu dng v thi gian dng ca

paracetamol. Tng tc ny khng c ngha lm sng khi dng 6 vin 325

mg/tun. Trong nghin cu ca chng ti, hu ht cc bnh nhn c tng tc ny

u s dng paracetamol qu gii hn trn, c nhng bnh nhn s dng 6 vin

Efferagan codein (paracetamol 500 mg)/ngy. Chy mu do tng tc ny khng

xut hin trn lm sng. Tuy nhin, cn hn ch k n paracetamol v theo di

cht ch ch s INR (2- 3 ln/tun), hiu chnh liu ph hp trnh nguy c xut

huyt.

Cp tng tc ca AVK PPI cng chim t l ln (22,6%) trong phn

ln l tng tc ca acenocoumarol esomeprazole; tng tc acenocoumarol

41

patoprazol t gp hn. Cc PPI c ch nh trnh lot d dy t trng do vic

s dng ng thi nhiu thuc; d phng xut huyt tiu ha do stress trong qu

trnh nm vin ca bnh nhn. Theo Stockley drug interaction, PPI c ch chuyn

ha acenocoumarol, tuy nhin nh hng c ch ny rt nh v khng li hu

qu trn lm sng. Vi warfarin, pantoprazol, lansoprazol khng lm thay i dc

ng hc cng nh tc dng chng ng ca thuc ny. Esomepazol gy tng nh

nng R warfarin, khng nh hng n S warfarin do tc dng chng

ng tng nh. Tuy nhin, kt qu mt nghin cu thun tp nh gi nguy c qu

liu chng ng (INR > 6,0) trn 2755 bnh nhn dng acenocoumarol v PPI cho

thy; nguy c qu liu chng ng tng mnh m khi s dng esomeprazole (HR:

1,99; CI 95%: 1,55 2,55), lansoprazol (HR 1,49; CI 95%: 1,05 2,10) cc PPI

khc c nguy c thp hn hoc nguy c khng ng k [42]. Mt case lm sng

khc m t mt ph n 78 tui s dng acenocoumarol trong 60 ngy, c chy

mu ng niu sau nm ngy s dng esomeprazole, INR ca bnh nhn tng t

2,5 3 ln 5,7; sau khi ngng omeprazole, INR li gim [27]. Do , chng ti

ngh cn gim st cht ch INR v thi gian prothrombin khi k n cc PPI cng

vi thuc chng ng khng vitamin K, c bit l esomeprazole. Ngoi ra, bit

dc Nexium vi hot cht esomeprazole c gi thnh cao, do c th cn nhc

sang s dng Pantoloc (pantoprazol) hoc lansoprazol gim nguy c tng tc.

C 6 bnh nhn gp c tng tc gia AVK amiodaron, chim t l nh

5,7%. C ch ca tng tc ny l amiodaron c ch chuyn ha AVK bng cch

c ch h enzym chuyn ha thuc CYP2C9, CYP3A4 v CYP1A2, tng cng tc

dng chng ng ca AVK. Tng tc ny c m t vi Sintrom, Coumadin

cho thy thi gian Quick c th tng gp i, thm ch gp 3 ln [6]. Theo Stockley

Drug Interaction v Tng tc thuc v ch khi ch nh, cn gim 30 50%

liu AVK cng vi theo di cht ch gi tr INR khi phi hp hai thuc ny trnh

nguy c chy mu. C 6 bnh nhn gp tng tc ny c s dng acenocoumarol

vi mc liu bt u dao ng t 1 2mg, kt hp vi vic gim st INR cht ch,

khng xy ra trng hp no qu liu chng ng.

42

Cc tng tc thuc mc 3 chim t l nh trong nghin cu (15,08%)

bao gm cc cp tng tc AVK aspirin; AVK ceftriaxone. C ch ca cp

tng tc aspirin AVK l aspirin v cc NSAIDs khc kch ng nim mc d dy,

lm tng nguy c xut huyt tiu ha khi s dng thuc chng ng, ng thi

aspirin chng kt tp tiu cu, hip ng tc dng chng ng vi cc AVK [6][17].

Trong thc t vic s dng AVK + liu thp aspirin (81 100 mg/ngy) kh ph

bin nhng bnh nhn suy tim, c bnh mch vnh, hay nhi mu c tim. Do ,

cn tng cng gim st INR nhng bnh nhn ny.

3.2.6.2. T l bnh nhn c tng tc thuc

Bng 3.16. T l bnh nhn c tng tc thuc

Tng tc S BN T l (%)

C tng

tc

S tng tc =

1 31

62

36,0

73,1 S tng tc =2 19 22,1

S tng tc 3 12 14,0

Khng tng tc

24 27,9 27,9

Tng 86 100,0

Nhn xt:

T l bnh nhn s dng AVK c tng tc thuc chim 73,1%. Trong mu

nghin cu ch c 24 bnh nhn c s dng thuc khng c tng tc no lin

quan n thuc chng ng khng vitamin K. Trong nhng bnh nhn c tng tc

thuc, s lng bnh nhn c 2 tng tc chim 36,1%; s bnh nhn c 3

tng tc chim 14%.

Tc dng ca AVK b nh hng bi rt nhiu thuc do c nhng thay i v

dc ng hc v dc lc hc. Kt qu mt nghin cu cho thy hn 1/3 s bnh

nhn dng thuc chng ng c k n vi t nht mt thuc c bit n l c

tng tc vi AVK [45]. Trong nghin cu ca chng ti, t l bnh nhn c tng

43

tc thuc kh ln 73,1% do cc bnh nhn iu tr ni tr thng phi s dng ng

thi nhiu thuc. Tuy nhin, do kim sot tt INR nn khng c bin chng huyt

khi cng nh xut huyt no xy ra do tng tc thuc.

3.2.7. Kt qu iu tr

3.2.7.1 Kt qu INR trong qu trnh iu tr

Bng 3.17. Phn b INR trong mu nghin cu

Khong INR S lt INR T l (%)

< 2 228 65,9

2 INR 3 73 21,1

3 < INR < 5 34 9,8

INR > 5 11 3,2

Tng 346 100

Nhn xt:

Da vo bng s liu 3.17 ta thy:

- Khong INR < 2 chim t l cao nht: 65, 9%

- Khong INR t mc tiu iu tr 2 3 chim t l t: 21,1%

- INR > 5 chim t l nh nht: 13%

T l INR < 2,0 trong mu nghin cu chim 65,8%, iu ny c ngha l c

nhng bnh nhn c INR < 2,0 trong sut qu trnh iu tr, cho thy vic s dng

AVK nhng bnh nhn ny cha t mc tiu chng ng, nguy c hnh thnh

huyt khi. Ch c 21,1% t l INR nm trong khong mc tiu iu tr. S lt

INR > 3,0 chim t l nh 13,0%.

C mi lin h cht ch gia t l INR nm trong khong mc tiu iu tr

vi hiu qu cng nh an ton khi s dng cc thuc chng ng ng ung.

Kt qu nghin ca Reynolds trn bnh nhn rung nh cho thy, nguy c t qu khi

cha liu chng ng (INR < 2) v nguy c chy mu khi qu liu chng ng

(INR > 3) cao hn ng k so vi nhng bnh nhn c INR 2 3 [36]. Mt nghin

cu khc ca T Mnh Cng cng ghi nhn INR khng t ch iu tr l yu t

44

nguy c cao ca bin chng (chy mu, huyt khi) khi dng AVK trn bnh nhn

sau thay van tim c hc [7].

Nh vy, t l INR t mc tiu iu tr trong thi gian theo di thp (21,1

%). Phn ln cc lt xt nghim INR c kt qu di mc tiu iu tr (INR < 2).

Cc AVK ch yu c dng ngoi tr d phng huyt khi di hn. Cn mt

khong thi gian nht nh bnh nhn t c trng thi chng ng n nh.

Kt qu nghin cu ca Caraco v cng s cho thy, khong thi gian cn thit

cc bnh nhn dng warfarin t c trng thi chng ng n nh l 40,27 ngy

(CI 95%: 35,9 44,6 ngy) [20]. Vi acenocoumarol, Gadisseur v cng s cho

thy ch 30% thi gian trong 6 tun u tin sau khi iu tr, cc bnh nhn duy tr

INR trong khong mc tiu iu tr [26]. Do , iu tr chng ng ni tr ch yu

l phc d liu da trn p ng INR a ra phc liu dng ph hp cho

tng bnh nhn.

3.2.7.2 Kt qu INR trc khi ra vin

Bng 3.18. Kt qu INR ca bnh nhn trc khi ra vin

Gi tr INR S BN T l (%)

INR < 2,0 42 48,9

2,0 INR 3,0 36 41,7

3 < INR < 5 8 9,4

Tng 86 100,0

INR trung bnh: 2,08 0,78

Nhn xt:

48,9% bnh nhn c kt qu INR < 2,0 trc khi ra vin. C 41,7% bnh

nhn c INR t mc tiu iu tr 2,0 3,0. S bnh nhn c INR nm trong khong

3 5 chim t l t nht (9,4%) v khng c bnh nhn no c INR trc khi ra vin

ln hn 5. Nh vy, s bnh nhn c INR t mc tiu iu tr trc khi xut vin

chim t l thp (41,7%), cc bnh nhn cn li c cho ra vin khi kt qu INR

cha t mc tiu chng ng. Thc t trong qu trnh theo di chng ti nhn thy,

45

s lng bnh nhn iu tr ti khoa C6 rt ng, bnh phng lun lun trong tnh

trng qu ti. Do , cn c vo mc ci thin triu chng lm sng, bnh nhn

s c cho ra vin, vic iu chnh liu thuc chng ng tip theo c thc hin

khi bnh nhn ti khm vo mt hoc hai tun sau . Nh vy, kt qu iu tr

chng ng ca cc bnh nhn trong thi gian theo di ni tr cha cao.

46

KT LUN V XUT

KT LUN

Qua thi gian nghin cu v tnh hnh s dng thuc khng vitamin K ti khoa

C6 Vin Tim mch Quc gia, chng ti i n nhng kt lun:

c im bnh nhn trong mu nghin cu

- Nhm tui s dng thuc khng vitamin K nhiu nht l 40 60 tui. T l

s dng thuc tng theo tui, t l s dng thuc khng vitamin K n nhiu

hn nam gii. Tui trung bnh ca bnh nhn trong mu nghin cu l 54,9315,43.

- Nhm bnh l hay gp phi s dng AVK l: huyt khi tnh mch su

(30,3%), rung nh (23,1%), thay th van tim (24,4%), bnh van tim v cc bnh tim

mch khc chim t l t hn.

- Chc nng gan ca cc bnh nhn: 3,5% bnh nhn c men gan tng 3

ln tr s bnh thng; 27,9% bnh nhn c men gan tng nh.

- Chc nng thn ca cc bnh nhn: 12,8% bnh nhn c suy thn nh (

II), 17,4 % bnh nhn c suy thn I, khng c bnh nhn suy thn nng.

Thc trng s dng thuc AVK

- Danh mc AVK: acenocoumarol (Sintrom) c s dng nhiu nht chim

95,35%, t l s dng warfarin l 4,65%.

- ng dng: 100% bnh nhn dng theo ng ung.

- Cch dng: 100% bnh nhn ung warfarin 1 ln/ngy vo bui ti; 97,6%

bnh nhn dng Sintrom 1 ln/ngy vo bui ti: 2,4% s bnh nhn dng Sintrom

2 ln/ngy (sng-ti).

- Liu dng: Liu dng ban u c s dng theo kinh nghim ca bc s v

kt qu INR u tin, v liu chng ng bnh nhn dng trc . Mc liu 1

mg acenocoumarol c s dng nhiu nht. Liu trung bnh ca acenocoumarol l

1,47 0,65 mg, liu trung bnh ca warfarin l 2,95 1,02 mg.

- Liu s dng cho cc bnh nhn suy gan thn l hp l.

- Gim st INR c thc hin vi tn sut 2 3 ln/ngy, khong cch

trung bnh gia 2 ln xt nghim l 3,3 2,5 ngy.

47

- Hiu chnh liu theo INR: Vi INR < 2, t l hiu chnh l 18,4%, khng

hiu chnh l 81,6%; khong INR: 3 - 5 c c t l hiu chnh l 38,2%, 61,8%

khng hiu chnh liu. Vi INR > 5, 100% bnh nhn u c hiu chnh liu. Kt

qu hiu chnh liu nh sau: vi INR < 2; 42,9% lt bnh nhn c INR sau hiu

chnh t mc tiu iu tr; t l ny vi khong INR : 3 5 l 61,5%; khong INR

> 5 l 72,7%.

- Tc dng ph hay gp nht ca khng vitamin K l chy mu. T l chy

mu nng l 4,7%, chy mu nh l 2,3%.

- Tng tc thuc: C tng s 106 tng tc thuc, trong , tng tc

mc 2 chim t l cao nht, cp tng tc ph bin l AVK paracetamol, AVK

PPI. T l bnh nhn c s tng tc = 2 l 22,1%, 14% s bnh nhn c s tng

tc thuc > 2.

- Kt qu INR trong qu trnh iu tr: T l INR t ch l 21,1%, t l

INR di mc tiu iu tr l 65,9% v t l INR trn khong mc tiu iu tr l

12%.

- Kt qu INR ca bnh nhn trc khi ra vin: 41,7% s bnh nhn c INR

t mc tiu iu tr trc khi ra vin.

XUT

- Tng liu Sintrom, Warfarin c s dng.

- Tng liu thuc chng ng nhng bnh nhn c INR < 2.

- Nng cao nhn thc ca bnh nhn v ch n ung v tm quan trng ca

vic tun th iu tr.

- Xem xt k n Warfarin v tin hnh nghin cu so snh hiu qu iu tr v

n nh ca Warfarin v Sintrom c th la chn thuc an ton v t mc

tiu iu tr.

48

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PH LC 1

PHIU THU THP S LIU

(Kho st tnh hnh s dng thuc chng ng khng vitamin K ti khoa C6 Vin

Tim mch Quc gia)

M nghin cu:

I. C IM BNH NHN

1. H v tn: ................................................ Tui ............. Gii tnh: .........................

2. M bnh nhn: ........................................................................................................

3. Chiu cao: ................................... Cn nng: ............. (kg).

4. Ngy nhp vin: ................................. Ngy ra vin: ............................................

5. Chn on: ..............................................................................................................

................................................................................................................................

6. c im chc nng gan thn:

Ch s Ngy/.

Ngy/.

Ngy/.

Ngy/.

Ngy/.

Ngy/.

ASAT

(U/L)

ALAT

(U/L)

Creatinin

(mg/dL)

II. C IM S DNG THUC CHNG NG KHNG VITAMIN K

1. Thuc s dng: .......................................................................................................

2. Ch nh chng ng: ............................................................................................

...............................................................................................................................

3. Liu dng:

Liu dng 1

S ngy dng 1

Liu dng 2

S ngy dng 2

Liu dng 3

S ngy dng 3

Tng s ngy dng:(ngy).

Cch dng:

................................................................................................................................

................................................................................................................................

4. Theo di iu tr:

Thi gian lm xt nghim INR Kt qu

- Tng s ln lm xt nghim:..(ln)

- S ln INR t ch ( 2- 3):

5. Hiu chnh liu theo INR

Ln 1:

INR trc INR sau Liu dng trc Liu dng sau

Ln 2:

INR trc INR sau Liu dng trc Liu dng sau

Ln 3:

INR trc INR sau Liu dng trc Liu dng sau

Tng s ln hiu chnh:

III. TC DNG PH V TNG TC THUC

1. Tc dng ph

1.1. Xut huyt

V tr xut huyt Ngy ghi nhn INR ti thi im xut huyt

1.2. Cc tc dng ph khc

...........................................................................................................................................

...........................................................................................................................................

...........................................................................................................................................

...........................................................................................................................................

2. Tng tc thuc:

Mc tng tc Tn cp tng tc

Tng s cp tng tc:

III. KT QU IU TR

1. Kt qu iu tr: Khi - khng - cht

2. INR trc khi ra vin:

IV. CC LU KHC

....................................................................................................................................

....................................................................................................................................

....................................................................................................................................

....................................................................................................................................

....................................................................................................................................

....................................................................................................................................

....................................................................................................................................

PH LC 2

DANH SCH BNH NHN

M

NC

H v tn M bnh nhn

Ngy nhp