DEMA-CVN.

COM
GiITHIU

CC TI BO CO TI HI NGH TIM MCH MIN TRUNG- TY NGUYN M RNG LN TH VI TI BUN MA THUT THNG 8 NM 2011

CP NHT VAI TR CA CHN BTA GIAO CM QUA MT S KHUYN CO GN Y

GS.TS. NGUYN LN VIT (Vin Tim mch Vit Nam)

VAI TR CA H THN KINH GIAO CM TRONG BNH L TIM MCH

Upregulated SNS
Increased NE level
Direct Myocardial toxicity

Increased RAS

Decreased Renal blood flow

Myocyte dysfunction
Apoptosis

Increased AngII, AldoIncreased HR, PVR

Myocyte Intracellular & vasoconstriction necrosis Ca+ overload/

energy depletion

Na & water retension

Increased myocardial O2 demand

Vasconstricti on

Cardiac remodeling

CC THUC CHN BTA GIAO CM

* nh ngha : l cc thuc i khng tranh chp c hiu vi tc dng bta giao cm ca catecholamine. Vic phn loi cc thuc chn bta giao cm thng cn c vo: c ch chn lc th th 1 hay c ch khng chn lc (c ch c 1v 2)? C hot tnh ging giao cm ni ti khng? C c ch ng thi c th th v khng?

BNG PHN LOI CC THUC CHN BTA GIAO CM

c ch th th Khng c hot tnh giao cm ni ti
- Propranolol (Avlocardyl) -Sotalol (Sotalex) -Nadolol (Corgard) -Tertatolol (Artex) -Timolol (Timacor) -Carvedilol (Dilatrend) (*) -Bucindolol (*) - Labetalol (Trandate) (*)

C hot tnh ging giao cm ni ti

Alprenolol (Aptin) Carteolol (Carteol) Oxprenolol (Trasicor) Penbutolol (Levatol) Pindolol (Visken) Bopindolol (Sandonorm)

1 + 2

1 (chn lc cho tim)

Atenolol (Tenormine) Betaxolol (Kerlone) Bisoprolol (Concor) Metoprolol (Betaloc)

Acebutolol (Sectral) Esmolol (Brevibloc) Xamoterol Celiprolol (Celectol) (*)

(*)c ch c th th v

TNH CHN LC TRN TH TH 1

100 75 75/ 1

B1/B2 Selectivity Ratios

50 25 0 1/25 1/ 50 1/ 300 1/ 2 20/ 1

35/ 1

35/ 1

Propranolol Atenolol Bisoprolol Metoprolol Betaxolol

1/300
ICI 118,551

Wellstein et al Europ Heart J 1987

NG O THI CHN BTA

TL : Opie LH. Drugs for the Heart. WB Saunders 2005, 6th ed, p.21

TC NG CA THUC CHN BTA GIAO CM TRN H TIM MCH

Lm tnh t ng ca nt xoang cng nh cc ch nhp tim tng khc lm cc p ng giao cm ca c th khi phi gng sc hoc b Stress lm cho huyt p khng b ln t ngt. Lm tnh dn truyn nh, tht v nt nh - tht lm nhp tim chm li. Lm tnh kch thch, ko di thi k tr c hiu lc ca nt nh - tht thuc c xp vo nhm II ca cc thuc chng lon nhp.

TC NG CA THUC CHN BTA GIAO CM TRN H TIM MCH (Tip)

Lm sc co bp ca c tim cng ca tim mc

tiu th xy ca c tim C li cho BN b thiu nng vnh.

Lm HA M : Do cung lng tim gim. Do c ch vic gii phng Renin v lm hot tnh

Renine huyt tng.

Do tng tit Prostacyclin gin mch, gy sc cn

ngoi vi.

NHNG TC DNG KHNG MONG MUN CA THUC CHN BTA GIAO CM

Sc co bp c tim. Lm nhp tim chm li. Lm tng Bloc nh - tht. Lm nh Triglycerid mu v nh HDL-C (cc thuc c

hot tnh ging giao cm ni ti t b nh hng ny).

Co tht ph qun (Loi chn bta khng chn lc) nh ng mu (do phn hu Glycogne gan v c

ch Glucagon).
khng Insulin c th dn ti tiu ng. i khi gy ra hin tng Raynaud.

 Blockers TRONG IU TR TNG HUYT P

VAI TR CA THUC CHN BTA GIAO CM TRONG IU TR THA

Gim HA r rng . Gim cc bin chng do THA (ph i tht tri, TBMN,

NMCT, suy tim...).

Gim t l t vong ni chung.

- Nhiu N/C nh IPPPSH, MAPHY, HAPPHY, STOP, SHEP... chng minh c rng cc thuc chn bta giao cm c cc tc dng ni trn.

Nghin cu MAPHY *(Metoprolol Atherosclerosis Prevention in Hypertensives study): N/C trn 3.234 BN b THA, tui t 40-64, Cc BN c chia lm 2 nhm: - Dng Metoprol - Dng Thiazid Kt qu: so vi nhm dng Thiazid th nhm dng Metoprolol : hn hn cc yu t nguy c v tim mch (p=0,001) T l t vong ni chung (p=0,028) T l t vong do nguyn nhn tim mch (p=0,012) T l t vong do bnh mch vnh (p=0,048) T l t vong do t qu (p=0,043)

(*) Am.J. Hypertens, 1991; 4: 151-158

HNG DN IU TR THA

JNC-7 (2003) JNC-8 (2012 ?)

ESH/ESC Hypertension Guidelines (2003) ESH/ESC Reappraisal Hypertension Guidelines (2009)

BHS NICE (2006)

Canadian Hypertension Education Program Recommendations (2009)

KHUYN CO IU TR TNG HUYT P

The controversy: Use of -blockers as first-line therapy in hypertension (?)

NICE UK guidelines 20061 -blockers considered less effective than other groups of antihypertensives at reducing major CV events, particularly stroke -blockers NOT a preferred initial therapy for hypertension unless with additional indication
CV, cardiovascular 1. NICE Clinical Guidelines. Hypertension.Management in adults in primary care: pharmacological update. 16 2004 Available at: www.nice.org.uk

KHUYN CO CHNG TRNH GIO DC THA CA CANADA

ch <140/90 mmHg
Thay i li sng
Nu HATTh >20 mmHg hay HATTr >10 mmHg trn gi tr ch xem xt dng 2 thuc t u

Khi u iu tr

Thiazide diuretic

ACEI

ARB

Long- acting CCB

Betablocker*

Xem xt Khng tun th THA th pht Tng tc thuc hay li sng THA o chong trng

iu tr 2 thuc
*Khng ch nh nh l liu php bc mt cho BN trn 60t.

Dng 3 hay 4 thuc

2009 Canadian Hypertension Education Program Recommendations

Thuc chn c u tin chn la trong THA c km: - au tht ngc - Sau nhi mu c tim - Suy tim - Nhp tim nhanh - Tng nhn p - C thai

ESH/ES
Condition

nh gi li hng dn iu tr tng huyt p ca Hip hi tng Huyt p chu u 2009

CHN LA THUC IU TR TNG HUYT P

5 nhm thuc h p: Li tiu, Chn , c ch men chuyn, c ch th th angiotensin, c ch canxi Khng khc nhau v kh nng h HA u thch hp l mt trong nm la chn u tin iu tr tng huyt p.

Hng dn iu tr Tng Huyt p ca Chng trnh Gio dc Tng HA Canada 2010

Asian regional guidelines

Majority of Asian country guidelines consider -blockers an appropriate first-line option in treating hypertension18 Most commonly used -blockers: atenolol, bisoprolol, carvedilol, metoprolol, and nebivolol -blockers used for long-term treatment of hypertension indefinitely, within recommended dosing ranges, unless contraindicated

1. Chinese Medical Association and Chinese Society of Cardiovascular Diseases. The expert consensus: The use of beta-blockers in patients with cardiovascular diseases, March 2009 [Chinese]. 2. India (CSI), Indian College of Physicians (ICP), Hypertension Society of India (HSI). Indian Hypertension Guidelines II 2007; Available at http://www.apiindia.org/hypertension_guideline.php. 3. Indonesian Society of Hypertension. Hypertension management 2007 [Bahasa Indonesia], 4. The Korean Society of Hypertension. 2004 Korean Hypertension Treatment Guidelines [Korean]. Available at http://www.koreanhypertension.org/notice/view.php? codetguide&page1&number106&keyfield&key [Last accessed 4 November 2010] 5. Ministry of Health Malaysia, Academy of Medicine of Malaysia, Malaysia Society of Hypertension. Clinical Practice Guideline: Management of Hypertension 2008 Available at http://www.acadmed.org.my/index.cfm?& menuid67#Cardiovascular_Disease. [Last accessed 4 November 2010]. 6. Multisectoral Task Force on the detection and management of hypertension. Philippine J Intern Med 1997;35:67-85. 7. Philippine Society of Hypertension. The 140/90 report 2009 (in press). 8. Ministry of Health Singapore, MOH Clinical Practice Guidelines 2/2005. Hypertension, 2005

KHUYN CO V S DNG CHN CA HI TNG HUYT P MT S NC CHU

Guidelines Chinese Expert Consensus1 Recommendations

-blockers are recommended as first line treatment, for long-term treatment, as monotherapy and in combination -blockers are recommended for ACS with hypertensive emergencies and severe uncontrolled chest pain Adapted from JNC 7, ESH/ESC guidelines Any of the 5 drug classes are recommended as first-line treatment Use of compelling indication Target BP < 140/90 mmHg or < 130/80 mmHg in diabetic patients or those with kidney disease

Indian Society of Hypertension Guidelines2

Indonesian Society of Refer to JNC 7 Hypertension All antihypertensive drug classes are recognized as a first-line option Consensus 20073 Use of compelling indications

Combination therapy for BP 160/100 mmHg Target BP of < 140/90 mmHg or < 130/80 mmHg in diabetic patients and patients with renal failure Similar to JNC 7, ESH/ESC guidelines -blockers are considered as as a first-line option for hypertension

Korean Society of Hypertension Guidelines 20044

1. Chinese Medical Association and Chinese Society of Cardiovascular Diseases.The expert consensus: The use of beta-blockers in patients with cardiovascular diseases, March 2009 [Chinese]. 2. India (CSI), Indian College of Physicians (ICP), Hypertension Society of India (HSI). Indian Hypertension Guidelines II 2007; Available at http://www.apiindia.org/hypertension_guideline.php 3..Indonesian Society of Hypertension. Hypertension management 2007 [Bahasa Indonesia] 4. The Korean Society of Hypertension. 2004 Korean Hypertension Treatment Guidelines [Korean]. Available at http://www.koreanhypertension.org/ [Last accessed 4 November 2010]

KHUYN CO V S DNG CHN CA HI TNG HUYT P MT S NC CHU (tip)

Guidelines Recommendations

Malaysian Clinical Four classes of antihypertensive agents except -blockers are recommended Practice Guideline on as first-line in newly Hypertension 20081 diagnosed, uncomplicated hypertensives with no compelling indication

Combination therapy for systolic BP160 and/or diastolic BP100 mmHg Target BP on therapy <140/90 mmHg for all and < 130/80 mmHg for diabetics Drug of choice for compelling indications listed

Philippine Society of Initiate medical treatment if hypertensive (regardless of risk classification) Hypertension2,3 Focus on BP control

All antihypertensive drug classes recognized

Singapore MOH Guidelines 20054

All 5 drug classes recognized as first-line option Use compelling indications, contraindications Combination therapy for BP160/100 mmHg Target BP < 140/90 mmHg Lower BP target of < 130/80 mmHg for diabetics and renal failure No prehypertension classification

1. Ministry of Health Malaysia, Academy of Medicine of Malaysia, Malaysia Society of Hypertension. Clinical Practice Guideline: Management of Hypertension 2008 Available at http://www.acadmed.org.my/index.cfm?&menuid67#Cardiovascular_Disease. [Last accessed 4 November 2010]. 2. Multisectoral Task Force on the detection and management of hypertension.Philippine J Intern Med 1997;35:67-85. 3. Philippine Society of Hypertension. The 140/90 report 2009 (in press) 4. Ministry of Health Singapore, MOH Clinical Practice Guidelines 2/2005. Hypertension, 2005

CHN BTA TRONG IU TR BNH TIM THIU MU CC B

CH NH THUC CHN TRONG BNH TIM THIU MU CC B

au tht ngc n nh. Hi chng mch vnh cp : au tht ngc khng n nh. NMCT khng c ST chnh ln NMCT c ST chnh ln.

HNG DN IU TR NI KHOA BNH AU THT NGC N NH

KHUYN CO S DNG CHN BTA TRONG BNH TIM THIU MU CC B

Jos Lopz-Sendon. European Heart Journal 2004: 25, 1341-1362

CHN BTA TRONG BNH TIM THIU MU CC B MN TNH

Tt c bnh nhn thiu mu c tim n nh mn tnh nn c iu tr di hn chn kim sot thiu mu c tim cc b, ngn nga nhi mu c tim v ci thin t l sng cn. Nhm I, mc chng c A bnh nhn c nhi mu c tim trc . kim sot thiu mu c tim (chng c A), ngn nga nhi mu c tim (chng c B), ci thin sng cn (chng c C) vi nhng trng hp khng c nhi mu c tim trc .
Jos Lopz-Sendon. European Heart Journal 2004: 25, 1341-1362

Total Ischaemic Burden Bisoprolol Study Total Ischaemic Burden Bisoprolol Study

T II B B S T BBS

Nghin cu ngu nhin, m i ,c i chng vi hai nhm song song

Mc tiu:

nh gi hiu qu ca Bisoprolol v Nifedipine phng thch chm ln tn sut v phn b cc cn thiu mu c tim cc b bnh nhn au tht ngc n nh.

von Arnim Th et al. JACC 1995; 1: 231230

NGHIN CU HIU QU CA CONCOR (Bisoprolol) LN TNG GNH THIU MU C TIM.

N=330 bnh nhn c CTN n nh. 30 trung tm/ 7 quc gia Chu u. Nghin cu m i ngu nhin c i chng gia hai nhm song song. Nhm Bisoprolol 10 20 mg/ngy, nhm Nifedipine 20 -40mg/ngy.

TIBBS: THIT K NGHIN CU

20 mg o.d. Bisoprolol Gi dc 10 mg o.d. Bisoprolol 20 mg b.i.d. Nifedipine s.r. 40 mg b.i.d. Nifedipine s.r. 4 tun 4 tun

10 ngy C tin s thc hin Nghim php gng sc Holter

Nu c 2 cn thiu mu s c chn a vo iu tr Holter Holter

von Arnim Th et al. JACC 1995; 1: 231238

TIBBS: Concor GIP GIM S CN THIU MU HIU QU HN SO VI Nifedipine s.r.

No./48 h 10 8 6 4 2 0
Baseline 10 mg 20 mg Baseline 20 mg 40 mg

Bisoprolol o.d. (n = 111)

x SEM
von Arnim Th et al. JACC 1995; 1: 231238

Nifedipine s.r. b.i.d. (n = 112)

TIBBS : LM GIM TNG THI GIAN CC CN THIU MU C TIM

(Pht)

120 90 60 30 0 Mc ban au mg 10

20 mg Mc ban au mg 40 mg 20 Bisoprolol 1 lan/ngay Nifedipine s.r. 2 lan/ngay (n =111) (n = 112) X SEM

Ref.: Von Arnim Th et al. JACC 1995; 1: 231-238

TIBBS: LM GIM NHIU CC CN AU THT NGC VO C BUI SNG V BUI CHIU

S cn/bnh nhn/gi 0.45

Baseline (n = 111) Bisoprolol 10 mg o.d. Baseline (n = 112) Nifedipine s.r. 20 mg b.i.d.

0.30

68%

0.15

0.00 1 4 8 12 16 20 24 time of day

von Arnim Th et al. JACC 1995; 1: 231238

T II B B S Follow-up T B B S Follow-up
Theo di 1 nm sau nghin cu TIBBS Mc tiu: nh gi t l cc bin c trn 2 nhm nghin cu.

von Arnim Th et al. JACC 1996; 1: 2024

TIBBS Follow-up: Concor gip tng t l BN sng khng bin c nhiu hn Nifedipine s.r.
T l BN sng khng bin c
1.0 0.9 Bisoprolol (n = 154) 0.8 0.7 Nifedipine s.r. (n = 163) 0.6 0.5 0 50 100 150 200 250 log-rank test p = 0.0197 300 350 400 days

% bin c trong nhm bisoprolol:22,1% % bin c trong nhm nifedipine s.r : 33,1%

von Arnim Th et al. JACC 1996; 1: 2024

THUC CHN BTA GIAO CM TRONG NMCT CP : C NN CHO SM NGAY SAU B NMCT KHNG ?

THIT K NGHIN CU: COMMIT

Tiu chun la chn: nghi ng NMCT trong vng 24h k t khi au (c ST chnh ln hoc bloc nhnh tri hon ton) Tiu chun loi tr: Sc tim, HATT < 100 mmHg, nhp tim < 50ck/pht hoc bloc NT cp II/III. iu tr: truyn TM 15 mg Metoprolol trong 15 pht, sau ung 200mg/ngy. Tiu ch nh gi: t l t vong, ti NMCT, rung tht, ngng tim trong vng 4 tun trong bnh vin hoc trc khi ra vin. Thi gian iu tr trung bnh l: 16 ngy.

NHN XT RT RA T NGHIN CU COMMIT

Sau NMCT cp, thuc chn bta giao cm :

C li ch lu di kh r: T l ti NMCT T l rung tht c 5/1000 BN

Nhng khng lm thay i t l t vong ti Vin. Nu cho chn bta giao cm qu sm (trong ngy th 1 hoc th 2 sau NMCT) th c th lm tng nguy c sc tim (tng 11/1000 BN), vi p< 0,0001.

-blockers TRONG IU TR SUY TIM

VAI TR CA CC THUC CHN BTA GIAO CM TRONG IU TR SUY TIM

Trc y: cc thuc chn bta giao cm l chng ch nh tuyt i trong trng hp suy tim. Gn y c nhiu nghin cu cho thy c mt s thuc chn bta giao cm c hiu qu trong iu tr suy tim:
1. Metoprolol: Th nghim MDC, MERIT. 2. Bisoprolol: Th nghim CIBIS, CIBIS II. 3. Carvedilol: Th nghim OPERNICUS, PRECISE.

NGHIN CU CIBIS II
Nghin cu trn 2.647 bnh nhn b suy tim vi NYHA III hoc

IV.
Phn s tng mu (EF 35%). Tui t 18-80. u c iu tr bng CMC v li tiu. Chia ra 2 nhm :

Dng Bisoprolol (n=1.327). Dng gi dc (n= 1.320).

Liu Bisoprolol c tng dn t : 1,25--> 2,5--> 3,5-->5 -->5,75

v ti a l 10mg/ngy.
Thi gian theo di trung bnh l 1,3 nm.

KT QU NGHIN CU CIBIS II
Thng s theo di Nhm dng Bisoprolol 156 (11%) Nhm dng gi dc 228 (17,3%) P

T vong do mi nguyn nhn T vong do nguyn nhn v Tim mch Phi nhp Vin v bt c l do g. t t

0,0001

119 (9%)

161 (12%)

0,0049

440 (33%)

513 (39%)

0,0006

48 (4%)

83 (6%)

0,0011

Betablockers in HF: all-cause mortality

Survival % 1.0

US Carvedilol Program
Carvedilol

Survival % 100 90

COPERNICUS
Carvedilol

0.9

N=1094
0.8 0.7 0.6 0.5

Placebo (n=398)

80 70 60 50 0

N=2289

Risk reduction=65%
p<0.001

Risk reduction=35%
p=0.00014

Placebo

0 50 100 150 200 250 300 350 400 days

12

16

20

24

28 months

Survival % 1.0

Mortality %

CIBIS-II
Bisoprolol

20

MERIT-HF N=3991
Placebo

N=2647
0.8

15

Placebo
0.6 0 0 200 400 600 800 days

10 5

Metoprolol CR/XL

Risk reduction=34%
p<0.0001

Risk reduction=34%
p=0.0062
0 3 6 9 12 15 18 21 months

Nghin cu CIBIS III: Bisoprolol (Concor ) c th s dng trc UCMC trong iu tr suy tim NYHA II cho hiu qu & an ton tng ng UCMC

CIBIS III : Bisoprolol-first gim 46% T T trn bnh nhn suy tim sau nm u tin
% t t
10 8

Bisoprolol-first vs enalapril-first: 16 versus 29 sudden deaths; HR 0.54; 95% CI 0.29-1.00; P=0.049 2.6% ARR
Enalapril-first Bisoprolol-first

46%

N at risk0 505 505

3 481 485

6 467 473

9 440 452

Time 12 (months) 373 384

MT S IM CN CH KHI S DNG CHN BTA GIAO CM TRONG IU TR SUY TIM

Ch dng khi BN c iu tr nn bng (li tiu, CMC, Digoxin, ) v khng cn cc du hiu dch (ph, gan to, trn dch cc mng, ) Khng dng cho cc trng hp c:
- Hen ph qun, bnh phi tc nghn mn tnh, nhp tim

chm, suy nt xoang, )

Phi bt u t nhng liu rt nh, sau mi t t tng

dn liu lng. Mi ch c mt s thuc chn bta giao cm c dng trong iu tr suy tim thi (Metoprolol, Bisoprolol, Carvedilol).

TNH CHN LC TRN TH TH 1

100 75 / 75 1

B1/B2 Selectivity Ratios

50 25 0 1/25 1/ 1/ 50 1 /300
ICI 118,551

35 / 20 / 1/ 2
Propranolol Metoprolol

35 /

Atenolol Betaxolol

Bisoprolol

300

Wellstein et al Europ Heart J 1987

NH HNG CA CC THUC CHN KHC NHAU TRN HDL - CHOLESTEROL

+10

% HDL-cholesterol

0 -10 -20 -30 -40 6 *p<0.05 **p<0.01 12 18 24 30 36

Mepindolol 10 mg/day (n=16) Bisoprolol 10 mg/day (n=17) Propranolol 160 mg/day (n=15) Atenolol 100 mg/day (n=22)

** **

**

** **

** **

**

**

vs baseline

Fogari R et al. J Cardiovasc Pharmacol 1990;16 (Suppl 5):S7680

months

NH HNG CA BISOPROLOL TRN CHUYN HA NG HUYT CA BNH NHN I THO NG TYPE 2

Glucose
170 160 150 140 9 8 10

HbA1c

(mg/dL)

120 110 100 A B C (PCB >0.05)

(%)
7 6

130

A B C (PCB >0.05)

A: initial value n=20 XSEM

B: after 2 weeks C: after 2 weeks of bisoprolol of placebo

Janka HU et al. J Cardiovasc Pharmacol 1986;8(Suppl. 11):9699

NH HNG CA Beta Blockers TRN HDL-Cholesterol

+10 % HDL0 cholesterol -10 -20 -30 -40 6

Mepindolol Bisoprolol

** **

** **
12 * p < 0.05 ** p < 0.01

** **
18

** **
24

** **
30

Propranolol Atenolol

36 months

} vs. baseline
Fogarl et al 1980

NH HNG CA beta-blocker TRN CHC NNG TNH DC SO VI placebo

Beta-blocker Sexual dysfunction - % increase vs placebo 13.5 5.0 Reference

Carvedilol Propranolol

Fogari R et al 2001 MRC-Mild Hypert 1985

Atenolol

3.0

Silvestri A et al 2003

Bisoprolol

0.0

Broekman CP et al 1992

VAI TR CA CHN BTA TRONG MT S BNH L KHC

Chn c hiu qu tt trong: 1. Ri lon thn kinh thc vt kiu cng giao cm. 2. Phi hp iu tr trn bnh nhn cng gip. 3. Mt s ri lon nhp tim: nhanh xoang, nhp xoang trn tht, 4. Bnh c tim ph i tc nghn. 5. Tch thnh ng mch ch. 6. Phng nga cc bin c chu phu hay cc phu thut ngoi tim cc bnh nhn tim mch.

KHUYN CO V CH NH THUC CHN TRONG IU TR BNH L TIM MCH TI MT S NC CHU

B. Tomlinson v CS. CMRO, Vol 27, No 5, 2011

KT LUN
Cc thuc chn bta giao cm ng vai tr quan trng trong iu tr nhiu bnh l tim mch, c bit l trong:
THA Bnh tim TMCB (l thuc iu tr nn)

- au tht ngc n nh. - Hi chng mch vnh cp. - Sau NMCT.

 Suy tim: l iu tr b sung cn thit khi iu tr nn p

dng, song cn tn trng cc chng ch nh v bt u t nhng liu rt nh.

Mt s lon nhp tim; Bnh c tim ph i. Phng nga cc bin c chu phu hay cc phu thut ngoi

tim cc bnh nhn tim mch ./.

XIN CM N