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    TNG P MCH PHI:TNG P MCH PHI:

    Chin lc chn onChin lc chn on

    v iu tr mi nhtv iu tr mi nht

    Michael D. McGoonMichael D. McGoonProfessor of MedicineProfessor of Medicine

    Consultant, Cardiovascular DiseasesConsultant, Cardiovascular Diseases

    Mayo ClinicMayo Clinic

    Rochester, MNRochester, MN

    H Ni 4/2009

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    p dng cho tt ccc tr-ng hp tng

    p mch phi

    Cc nh ngha huyt ngCc nh ngha huyt ng

    > 3 USc cn mchphi

    > 30 mm HgALMP trung bnhkhi gng sc

    < 15 mm HgPCWP, LAP, LVEDP

    > 25 mm HgALMP trung bnhkhi ngh

    >15 mm HgALMP tm tr-ng khi ngh

    >35 mm HgALMP tm thukhi ngh

    p dng cho cctrng hp tng p

    lc ng mchphi

    kin chuyngia

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    Bnh th-ng

    Mch mu

    Trung mc

    Ni mc

    Thi gianThi gian

    PAPPAP

    PVRPVR

    COCO

    IINYHANYHA

    TAMP: TiTAMP: Tin trin huyt ng v lm sngn trin huyt ng v lm sng

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    Bnh thng

    Mch mu

    Trung mc

    Nimc

    Ph i t bo c

    trn

    Dy ni mcsm

    Tn thng cn bo tn

    Thi gianThi gian

    PAPPAP

    PVRPVR

    COCO

    II IIII IIIIII

    BNPBNP

    NYHANYHA

    TALMP: Tin trin huyt ng v lm sngTALMP: Tin trin huyt ng v lm sng

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    Bnh thng

    Mch mu

    Trung mc

    Ni mc

    Ph i lp t bo

    c trn

    Dy ni mcsm

    Tn thng c th hi phc Tn thng khng th hi phc

    Tn thngtnh co gin

    Huyt khi

    Tng sinh mchmu v lp ni mc

    Ph i t bo ctrn

    Thi gianThi gian

    PAPPAP

    PVRPVR

    COCO

    II IIII IIIIII IVIV

    BNPBNP

    NYHANYHA

    TALMP: Din bin huyt ng v lm sngTALMP: Din bin huyt ng v lm sng

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    Cc bnh khc c nh hng n h mch mu phiNhm 5:

    Nhi mu phi hoc bnh phi tc nghn mn tnhNhm 4:

    Thiu oxy hoc bnh phiNhm 3:

    Bnh tim triNhm2:

    TALMP TALMP tin pht (IPAH) TALMP c tnh cht gia nh (FPAH) TALMP c nh tr s sinh (PPHN)

    Bnh tc nghn tnh mch phi (PVOD) TALMP v cc bnh lin quan (APAH)

    Nhm 1:

    PhPhn loi TALMPn loi TALMP33rdrd World Conference on Pulmonary Hypertension, Venice 2003World Conference on Pulmonary Hypertension, Venice 2003

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    L nhm TALMP trc mao mchL nhm TALMP trc mao mch T l mc bnh n/nam 4:1T l mc bnh n/nam 4:1

    Tui trung bnh 50 tuiTui trung bnh 50 tui

    T l mc 6/million; mc ph bin ca bnhT l mc 6/million; mc ph bin ca bnh15/million15/million

    Thi gian sng trung bnh bnh nhn khng c iuThi gian sng trung bnh bnh nhn khng c iu

    tr: 2.8 nmtr: 2.8 nm

    Thi gian t khi xut hin triu chng n khi cThi gian t khi xut hin triu chng n khi cchn on: >2 nmchn on: >2 nm

    NhNhmm 1: TAL1: TALMP tin phtMP tin pht((IPAHIPAH))

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    TALMP trc mao mchTALMP trc mao mch Ri lon nhim sc thRi lon nhim sc th

    Ri lon genRi lon gen

    c pht hin sm hn v nng hnc pht hin sm hn v nng hn Tn thng thm nhim khng hon tonTn thng thm nhim khng hon ton

    2020% cc trng hp t bin tin trin thnh TALMP% cc trng hp t bin tin trin thnh TALMP

    Gen m ho th th 2 ca protein Bone MorphogeneticGen m ho th th 2 ca protein Bone Morphogenetic(BMPR2)(BMPR2)

    Quan trQuan trng trong kim sot cht t bo theo chngng trong kim sot cht t bo theo chngtrnhtrnh

    NhNhmm 1: TAL1: TALMP c yu t gia nhMP c yu t gia nh ((FPAHFPAH))

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    Bnh m lin ktBnh m lin kt

    Shunt ch-phi bm sinhShunt ch-phi bm sinh TALTM caTALTM ca Nhim HIVNhim HIV Thuc v nhim cThuc v nhim c

    Cc bnh l khc:Cc bnh l khc:

    Tn thng tuyn gipTn thng tuyn gip

    Bnh tch lu glycogenBnh tch lu glycogen

    Bnh GaucherBnh Gaucher

    Bnh gin mch xut huyt di truyn (Bnh Osler WeberBnh gin mch xut huyt di truyn (Bnh Osler WeberRendu)Rendu)

    Bnh l Hemoglobin (Bnh hng cu hnh lim)Bnh l Hemoglobin (Bnh hng cu hnh lim)

    Hi chng tng sinh tuHi chng tng sinh tu

    Ct lchCt lch

    NhNhmm1: TAL1: TALMP v cc bnh lin quanMP v cc bnh lin quan ((APAHAPAH))

    Bnh thng gp nht lx cng b (CREST);TALMP l nguyn nhndn n t vong nhtthng gp nht

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    NhNhmm 1: Ng1: Ng c c

    Fenfluramine/Phentermine,Fenfluramine/Phentermine,Dexfenfluramine, MethamphetamineDexfenfluramine, Methamphetamine

    Tng lin kt caTALMP 23XTng lin kt caTALMP 23X

    CH3

    NH2

    C2H5

    Fenfluramine

    NH2

    Aminorex

    O

    NCH3

    NH2

    Phentermine

    CH3CH3

    NH2

    Amphetamine

    CH3

    NH2

    CH3

    Methamphetamine

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    Chin lc chn onChin lc chn on

    Pht hin triu chngPht hin triu chng Tm hiu (hoc loi tr) cc nguyn nhn.Tm hiu (hoc loi tr) cc nguyn nhn.

    Xc nh kiu huyt ngXc nh kiu huyt ng

    Mc nngMc nng Kiu trc/sau mao mchKiu trc/sau mao mch p ng vi thuc gin mchp ng vi thuc gin mch

    Xc nh kh nng gng scXc nh kh nng gng sc

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    Hng dn chn onHng dn chn on

    Siu m timSiu m tim PFTsPFTs Thm d khi ngThm d khi ng

    Chp CT thng khChp CT thng khti mu phi,ti mu phi,Chp CT c cnChp CT c cnquang,quang,

    Chp mchChp mch

    XN min dchXN min dchXN HIVXN HIV

    LFTs v bngLFTs v bngchng LSchng LSca x ganca x ganhay TALTMChay TALTMC

    RVE, RAE,RVE, RAE, RVSPRVSPBnh tim triBnh tim tri

    VHDVHDCHDCHD

    Kh ph thng vKh ph thng v

    cc bt thng v lng ngccc bt thng v lng ngc Ri lon khi ngRi lon khi ng

    Huyt khiHuyt khitc mch mn tnhtc mch mn tnh

    X cng bX cng bLupusLupus

    RARAVim mchVim mch

    HIVHIVTAL ca phiTAL ca phi

    Test chc nngTest chc nngBNPBNPThng tim phiThng tim phi

    Test gin mchTest gin mch

    Khm LSKhm LSX. QuangX. Quang

    TT

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    Siu m v thng tim phi Cc thng tin b sungSiu m v thng tim phi Cc thng tin b sung

    Siu m timSiu m tim

    nh gi bnh nnnh gi bnh nn

    nh gi RVSP, Pam, Pad,nh gi RVSP, Pam, Pad,SV/PP, RV dP/dt, PVRSV/PP, RV dP/dt, PVR

    Chc nng tht phiChc nng tht phiQuan stQuan st

    RV-IMPRV-IMP

    Siu m Doppler mSiu m Doppler m

    TAPSETAPSE

    Strain, Strain RateStrain, Strain Rate

    Isovolumic AccelIsovolumic Accel

    RHCRHC

    nh gi huyt ngnh gi huyt ng

    AL mao mch phi btAL mao mch phi bt

    PBFPBF

    ALMP trung bnhALMP trung bnh

    p ng vi cht gin mchp ng vi cht gin mch

    bo ho Oxy bo ho Oxy

    nh gi tnh trng shuntnh gi tnh trng shunt

    Sng lc v theo diSng lc v theo di

    Chn on xcChn on xc

    nhnh

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    Cc yu t chi phi mch phiCc yu t chi phi mch phi

    argininearginine

    NONO

    GTPGTP

    cGMPcGMP

    eNOSeNOS

    GCGC

    AAAA

    PGIPGI22

    ATPATP

    cAMPcAMP

    PSPS

    ACAC

    Big-ETBig-ET

    ETET11

    ECEECE

    ETETAA ETETBB

    Gin mch, Chng tng sinhGin mch, Chng tng sinh Co mch, tng sinhCo mch, tng sinh

    5`GMP5`GMP

    PDEPDEPDE5iPDE5i

    PGIPGI22ETRAETRA ETRAETRA

    Tboni

    Tboni

    mc

    mc

    Tbo

    c

    Tbo

    c

    trntrn

    Con ngNitrite oxide

    Con ngProstacyclin

    Con ngEndothelin

    CaCa++++

    CCBsCCBs

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    Chn knh CalciumChn knh Calcium

    Rich S, Kaufmann E, Levy PS: Tc dng ca thuc chn knh canxiliu cao ln t l sng cn ca TALMP tin pht.

    N Engl J Med 327:76-81, 1992

    N=17N=17

    N=47N=47

    N=187N=187

    30

    40

    50

    60

    70

    80

    90

    100

    0 6 12 18 24 30 36 42 48 54 60

    Thng

    Tlsngc

    n,%

    p ng vi iu tr

    Khng p ng vi iu tr

    NIH Registry

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    Nn iu tr thuc chn knhcni cho nhng bnh nhn cp ng vi cht gin mch.

    557 bnh nhn c test chtgin mch c tc dng ngn:

    70 (12%) gim ALMPTB vsc cn phi >20% v c

    iu tr thuc chn knh Ca.

    54% bnh nhn p ng (6%tng s BN) c chng

    minh c ci thin lu di khi

    iu tr chn knh Ca.

    Sitbon O, Humbert M, Jais X, et al. Circ 2005;111:3105-11.Sitbon O, Humbert M, Jais X, et al. Circ 2005;111:3105-11.

    Chn knh CalciumChn knh Calcium

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    Sitbon O, Humbert M, Jais X, et al. Circ 2005;111:3105-11.Sitbon O, Humbert M, Jais X, et al. Circ 2005;111:3105-11.

    Chn knh CalciumChn knh Calcium

    p ng gin mchp ng gin mch

    Gim ALMPTB trnGim ALMPTB trn 10 mm Hg10 mm Hg

    Gim ALMPTM cnGim ALMPTM cn 40 mmHg40 mmHg

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    Cc cht tng t ProstacyclinCc cht tng t Prostacyclin

    Ci thin kh nng gng scCi thin kh nng gng scKhong 15 - 50 met trong nghim php 6 pht i bKhong 15 - 50 met trong nghim php 6 pht i b

    Ci thin triu chngCi thin triu chng Gim PVR > PAPGim PVR > PAP Li ch trn t l sng cnLi ch trn t l sng cn

    McLaughlin VV et al. Circulation.McLaughlin VV et al. Circulation.2002;106:1477-1482.2002;106:1477-1482.

    ThngThng

    0.20.2

    0.40.4

    0.60.6

    0.80.8

    11

    %Tl

    sng

    %Tl

    sng

    cncn

    1212 2424 3636

    ExpectedExpected

    Observed (n=162)Observed (n=162)

    **

    **

    ***p*p

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    860 PAH pts

    87

    7871

    68

    Tc dng ca Treprostinil tiTc dng ca Treprostinil tim di dam di daln t l sng cnln t l sng cn

    Barst RJ et al. Eur Respir J 2006;28(6):1195-203.Barst RJ et al. Eur Respir J 2006;28(6):1195-203.

    n tr liu 332 IPAH pts

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    Cc cht tng t ProstacyclinCc cht tng t Prostacyclin

    Tim TM, Tim di da hoc kh dungTim TM, Tim di da hoc kh dung Mt s tc dng phMt s tc dng ph Tn kmTn km

    Epoprostenol (FlolanEpoprostenol (Flolan))

    Treprostinil (RemodulinTreprostinil (Remodulin

    ))

    Treprostinil (RemodulinTreprostinil (Remodulin))

    Iloprost (VentavisIloprost (Ventavis))tepoprostenol = 6 mintreprostinil = 4.5 hr

    au hmBng mt

    au chna chyQu liu

    Ho

    auNhim trngngc dng

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    NghiNghin cun cu Treprostinil PivotalTreprostinil Pivotal

    Mt

    Mt

    -5-5

    00

    55

    1010

    1515

    2020

    2525

    3030

    3535

    4040Trung bnh SE thay i so vi ng c bn(met)Trung bnh SE thay i so vi ng c bn(met)

    1st Quartile1st Quartile< 5.0< 5.0

    (2.5 0.2)(2.5 0.2)

    -4 12-4 12(N=34)(N=34)

    2nd Quartile2nd Quartile5 to

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    Cht i khngCht i khng Endothelin - BosentanEndothelin - Bosentan

    BREATHE-1 (PAH):BREATHE-1 (PAH):

    Theo di 12 week soTheo di 12 week sosnh vi placebosnh vi placebo

    CICI 1.0 L/min/m1.0 L/min/m22 mPAPmPAP 7 mmHg7 mmHg PVRPVR 5 U5 U Ci thin khong cchCi thin khong cch

    i b trong ti b trong test i best i b 66pht.pht. -40-40

    -20-20

    00

    2020

    4040

    6060BosentanBosentan(n=144)(n=144)

    PlaceboPlacebo(n=69)(n=69)

    BaselineBaseline 44 88 1616

    PP=0.0002=0.0002

    BREATHE-1BREATHE-1

    TunTun

    Rubin LJ et al. NEJM 2002;346(12):896-903.Rubin LJ et al. NEJM 2002;346(12):896-903.

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    BREATHE-5: Eisenmenger PAH (16 weeks):BREATHE-5: Eisenmenger PAH (16 weeks): Tiu ch nh gi u tin: huyt ng (placebo-hiu chnh)Tiu ch nh gi u tin: huyt ng (placebo-hiu chnh)

    mPAP (-5.5 mmHg); PVR (-472 dmPAP (-5.5 mmHg); PVR (-472 dsscmcm-5-5) both p

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    ng ungng ung Bosentan cht i khng receptor (khng chnBosentan cht i khng receptor (khng chn

    lc)lc)

    Tc dng ph:Tc dng ph: Ng c ganNg c gan Tng tc thucTng tc thuc TeratogenTeratogen

    Ambrisentan chn lc (ET-A affinity 4000x ET-Ambrisentan chn lc (ET-A affinity 4000x ET-B)B)

    Sitaxsentan khng c dng MSitaxsentan khng c dng M

    10% pht trin thnh bt thng LFT10% pht trin thnh bt thng LFTv phi dng li, cn kim tra li hngv phi dng li, cn kim tra li hngthngthng

    Bosentan gim AUC ca sildenafil AUC khongBosentan gim AUC ca sildenafil AUC khong50%50%

    Paul, G. A., J. S. Gibbs, et al. (2005).Paul, G. A., J. S. Gibbs, et al. (2005)."Bosentan lm gim tp trung huyt"Bosentan lm gim tp trung huyttng ca sildenafil khi phi hp iu trtng ca sildenafil khi phi hp iu trTALMP."TALMP." British Journal of ClinicalBritish Journal of ClinicalPharmacologyPharmacology 60(1): 107-112.60(1): 107-112.

    Glyburide Tng nhim c ganGlyburide Tng nhim c ganLm gim nng hp thu CyclosporinLm gim nng hp thu Cyclosporin

    PhPh2% pht trin thnh bt thng LFT v2% pht trin thnh bt thng LFT vphi dng thuc, cn kim tra li hngphi dng thuc, cn kim tra li hngthngthng

    Cht i khng EndothelinCht i khng Endothelin

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    1.1.McLaughlin VV et al. Eur Respir J. 2005;25:244-249.McLaughlin VV et al. Eur Respir J. 2005;25:244-249.

    2.2.Provencher S et al. Eur Heart J. 2006;27:589-595.Provencher S et al. Eur Heart J. 2006;27:589-595.

    T l sngT l sngcn (%)cn (%)

    ThThi gian (thng)(thng)

    100100

    8080

    6060

    4040

    2020

    00

    T l sng cn c quan st (McLaughlin et alT l sng cn c quan st (McLaughlin et al11))T l sng cn(Provencher v cslT l sng cn(Provencher v csl22))T l sng cn d onT l sng cn d on

    00 66 1212 1818 2424 3030 3636 4242 4848 5454 6060

    TTc dng cac dng ca BosentanBosentan ln t l sng cnln t l sng cn ccaaTALMP tin phtTALMP tin pht (IPAH)(IPAH)

    Based on historicalBased on historicalcontrolcontrol

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    *C*Cc tiu ch nh gi kt hp; t l t vong, thay phi, ti nhp vin hoc khng tip tc tham gia nghinc tiu ch nh gi kt hp; t l t vong, thay phi, ti nhp vin hoc khng tip tc tham gia nghincu do bnh TALMP nng lncu do bnh TALMP nng ln, c, cn iu trn iu tr epoprostenol , hoepoprostenol , hoc ph vch lin nhc ph vch lin nh..Adapted from Rubin LJAdapted from Rubin LJet al, N Engl J Med. 2002;346;896-903et al, N Engl J Med. 2002;346;896-903..

    Time (weeks)Time (weeks)

    00

    2525

    5050

    7575

    100100

    00 44 88 1212 1616 2020 2424 2828

    PP=0.0015=0.0015PP=0.0038=0.0038

    89%89%

    63%63%

    Event-freeEvent-free(%)(%)

    Bosentan (144)Bosentan (144)

    Placebo (n=69)Placebo (n=69)

    Bosentan (n=35)Bosentan (n=35)

    Placebo (n=13)Placebo (n=13)

    Bosentan: ThBosentan: Thi gian triu chng lm sng xu ii gian triu chng lm sng xu i(BREATHE-1)*(BREATHE-1)*

    n=144n=144

    n=69n=69

    n=103n=103

    n=48n=48

    n=13n=13

    n=3n=3

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    AmbrisentanAmbrisentanARIES-1 and 2: Sau 12 tuARIES-1 and 2: Sau 12 tunn

    Ambrisentan ci thin ng k:Ambrisentan ci thin ng k:

    Khong cch i b 6 phtKhong cch i b 6 pht

    Thi gian triu chng lm sng xu iThi gian triu chng lm sng xu i

    Phn loi triu chng c nng WHOPhn loi triu chng c nng WHO

    Ch s kh th gng sc BorgCh s kh th gng sc Borg

    SF-36SF-36 Health SurveyHealth Survey B-type natriuretic peptideB-type natriuretic peptide

    Galie N et al. Circulation 2008;117(23):3010-9.Galie N et al. Circulation 2008;117(23):3010-9.

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    N=132 N=127 N=115 N=94N=132 N=127 N=115 N=94N=64 N=62 N=61 N=50N=64 N=62 N=61 N=50N=130 N=124 N=119 N=98N=130 N=124 N=119 N=98N=67 N=65 N=63 N=51N=67 N=65 N=63 N=51

    PlaceboPlacebo

    2.5 mg2.5 mg5 mg5 mg

    2.5 + 5.0 mg2.5 + 5.0 mg

    7070

    8080

    9090

    100100

    00 44 88 1212WeeksWeeks

    Event-Free(%)

    Event-Free(%)

    P-values represent log-rank comparison to placeboP-values represent log-rank comparison to placebo

    71% relative risk gim71% relative risk gimtriu chng lm sngtriu chng lm sng

    xu ixu i

    CCi thini thin BDIBDI c quan st thy sau 12 tun iu trc quan st thy sau 12 tun iu tr ambrisentan so vambrisentan so viiplaceboplacebo CCi thin sau 12 tun xut hin nhm >10mgi thin sau 12 tun xut hin nhm >10mg

    AmbrisentanAmbrisentanARIES-2: ThARIES-2: Thi gian triu chng lm sng xu ii gian triu chng lm sng xu i

    Galie N et al. Circulation 2008;117(23):3010-9Galie N et al. Circulation 2008;117(23):3010-9

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    00

    1010

    2020

    3030

    4040

    5050

    00 1212 2424 3636 4848Changein6MWD

    (meters)

    Changein6MWD

    (meters)

    Trung bnhTrung bnh 95% Kho 95% Khong tin cyng tin cy

    TunTunn=383n=383 n=338n=338 n=248n=248 n=193n=193 n=146n=146

    CCithin

    ithin

    +36.4 met+36.4 met

    sau 48 tunsau 48 tun

    Ambrisentan 2.5 10 mg once dailyAmbrisentan 2.5 10 mg once daily

    Oudiz RJ, et al. Oral presentation, American Thoracic Society Annual Meeting, 2007.Oudiz RJ, et al. Oral presentation, American Thoracic Society Annual Meeting, 2007.

    ARIES-E: Test i b 6 phtARIES-E: Test i b 6 phtso vi ng c bnso vi ng c bn

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    AMB 222: ALT/AST >3xULNAMB 222: ALT/AST >3xULNNg c gan do bosentan hoc sitaxsentanNg c gan do bosentan hoc sitaxsentan

    00

    2525

    5050

    7575

    100100

    00 1212 2424 3636 4848

    TunTun

    Khngc

    binc(%)

    Khngc

    binc(%)

    N = 36N = 36 N = 34N = 34 N = 32N = 32 N = 31N = 31 N = 30N = 30

    Ch 1 bnh nhn c ALT/AST >3xULNCh 1 bnh nhn c ALT/AST >3xULN

    McGoon MD et al. Chest 2008;http://chestjournal.org/cgi/content/abstract/chest.08-McGoon MD et al. Chest 2008;http://chestjournal.org/cgi/content/abstract/chest.08-1028v1:Published online Sept 23, 2008.1028v1:Published online Sept 23, 2008.

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    Cc thuc c ch PhosphodiesteraseCc thuc c ch Phosphodiesterase

    SildenafilSildenafil Dng ung, thi gian bn hu 5 gi, 20 mg TIDDng ung, thi gian bn hu 5 gi, 20 mg TID

    Dng liu duy nht *Dng liu duy nht *

    Ci thin 6MWD, kh nng gng sc, huyt ng, ch sCi thin 6MWD, kh nng gng sc, huyt ng, ch scht lng cuc sngcht lng cuc sng

    Gy gin mch, Chy mu camGy gin mch, Chy mu cam

    c FDA khuyn co Khng hn ch trn cc mc c FDA khuyn co Khng hn ch trn cc mc phn loi triu chng c nngphn loi triu chng c nng

    **Galie N, et al. N Engl J Med. 2005;353:2148-2157.Galie N, et al. N Engl J Med. 2005;353:2148-2157.

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    Cc thuc c ch PhosphodiesteraseCc thuc c ch Phosphodiesterase

    -3.5

    -3

    -2.5

    -2

    -1.5

    -1

    -0.5

    0

    0.5

    mPAP (mmHg)

    CI (l/min/m2)

    PVR (U)

    RAP (mmHg)

    **Galie N, et al. N Engl J Med. 2005;353:2148-2157Galie N, et al. N Engl J Med. 2005;353:2148-2157

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    Test gin mch cpTest gin mch cpChng ngChng ng ++ Li tiuLi tiu ++ oxyoxy ++

    digoxindigoxin

    Chn knh caChn knh cang ungng ung

    Tip tcTip tciu triu tr

    chn knhchn knhCaCa

    Nguy c cao

    p ng kop ng kodidi

    DngDngtnhtnh

    Nguy c thp

    CC

    m tnhm tnh

    RAP cao, CI thpHuyt ngRAP v CI bnh thng/gn bnh thng

    Trn dch mng timSuy tht phi ng k

    Siu m timSuy chc nng tht phit

    Tng nhiuBNPTng t

    Ngn hn (400 m)

    IVPhn loi theo WHOII, III

    NhanhMc tin trinT t

    CBng chng lm sngca suy tht phi

    Khng

    Xc nh mc nguyc

    Chin lc iu trChin lc iu tr

    ACCP Consensus: modified from Chest, 126,1(supp), July 2004 inACCP Consensus: modified from Chest, 126,1(supp), July 2004 inMcLaughlin VV, McGoon MD. Circulation 2006;114(13):1417-31.McLaughlin VV, McGoon MD. Circulation 2006;114(13):1417-31.

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    Test gin mch cpTest gin mch cpChng ng + Li tiu +Chng ng + Li tiu +

    oxy + digoxinoxy + digoxin

    Chn CaChn Caungung

    Tip tcTip tcdung chndung chnCa ungCa ung

    Nguy c cao

    EpoprostenolEpoprostenolTreprostinilTreprostinil

    IloprostIloprostETRAETRA

    c ch PDE-5c ch PDE-5

    ETRAETRAc ch PDE-5c ch PDE-5EpoprostenolEpoprostenolTreprostinilTreprostinil

    p ng lup ng ludidi

    Dngtnh

    Nguy c thpNguy c thp

    Yes

    NoNo

    Protocol nhProtocol nhgigi

    m tnh

    nh gi li xem xt ktnh gi li xem xt kthp iu trhp iu tr

    Chin lc iu trChin lc iu tr

    ACCP Consensus: modified from Chest, 126,1(supp), July 2004 inACCP Consensus: modified from Chest, 126,1(supp), July 2004 inMcLaughlin VV, McGoon MD. Circulation 2006;114(13):1417-31.McLaughlin VV, McGoon MD. Circulation 2006;114(13):1417-31.

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    BosentanBosentan ng ungng ung && EpoprostenolEpoprostenoltruytruyn tnh mchn tnh mch::

    BREATHE-2BREATHE-2 CC xu hng ci thin xu hng ci thin

    huyt ng v lm sng,huyt ng v lm sng,nhng khng c nghanhng khng c ngha

    thng kthng k TiTiu ch nh gi u tinu ch nh gi u tin

    = TPR,= TPR, c thay i:c thay i:

    -36% bosentan-36% bosentan

    -22% placebo-22% placebo

    p = 0.08%p = 0.08%

    6MWD6MWD

    68

    74

    0

    10

    20

    30

    40

    50

    60

    70

    80

    Bosentan +

    Epoprostenol

    Placebo +

    EpoprostenolMedianChang

    efrom

    Baselinein6-minuteWal

    (m)

    Humbert M, et al. Eur Respir J. 2004;24:353-359Humbert M, et al. Eur Respir J. 2004;24:353-359

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    7575

    5050

    2525

    00

    -25-25

    -50-50

    -75-75BaselineBaseline Week 4Week 4 Week 8Week 8 Week 12Week 12

    Changefro

    mBaselinein6MWD

    Changefro

    mBaselinein6MWD

    Bosentan + Iloprost (N = 34)Bosentan + Iloprost (N = 34)Bosentan + Placebo (N = 33)Bosentan + Placebo (N = 33)

    McLaughlin VV, et al. Am J Respir Crit Care Med. 2006;174:1257-1263McLaughlin VV, et al. Am J Respir Crit Care Med. 2006;174:1257-1263

    STEP: Kh dung Iloprost phi hp Bosentan ungSTEP: Kh dung Iloprost phi hp Bosentan ung

    Nhng bnh nhn n nh khi dng bosentan ti thiu 3

    thng c la chn ngu nhin vo nhm placebo vkh dung iloprost

    An ton, ci thin 6MWD, FC, thi gian n khi triuchng lm sng xu i

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    IV Epoprostenol phIV Epoprostenol phi hpi hp Sildenafil: PACES-1Sildenafil: PACES-1

    m 95% CI

    -20

    0

    20

    40

    60

    Baseline Week 4 Week 8 Week 12 Week 16

    Placebo Sildenafil

    Changein6MWDfrom

    Baseline(m)

    *

    30.1

    4.1

    Treatment Effect 26m

    *p=0.0009

    Simonneau G et al.. Ann Intern Med 2008;149(8):521-30Simonneau G et al.. Ann Intern Med 2008;149(8):521-30

    (n = 267)

    6 Minute Walk Test6 Minute Walk Test

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    iu tr sm c tt hn khng?iu tr sm c tt hn khng?

    Galie N et al: Treatment of patients with mildly symptomatic pulmonary arterial hypertension withGalie N et al: Treatment of patients with mildly symptomatic pulmonary arterial hypertension withbosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 371:2093-100, 2008bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 371:2093-100, 2008

    Nghin cu EARLY- BosentanNghin cu EARLY- Bosentan

    vv ci thin ci thin TTCW hTTCW hnn 32 tu32 tunnp = 0.0114p = 0.0114

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    Cc thuc ang tip tc nghin cu ?Cc thuc ang tip tc nghin cu ?

    Kh dung treprostinil (TRIUMPH-1; Viveta)Kh dung treprostinil (TRIUMPH-1; Viveta) Ung treprostinil, beraprostUng treprostinil, beraprost c ch PDE5 ko di (tadalafil)c ch PDE5 ko di (tadalafil)

    Genetically modified PAECsGenetically modified PAECs c ch Tyrosine kinase (imatinib, sorafenib)c ch Tyrosine kinase (imatinib, sorafenib) c ch Rho-Kinase (fasudil)c ch Rho-Kinase (fasudil) Hot ho PPAR (rosiglitazone, pioglitazone)Hot ho PPAR (rosiglitazone, pioglitazone)

    Vasoactive intestinal peptideVasoactive intestinal peptide SSRIs, statins, aspirinSSRIs, statins, aspirin Khc CO, c ch elastase, dichloroacetateKhc CO, c ch elastase, dichloroacetate

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    The EndThe End