Beta blockers activity of drugs with side effects

B blockers

1. Efficacy of Beta Efficacy of Beta
--
Blockers for  Blockers for 
First First
--
lineline
Antihypertensive;  Antihypertensive; 
All Beta All Beta
--
Blockers Same? Blockers Same?
연세대학교 연세대학교 연세대학교 연세대학교 연세대학교 연세대학교 연세대학교 연세대학교
원주의과대학 원주의과대학 원주의과대학 원주의과대학 원주의과대학 원주의과대학 원주의과대학 원주의과대학
순환기순환기순환기순환기순환기순환기순환기순환기
내과내과내과내과내과내과내과내과
유유유유유유유유
병수병수병수병수병수병수병수병수

2. Efficacy of Beta Efficacy of Beta
--
Blockers for  Blockers for 
First First
--
lineline
Antihypertensive;  Antihypertensive; 
All Beta All Beta
--
Blockers Same? Blockers Same?
►►
Current issue with beta Current issue with beta
--
blocker in   blocker in  
Hypertension Hypertension
►►
Comparisons between old and new  Comparisons between old and new  drugs drugs
►►
Logical Practice Logical Practice
ficcay oBeeia

3. Meta-analysis of 61 prospective, observational studies
One million adults, 12.7 million person-years
2 mmHg 
decrease in 
mean SBP
10% reduction in risk of stroke 
mortality
7% reduction in risk of 
ischaemic 
heart disease 
mortality
Lowering blood pressure  Lowering blood pressure 
reduces cardiovascular risk reduces cardiovascular risk
Lewington et al. Lancet.2002;360:1903–1913
Small SBP reductions yield significant benefit Small SBP reductions yield significant benefit
etaa-nlysiit-

4. 0.5 1.0 2.0
Comparisons of Different  Comparisons of Different 
Drugs Drugs
Relative Risk
RR (95% CI) RR (95% CI)
BP Difference BP Difference
(mm Hg) (mm Hg)
Favors Favors
First Listed First Listed
Favors Favors
Second Listed Second Listed
Major CV events Major CV events CV mortality CV mortality Total mortality Total mortality
1.02 (0.98, 1.07) 1.02 (0.98, 1.07)
2/02/0
ACEI vs D/BB ACEI vs D/BB
1.03 (0.95, 1.11) 1.03 (0.95, 1.11)
2/02/0
ACEI vs D/BB ACEI vs D/BB
1.00 (0.95, 1.05) 1.00 (0.95, 1.05)
2/02/0
ACEI vs D/BB ACEI vs D/BB
1.04 (0.99, 1.08) 1.04 (0.99, 1.08)
1/01/0
CA vs D/BB CA vs D/BB
1.05 (0.97, 1.13) 1.05 (0.97, 1.13)
1/01/0
CA vs D/BB CA vs D/BB
0.99 (0.95, 1.04) 0.99 (0.95, 1.04)
1/01/0
CA vs D/BB CA vs D/BB
0.97 (0.92, 1.03) 0.97 (0.92, 1.03)
1/11/1
ACEI vs CA ACEI vs CA
1.03 (0.94, 1.13) 1.03 (0.94, 1.13)
1/11/1
ACEI vs CA ACEI vs CA
1.04 (0.98, 1.10) 1.04 (0.98, 1.10)
1/11/1
ACEI vs CA ACEI vs CA
Blood Pressure Lowering Treatment  Blood Pressure Lowering Treatment 
Trialists Trialists
’’
Collaboration. Lancet. 2003;362:1527 Collaboration. Lancet. 2003;362:1527
--
1535. 1535.
s FnacaoAacao
no significant differences
hyo p v;oSvmpco?vcChpuve?i;vco
auay eowa AaayocabhSayeowveaCopyoHfdohynhwh pcego?v;?hiSovy vbpyhe ego
pcoChica h?eopcoow;p?Lace-o
s Fcav Say oAh novyPo?pSSpy;PDieaCocabhSayocaCi?aeo naocheLopRo p v;o
Svmpco?vcChpuve?i;vcoauay egovyC
larger reductions
hyow;ppCo(caeeicao
(cpCi?ao;vcbacocaCi? hpyeohyocheL-
ficcay oBeeia

5. Current Issue Current Issue
►►
Atenolol Atenolol
hyonP(ac ayehpy9oheoh ovoAheao hyonP(ac ayehpy9oheoh ovoAheao
choice? choice?
Carlberg Carlberg
%goIvy?a -ortt)oMjV)9kVT) %goIvy?a -ortt)oMjV)9kVT)
$$
9.9.
►►
.npi;Cowa v .npi;Cowa v
$$
w;p?LaceocaSvhyoRhce o?nph?ao w;p?LaceocaSvhyoRhce o?nph?ao
hyo nao cav Say opRo(chSvcPonP(ac ayehpy5oo hyo nao cav Say opRo(chSvcPonP(ac ayehpy5oo HoSa v HoSa v
$$
analysis. analysis.
Lindholm Lindholm
I0gooIvy?a orttlMjVV9kl)l I0gooIvy?a orttlMjVV9kl)l
$$
lj-olj-o
►►
2po%a v 2po%a v
$$
w;p?Laceo0vuaovo8p;aohyo w;p?Laceo0vuaovo8p;aohyo
0P(ac ayehpyoHyPoIpybac5 0P(ac ayehpyoHyPoIpybac5
0aycPo%;v?Lgo 0aycPo%;v?Lgo
Medscape Medscape
,aCh?v;o7aAeoHibie okkgorttVo ,aCh?v;o7aAeoHibie okkgorttVo

6. 0.910.91
––
1.211.21
1.051.05
MIMI
1.021.02
––
1.141.14
1.081.08
AllAll
--
cause mortality  cause mortality 
1.151.15
––
1.381.38
1.261.26
Stroke  Stroke 
95% CI 95% CI
Relative risk  Relative risk  with atenolol   with atenolol  
Outcome  Outcome 
Lindholm LH, et al. Lancet2005
Atenolol vs. other  Atenolol vs. other  antihypertensives antihypertensives
etaa-nlysiit-

7. 0.0
1.0
2.0
3.0
4.0
5.0%
Amlodipinel±±±±perindopril 
0.0 1.0 2.0
Atenolol±±±±thiazide
3.0 4.0 5.0Years
23%
0 180 360 540 720 900 1260 1440 1620 1980 1080 1800
Losartan
Atenolol
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
. iCPo2vP
25%
ββββββββ
--
Blockers vs.  Blockers vs. 
Fatal/Nonfatal Stroke Fatal/Nonfatal Stroke
ficcay oBeeia

8. ►►
–p?iehybo(chSvch;Popyo –p?iehybo(chSvch;Popyo headhead
--
toto
--
headhead
?pS(vchepyeo ?pS(vchepyeo
►►
Fnao(chy?h(v;oaRRh?v?Po Fnao(chy?h(v;oaRRh?v?Po outcomes outcomes
Mo,Bgoe cpLao Mo,Bgoe cpLao
vyCov;; vyCov;;
$$
?vieaoSpc v;h P- ?vieaoSpc v;h P-
►►
%a?vieaopRo naoaRRh?hay?Po %a?vieaopRo naoaRRh?hay?Po pRopRo
betabeta
blocker blocker
$$
wveaCo wveaCo
 cav Say ov ocaCi?hybo  cav Say ov ocaCi?hybo ?vcChpuve?i;vcoauay ego ?vcChpuve?i;vcoauay ego ae(a?hv;;Po ae(a?hv;;Po
stroke stroke
..
How was the guideline developed?  How was the guideline developed? 
(Why do rapid update?)   (Why do rapid update?)  
ficcay oBeeia

9. BHS/NICE Guideline on Treatment of  BHS/NICE Guideline on Treatment of 
Hypertension in Adults in Primary Care Hypertension in Adults in Primary Care
< 55 years old
> 55 years old;
Blacks of any age
A
C or D
(A + C) or (A + D)
A + C + D
. a(ok
. a(or
. a(oj
ficcay oBeeia

10. ►►
Are all beta blockers equally  Are all beta blockers equally  ineffective? ineffective?
►►
Other beta blockers might give  Other beta blockers might give  different results. different results.
Efficacy of Beta Efficacy of Beta
--
Blockers for First Blockers for First
--
lineline
Antihypertensive;  Antihypertensive; 
All Beta All Beta
--
Blockers Same? Blockers Same?
ficcay oBeeia

11. Efficacy of Beta Efficacy of Beta
--
Blockers for First Blockers for First
--
lineline
Antihypertensive;  Antihypertensive; 
All Beta All Beta
--
Blockers Same? Blockers Same?
►►
Current issue with beta Current issue with beta
--
blocker in   blocker in  
Hypertension Hypertension
►►
Comparisons between old and new  Comparisons between old and new  drugs drugs
►►
Logical Practice Logical Practice

12. Selectivity of  Selectivity of 
ββββββββ
--
Blocking Agents Blocking Agents
1#L&saJuay tB aygsaypl
β
1
receptors
β
2
receptors
α
1
receptors
Cardiotoxicity
β
1
$selective
blockade
β$nonselective
blockadeβ
1
!tβ
2
!tα
1
blockade
i2:!t5o!t2m6!t35!tolnr.ylt4unynasl u
)cynapHt54btCirculationbtdDDD,MDM'ee/$e.0
Comparison

13. Potential Cardiovascular Benefits Potential Cardiovascular Benefits
of of 
ββββββββ
--
Blockade Blockade
►►
AntiAnti
$$
atherogenic atherogenic
CC
4uEr untyl%.sLLsaypl!tnJusctnacunn!tulEpaJu.ys.t 4uEr untyl%.sLLsaypl!tnJusctnacunn!tulEpaJu.ys.t E#n%rl aypl!tslEt.unyplt&cp=cunnypl E#n%rl aypl!tslEt.unyplt&cp=cunnypl
►►
AntiAnti
$$
arrhythmic arrhythmic
CC
3u cusnunt24tslEtn#L&saJuay ts aygya# 3u cusnunt24tslEtn#L&saJuay ts aygya#
CC
4uEr untnrEEultEusaJtcyn" 4uEr untnrEEultEusaJtcyn"
►►
AntiAnti
$$
ischemic ischemic
CC
3u cusnunt24tslEt)< 3u cusnunt24tslEt)<
CC
<cp.pl=ntEysnap.ut=%y..yl=t pcplsc#tscaucyun> <cp.pl=ntEysnap.ut=%y..yl=t pcplsc#tscaucyun>
►►
Cardio Cardio
$$
protective protective
CC
4ugucnunt scEys tcuLpEu.yl= 4ugucnunt scEys tcuLpEu.yl=
CC
<cugulant2: <cugulant2:
mnu [email protected] MedbtM00+,MM'M-9$M++b
Comparison

14. ►
β1$Selectivity
►
By chyeh?oePS(v npShSa h?v? huh Popco
(vc hv;ovbpyhe ov? huh Po
►
.p;iwh;h Pgoa;hShyv hpygovyCoCicv hpyopRoo
effects
►
fpSwhyaCoαgoβDvCcayacbh?ow;p?Lhybov? huh P
►
d6 ayCaCDca;aveao(ca(vcv hpye
ββββββββ
--
Blockers : Pharmacological Effects  Blockers : Pharmacological Effects 
Comparison

15. ββββββββ
--
Blocking Agents ; Classification Blocking Agents ; Classification
Comparison

16. Properties of selected  Properties of selected 
ββββββββ
--
blockers blockers
Comparison

17. Bisoprolol Bisoprolol
►►
BetaBeta
$$
koca?a( pcoea;a? hua koca?a( pcoea;a? hua
EE
7povCuaceaoaRRa? opyo;h(hCoSa vwp;heS 7povCuaceaoaRRa? opyo;h(hCoSa vwp;heS
EE
7povCuaceaoaRRa? opyob;i?peaoSa vwp;heS 7povCuaceaoaRRa? opyob;i?peaoSa vwp;heS
►►
%a  aco nvyo %a  aco nvyo
atenolol atenolol
MoveobppCoveoyaAacooooo MoveobppCoveoyaAacooooo
drugs drugs
►►
%a  acor)onpico?puacvba %a  acor)onpico?puacvba
►►
.ie vhyaCo%Oo?py cp;opuaco;pybo acS .ie vhyaCo%Oo?py cp;opuaco;pybo acS
►►
7poeiCCayo?nvybaeoCichyboa6ac?hea 7poeiCCayo?nvybaeoCichyboa6ac?hea
Comparison

18. Carvedilol Carvedilol
►►
βDvyCoαkDvCcayacbh?o
ca?a( pcow;p?Lac ►
Op ay ovy hp6hCvy oaRRa? oM
ktDRp;CoSpcao(p ay o nvyo<h Dd ►
%;p?Leo nao(cpCi? hpyopRo
angiotensinII ►
.i((caeeaeo naoePy naeheopRo
endothelin ►
Antiproliferativeactivity
Comparison

19. Nevibolol
►
7awhup;p;heovouvepCh;v hybβDw;p?Lacgo
uvepCh;v hybaRRa? oSaChv aCowPo nao
ayCp na;hv;o7>o(v nAvPg
►►
%Oo;pAachyboaRRa? oheo;hyLaCo povocaCi? hpyohyo
O<8o
►
dyCp na;hiSDCachuaCo7>9o naocabi;v hpyo
pRo;vcbaovc achv;oe hRRyaeeo
Comparison

20. Do Do 
ββββββββ
--
blockers differ in their blockers differ in their
efficacy and safety in  efficacy and safety in 
Hypertension Hypertension
??
►►
ββββββββ
blockers differ in their pharmacological  blockers differ in their pharmacological 
properties properties
►►
ββββββββ
blockers differ in their clinical effects blockers differ in their clinical effects
::
Atenolol Atenolol
, , 
MM
etoprolol etoprolol
, , 
BB
isoprolol isoprolol
,,
CC
arvedilol arvedilol
, , 
Nevibolol Nevibolol
, , 
Comparison

21. Why not Beta Blocker? Why not Beta Blocker?
►►
Major Reason 1: Major Reason 1: EE
hy?caveaCocheLopRo hy?caveaCocheLopRo
newnew
--
onset diabetes onset diabetes
gogo
ae(a?hv;;PoAnayoieaCohyo?pSwhyv hpyoAh no ae(a?hv;;PoAnayoieaCohyo?pSwhyv hpyoAh no thiazide thiazide
diuretic diuretic
►►
Major Reason 2: Major Reason 2: EE
?pS(vcaCoAh nop nacovbay ego%%obayacv;;Po;aeeo ?pS(vcaCoAh nop nacovbay ego%%obayacv;;Po;aeeo aRRa? huaohyocaCi?hybo?vcChpuve?i;vcoauay ego aRRa? huaohyocaCi?hybo?vcChpuve?i;vcoauay ego ae(a?hv;;Po ae(a?hv;;Po
stroke stroke
..
Comparison

22. ►►
Are all beta blocker equally  Are all beta blocker equally  ineffective? ineffective?
►►
Other beta blocker might give  Other beta blocker might give  different results. different results. Soft Endpoint : Metabolic Effect, DM Soft Endpoint : Metabolic Effect, DM Hard Endpoint : Stroke or CVD Hard Endpoint : Stroke or CVD
Comparison

23. ►
*pHucts aygya#tp%t*<*
►
4uEr ut*iBmts aygya#
►
ol cusnutPpE#tHuy=Ja
►
oL&syct%ycnat&Jsnutylnr.yltnu cuaypl
►
4uEr utylnr.ylt .uscsl u
►
4uEr ut&ucy&Jucs.tP.ppEt%.pHtslEt
yl cusnutm<4
Ds pPt1tuats.btAmJ Hypertens.1998;11:1258–1265.
Adverse metabolic  Adverse metabolic 
effects of  effects of 
ββββββββ
--
blockers blockers
Comparison

24. ββββββββ
--
Blockers and the Risk of  Blockers and the Risk of 
Developing New Developing New
--
Onset DM Onset DM
25% Increased Risk
Baulp.pt44tMbdet=MbMd$Mb-9>
p<.001
17.4
13.0
0
5
10
15
20
Atenolol Lasartan
LIFE
1
6uHtisnunt&uctMDDDt<ucnpl$
8uscn!t7
28% Increased Risk
P.p "uct44tMbd/t=MbD+$Mbe9>
p<.05
0.91
1.28
1.17
0.98 1.0
0
0.5
1
1.5
Thiazide $blocker None CCB ACEI
ARIC
2
2sCscEt4sayp
β
β$
*o:vbt*pnscasl ylaucgulayplt:pctvlE&pylat4uEr aypl,t B4oibtBaJucpn .ucpnynt4yn" yltipLLrlyayunb
1
3sJyp%t)!tuats.btLancetbtdDDd,-e0'00e$MDD-bt
2
Gcunntm?btvats.btN Engl J MedbtdDDD,-+d'0De$0Mdb
<cpn&u aygutnarE#tp%t0M0-t&sayulantHyaJtJ#&ucaulnyp lts=uEteet
apt/DtslEt%p..pHuEt%pct+b/t#uscnbtBls.#nyntp%t900/t HyaJprat
EysPuauntsatPsnu.ylu
<cpn&u aygutnarE#tp%tMd!eeDt&sayulantHyaJtEysPuaunt s=uEt+etapt
.+tslEt%p..pHuEt%pct.t#uscnbt5r.aygslsau sls.#nyntp% t-/D+tHJpt
JsEtJ#&ucaulnypltsatPsnu.ylub
Comparison

25. Incident diabetes of network meta Incident diabetes of network meta
--
analysis of 22 clinical trials  analysis of 22 clinical trials 
Elliott WJ, Lancet 2007; 369: 201–07
Comparison

26. Effect of  Effect of 
ββββββββ
--
Blockers on  Blockers on 
Insulin Sensitivity Insulin Sensitivity
Propranolol
Metoprolol
Atenolol
Pindolol
Dilevalol
Carvedilol
Celiprolol
fnvybaoHwpuaopco%a;pAo%vea;hyaoz/N
Jacob S et al. Am J Hypertens.1998;11:1258-1265.
-40 -20 0 20 40
Comparison

27. Beneficial metabolic effects of  Beneficial metabolic effects of 
third generation  third generation 
ββββββββ
--
blockers  blockers 
==
+ 5%+ 5%
--
15%15%
+ 35% + 35%
Celiprolol Celiprolol
==
==
==
+ 13% + 13%
Carvedilol Carvedilol
==
==
==
--
17%17%
Pindolol Pindolol
==
--
9%9%
+ 18% + 18%
--
22%22%
Atenolol Atenolol
--
1%1%
--
7%7%
+ 30% + 30%
--
21%21%
Metoprolol Metoprolol
+ 9%+ 9%
--
10%10%
+ 25% + 25%
--
33%33%
Propranolol Propranolol
T.Chol T.Chol
(%)(%)
HDL(%) HDL(%)
Triglyceride(%) Triglyceride(%)
Insulin  Insulin 
sensitivity sensitivity
Jacobs S et al. Am J  Jacobs S et al. Am J 
Hypertens Hypertens
1998;11:1258 1998;11:1258
--
1265  1265 
Comparison

28. Lekakis Lekakis
JP. JP. 
Cardiovasc Cardiovasc
Drugs  Drugs 
TherTher
2005;19:277 2005;19:277
--
281281
3rd generation  3rd generation 
ββββββββ
--
blockers &  blockers & 
endothelial function  endothelial function 
Comparison

29. 3rd generation  3rd generation 
ββββββββ
--
blockers &  blockers & 
endothelial function  endothelial function 
Kalinowski Kalinowski
L et al. Circulation 2003;107:2747 L et al. Circulation 2003;107:2747
--
27522752

30. GEMINI: Hemoglobin A GEMINI: Hemoglobin A
1c1c
7.1
7.2
7.3
7.4
)snu.ylut5plaJtetiscguEy.p.
(n=454)
)snu.ylut5plaJtet5uap&cp.p.
mscacsaut=lH.e9>
5uslt2PBM !t7
P=.65
P<.0001
Treatment
Difference:
Carvedilol vs
Metoprolol
-0.13%
(-0.22, -0.04)
P
=.004
1111 patients (90%) were evaluable for efficacy, having both a valid baseline and at least one on-therapy HbA1c assessment.
Bakris GL. et al.
JAMA
. 2004;292;2227-2236.
Comparison

31. Development of  Development of 
Microalbminuria Microalbminuria
inin
Previously  Previously 
Normoalbuminuric Normoalbuminuric
Participants Participants
6.4
10.3
0
4
8
12
16
iscguEy.p.t=lH-Dd> 5uap&cp.p.tmscacsaut=lH+-M>
<sayulan!t7
BEEntcsayp!tDb.D
0e7tiot=Db-.!tDb09>
P = .04
*81% of patients did not have microalbuminuria at screening.
Bakris GL. et al.
JAMA
. 2004:292:2227-2236.
Comparison

32. COMET; New Diabetes Endpoint COMET; New Diabetes Endpoint
(22%)
Comparison

33. ►►
Are all beta blocker equally  Are all beta blocker equally  ineffective? ineffective?
►►
Other beta blocker might give  Other beta blocker might give  different results. different results. Soft Endpoint : Metabolic Effect, DM Soft Endpoint : Metabolic Effect, DM Hard Endpoint : Stroke or CVD Hard Endpoint : Stroke or CVD
Comparison

34. 0.910.91
––
1.211.21
1.051.05
MIMI
1.021.02
––
1.141.14
1.081.08
AllAll
--
cause mortality  cause mortality 
1.151.15
––
1.381.38
1.261.26
Stroke  Stroke 
95% CI 95% CI
Relative risk  Relative risk  with atenolol   with atenolol  
Outcome  Outcome 
Lindholm LH, et al. Lancet2005
Atenolol vs. other  Atenolol vs. other  antihypertensives antihypertensives
Atenolol Atenolol
is less useful than other drugs in reducing cardiovascular even is less useful than other drugs in reducing cardiovascular even
ts ts
(especially strokes) amongst hypertensive patients (especially strokes) amongst hypertensive patients
Comparison

35. 0.670.67
––
1.111.11
0.860.86
MIMI
0.700.70
––
1.121.12
0.890.89
AllAll
--
cause mortality  cause mortality 
0.300.30
––
4.714.71
1.201.20
Stroke  Stroke 
95% CI 95% CI
Relative risk  Relative risk  with beta blockers  with beta blockers 
Outcome  Outcome 
Lindholm LH, et al. Lancet2005
NonNon
--
atenolol atenolol
beta blockers vs.  beta blockers vs. 
other antihypertensives other antihypertensives
NonNon
--
atenolol atenolol
ββ
blockers may be equivalent to other antihypertensive drugs blockers may be equivalent to other antihypertensive drugs
in cardiovascular protection in cardiovascular protection

36. Clinical Evidence ? Clinical Evidence ?
►►
ββββββββ
blockers differ in their pharmacological  blockers differ in their pharmacological 
properties properties
..
►►
Carvedilol Carvedilol
, , 
nebivolol nebivolol
, or other new  , or other new 
generation beta generation beta
--
blocker may have good  blocker may have good 
biologic properties.  biologic properties. 
►►
Clinical Evidences for CV outcomes ? Clinical Evidences for CV outcomes ?
NO !NO !
Comparison

37. Do Do 
ββββββββ
--
blockers differ in their blockers differ in their
efficacy and safety in efficacy and safety in
heart failure heart failure
??
►►
ββββββββ
blockers differ in their pharmacological  blockers differ in their pharmacological 
properties properties
►►
ββββββββ
blockers differ in their clinical effects blockers differ in their clinical effects
::
MM
etoprolol etoprolol
, , 
BB
isoprolol isoprolol
,,
CC
arvedilol arvedilol
Comparison

38. Carvedilol Carvedilol (n=696) (n=696)
Placebo Placebo (n=398) (n=398)
Survival Survival
DaysDays
00
5050
100100
150150
200200
250250
300300
350350
400400
1.01.0 0.90.9 0.80.8 0.70.7 0.60.6 0.50.5
Risk reduction=65% Risk reduction=65%
P<0.001 P<0.001
Packer et al (1996) Packer et al (1996)
CIBIS CIBIS
--
II Investigators (1999) II Investigators (1999)
0              200              400 0              200              400
600600
800800
1.01.0 0.80.8 0.60.6
00
Bisoprolol Bisoprolol Placebo Placebo
Time after inclusion (days) Time after inclusion (days)
P<0.0001 P<0.0001
Survival Survival
Risk reduction=34% Risk reduction=34%
The MERIT The MERIT
--
HF Study Group (1999) HF Study Group (1999)
Months of follow Months of follow
--
upup
Mortality (%) Mortality (%)
00
33
66
99
1212
1515
1818
2121
2020 1515 1010
55 00
Placebo Placebo Metoprolol Metoprolol
CR/XL CR/XL
P=0.0062 P=0.0062
Risk reduction=34% Risk reduction=34%
US US 
Carvedilol Carvedilol
Program Program
ββββββββ
−−−−−−−−
blockers in CHF  blockers in CHF 
;;
allall
--
cause mortality cause mortality
CIBIS CIBIS
--
IIII
MERIT MERIT
--
HFHF
(Atenolol, Propranolol : Not Approved)
Comparison

39. COMET; New Diabetes Endpoint COMET; New Diabetes Endpoint
(22%)
Comparison

40. COMET : Cardiovascular Mortality COMET : Cardiovascular Mortality
(20%)

41. COMET : Stroke Death COMET : Stroke Death
(67%)
Comparison

42. ►►
Are all beta blocker equally ineffective? Are all beta blocker equally ineffective?
►►
Other beta blocker might give different results. Other beta blocker might give different results.
Hard Endpoint : Stroke or CVD Hard Endpoint : Stroke or CVD
Comparison
Soft Endpoint : Metabolic Effect, DM Soft Endpoint : Metabolic Effect, DM

43. Effects of Different Antihypertensive Effects of Different Antihypertensive
Agents on Risk Factors Agents on Risk Factors
++
++
++
++
$$
I<onP(ac cp(nP I<onP(ac cp(nP
NSNS
NSNS
++
$$
NSNS
OnPeh?v;ov? huh P OnPeh?v;ov? huh P
++
NSNS
++
$$
$$
Hyperinsulinemia Hyperinsulinemia
++
NSNS
++
$$
$$
=;i?peao =;i?peao Intolerance Intolerance
NSNS
NSNS
NSNS
$$
NSNS
HDLHDL
$$
cholesterol cholesterol
NSNS
NSNS
++
NSNS
$$
Cholesterol Cholesterol
++
++
++
++
++
%;ppCoOcaeeica %;ppCoOcaeeica
ACEIACEI
CCBCCB
αααααααα
--
blocker blocker
ββ
$$
blocker blocker
Diuretic Diuretic
Kaplan NM. J Hypertens 1990; 8(Suppl.7): S175-9
Comparison

44. Quality data in ALLHAT (n=42,448) Quality data in ALLHAT (n=42,448)
►►
2cibo2he?py hyiv hpygolt/oz!ortgtttN 2cibo2he?py hyiv hpygolt/oz!ortgtttN
►►
2cibofcpeeo>uacgort/ozvwpi oktgtttN 2cibofcpeeo>uacgort/ozvwpi oktgtttN
►►
Ov hay o;pe o poRp;;pA Ov hay o;pe o poRp;;pA
$$
i(gor-V/ozkgk4VN i(gor-V/ozkgk4VN
HII0HFoAveonibao chv;oAh no;pAo HII0HFoAveonibao chv;oAh no;pAo (ca?hehpyovyConvuaoyiSacpieo(cpw;aSe- (ca?hehpyovyConvuaoyiSacpieo(cpw;aSe- dvc;Po. p(ohyo(v hay eoAh noH;(nv dvc;Po. p(ohyo(v hay eoAh noH;(nv
$$
w;p?Lac-o w;p?Lac-o
Comparison

45. Summary of Attributes of Newer  Summary of Attributes of Newer 
Generation  Generation 
ββββββββ
--
Blockers in Hypertension Blockers in Hypertension
►►
.hbyhRh?vy ocaCi? hpyohyof<oauay egohy?;iChybohyo .hbyhRh?vy ocaCi? hpyohyof<oauay egohy?;iChybohyo (v hay eoAh noChvwa aego(pe  (v hay eoAh noChvwa aego(pe 
$$
,BoI<2govyCo0– ,BoI<2govyCo0–
►►
7povCuaceaoaRRa? opyoRve hybo(;veSvob;i?pea 7povCuaceaoaRRa? opyoRve hybo(;veSvob;i?pea
►►
2poyp ovRRa? o;h(hCovyCo chb;P?achCaoSa vwp;heS 2poyp ovRRa? o;h(hCovyCo chb;P?achCaoSa vwp;heS
►►
,vhy vhyocayv;ow;ppCoR;pA ,vhy vhyocayv;ow;ppCoR;pA
►►
Iaeeo;hLa;Po po?vieao?p;Coa6 caSh hae Iaeeo;hLa;Po po?vieao?p;Coa6 caSh hae
►►
Hdo(cpRh;ao?pS(vcvw;ao po(;v?awpohyo?;hyh?v;o chv;e Hdo(cpRh;ao?pS(vcvw;ao po(;v?awpohyo?;hyh?v;o chv;e
Comparison

46. Clinical Evidence ? Clinical Evidence ?
►►
Carvedilol Carvedilol
, , 
nebivolol nebivolol
, or other new  , or other new 
generation beta generation beta
--
blocker may contribute    blocker may contribute   
to a reduction in CV risk. to a reduction in CV risk.
►►
Whether these are clinically beneficial  Whether these are clinically beneficial  remains undetermined. remains undetermined.
Comparison

47. Efficacy of Beta Efficacy of Beta
--
Blockers for First Blockers for First
--
lineline
Antihypertensive;  Antihypertensive; 
All Beta All Beta
--
Blockers Same? Blockers Same?
►►
Current issue with beta Current issue with beta
--
blocker in   blocker in  
Hypertension Hypertension
►►
Comparisons between old and new  Comparisons between old and new  drugs drugs
►►
Logical Practice Logical Practice $$
2,oXofpS(a;;hyboByCh?v hpyeo 2,oXofpS(a;;hyboByCh?v hpyeo
$$
3piyboHbao 3piyboHbao
$$
Tolerability Tolerability

48. Compelling Indication in  Compelling Indication in 
ββββββββ
--
Blockers Blockers
Practice

49. fcih?LenvyL q,- 0P(ac ayehpy vyC Chvwa ae9ov Rv aRi;ov;; iance.
.v a;;h aoePS(pehiS RcpSo naoUUBBofpybcaeeopRo naod. f-oHSe acCvSorVDjtoHibie orttt
Norepinephrine release
Ventricular
arrhythmias
%;ppCo(caeeica
KoypyDCh((hyb
at night
Intra$glomerular
pressure
+ nephropathy
ß
1e hSi;v hpyDhyCi?aCo?vcChv?
vyC ?pcpyvcPovc acPoCvSvba
z H nacpSvoooN
Hybhp ayehyoBB
PRA*
ßoO8Ho& (;veSvocayhyov? huh P
FP(aoroChvwa ae Sa;;h ie
Insulin resistance
Insulin levels
ßß
11
--
blockade benefits patients with  blockade benefits patients with 
type 2 diabetes and hypertension type 2 diabetes and hypertension
,a?nvyheSowcpLay
wPoQ
1$blockade
Practice

50. .74.74
1.121.12
Stroke Stroke
.30.30
1.291.29
Microvascular Microvascular
disease disease
.66.66
1.211.21
Heart failure Heart failure
.35.35
1.201.20
Myocardial infarction Myocardial infarction
.44.44
1.141.14
AllAll
--
cause mortality cause mortality
.28.28
1.271.27
Diabetes Diabetes
--
related deaths related deaths
.43.43
1.101.10
Any DM Any DM
--
related endpoint related endpoint
22
11
0.50.5
PP
RRRR
Relative Risk & 95% CI Relative Risk & 95% CI
Favors
ACE inhibitor
Favors
β-blocker
MM+/tJ#&ucaulnygut&sayulantHyaJta#&utdtEysPuaunbtB% taJut9e/t&sayulantcslEpLyCuEtaptay=Jat placp.tp%tP. ppEt&cunnrcubt+DDtHucuts..p sauEt
apt s&ap&cy. slEt-e/taptsaulp.p.bt:p..pH$r&tHsnt0t#u ars.
O@<31tGcpr&btBMJbtM00/'-M9'9M-$9dDb
DM and Beta Blocker in HTN DM and Beta Blocker in HTN
UKPDS:ACE Inhibitor vs.  UKPDS:ACE Inhibitor vs. 
ββββββββ
--
Blocker Blocker
Practice

51. American Association of Clinical  American Association of Clinical 
Endocrinologists 2006 Guidelines for Type 2  Endocrinologists 2006 Guidelines for Type 2 
Diabetes With Hypertension Diabetes With Hypertension
AA
11
ii)t=&cu%ucsP.#t ii)t=&cu%ucsP.#t
nondihydropyridine nondihydropyridine
>tsntnu plE >tsntnu plE
$$
!t!t
third third
$$
!tpct%prcaJ !tpct%prcaJ
$$
.yluts=ula .yluts=ula
AA
11
BB (preferably drugs that block both  BB (preferably drugs that block both 
αααααααα
and and 
ββββββββ
receptors) as second receptors) as second
--
or third or third
--
line agent line agent
AA
11
Thiazide Thiazide
Eyrcuay tsnt%ycna Eyrcuay tsnt%ycna
$$
pctnu plE pctnu plE
$$
.yluts=ulat=ylt.pHt .yluts=ulat=ylt.pHt
Epns=utHyaJtsEuPrsaut&pasnnyrLtcu&.s uLulatpct Epns=utHyaJtsEuPrsaut&pasnnyrLtcu&.s uLulatpct sparing) sparing)
AA
11
BivotpctB4)tsnt%ycna BivotpctB4)tsnt%ycna
$$
pctnu plE pctnu plE
$$
.yluts=ula .yluts=ula
AA
11
Gps.t)<t Gps.t)<t
≤≤
MdDQ9etLLt2=t?Jultnugucut MdDQ9etLLt2=t?Jultnugucut
proteinuria proteinuria
Exists Exists
AA
22
Gps.t)<t Gps.t)<t
≤≤
M-DQ/DtLLt2= M-DQ/DtLLt2=
m#&utdtEysPuaun m#&utdtEysPuaun
Grade Grade
Highest  Highest  Level of  Level of 
Evidence Evidence
Recommendation Recommendation
Indication Indication
mpccu DDbtuats.btBBivt2#&ucaulnypltGryEu.ylunbt Endocr PractbtdDD.,Md'M0-$dddb
Practice

52. ►►
Atenolol Atenolol
Aveo naowa v Aveo naowa v
$$
w;p?LacoieaCohyoSpe opRo w;p?LacoieaCohyoSpe opRo
 naeaoe iChaeovyCgohyo naovweay?aopRoeiwe vy hv;o  naeaoe iChaeovyCgohyo naovweay?aopRoeiwe vy hv;o Cv voAh nop nacovbay ego Cv voAh nop nacovbay ego
it is unclear whether this  it is unclear whether this 
conclusion applies to all beta conclusion applies to all beta
--
blockers blockers
..
►►
0pAauacgohRo 0pAauacgohRo
atenolol atenolol
e iChaeovcaoa6?;iCaCgo nao p v;o e iChaeovcaoa6?;iCaCgo nao p v;o
auhCay?aopyo naoieaopRowa v auhCay?aopyo naoieaopRowa v
$$
w;p?LaceoRpco nao w;p?LaceoRpco nao
 cav Say opRonP(ac ayehpyoheo  cav Say opRonP(ac ayehpyoheo
much less than much less than
RpcoRpco
 naop nacoSvhyoCcibo?;veeae-  naop nacoSvhyoCcibo?;veeae-
►►
B oAveo nacaRpcao?py?;iCaCo nv ohyo naovweay?aopRo B oAveo nacaRpcao?py?;iCaCo nv ohyo naovweay?aopRo p naco?pS(a;;hybohyCh?v hpyeoRpcowa v p naco?pS(a;;hybohyCh?v hpyeoRpcowa v
$$
w;p?LvCaozRpco w;p?LvCaozRpco
a6vS(;agovybhyvNgo a6vS(;agovybhyvNgo
betabeta
$$
w;p?Laceoenpi;Coyp  w;p?Laceoenpi;Coyp 
waovo waovo
(caRaccaCohyh hv;o cav Say oRpconP(ac ayehpy- (caRaccaCohyh hv;o cav Say oRpconP(ac ayehpy-
Key Messages in the NICE/BHS  Key Messages in the NICE/BHS  Hypertension Guideline Update: Hypertension Guideline Update:
Practice

53. Clinical Results vs. Interpretation Clinical Results vs. Interpretation Alcohol consumption vs. CV risk   Alcohol consumption vs. CV risk   ►►
France vs. Scotland or English France vs. Scotland or English
►►
Italian vs. English Italian vs. English
►►
Japanese vs. American Japanese vs. American
►►
Chinese vs. American Chinese vs. American
•There are race differences and alcohol drinking was not 
harmful in some nation.
••
In an ethnic group with using an English letters, t here  In an ethnic group with using an English letters, t here 
are higher CV risk than others. are higher CV risk than others.
Practice

54. BHS/NICE Guideline on Treatment of  BHS/NICE Guideline on Treatment of 
Hypertension in Adults in Primary Care Hypertension in Adults in Primary Care
< 55 years old
> 55 years old;
Blacks of any age
A
C or D
(A + C) or (A + D)
A + C + D
. a(ok
. a(or
. a(oj
Practice

55. Prospective Hard Prospective Hard
--
event Trials in  event Trials in 
Hypertension involving  Hypertension involving 
ββββββββ
--
Blockers Blockers
8181
177/96 177/96
6767
Atenolol Atenolol
LIFE(DM) LIFE(DM)
7676
174/98 174/98
6767
Atenolol Atenolol
LIFE(whole LIFE(whole
))
9494
185/91 185/91
7070
Atenolol Atenolol
MRCMRC
--
elderly elderly
9797
196/99 196/99
6969
Atenolol Atenolol
HEPHEPStudies with Unfavorable to beta Studies with Unfavorable to beta
--
blockers blockers
6565
159/94 159/94
5656
Atenolol Atenolol
UKPDS UKPDS
5959
167/108 167/108
5252
Metoprolol Metoprolol
MAPHY MAPHY
6363
161/98 161/98
5151
Prepranolol Prepranolol
MRCMRC
--
mildmild
6565
173/108 173/108
5252
Oxyprenolol Oxyprenolol
IPPPSH IPPPSHStudies with favorable to beta Studies with favorable to beta
--
blockers blockers
Pulse Pulse
--
Pressure Pressure (mm Hg) (mm Hg)
Starting BP Starting BP
(mmHg) (mmHg)
Mean age Mean age
(yr)(yr)
Drugs Drugs
Trial Trial

56. Why happen the different result between Why happen the different result between
UKPDS & LIFE Study ? UKPDS & LIFE Study ?
decreased decreased
Relatively Relatively
ββββββββ
1 receptor  1 receptor 
response response
8181
6565
Pulse pressure  Pulse pressure  (mmHg) (mmHg)
nonnon
--
compliant,  compliant, 
stiff stiff
Relatively  Relatively  compliance compliance
Vascular system Vascular system
67.4(Around 70) 67.4(Around 70)
56.3(56) 56.3(56)
Mean age Mean age
Elderly Elderly
Younger & middle  Younger & middle  ageage
AgeAge
LIFELIFE
UKPDS UKPDS
Practice

57. Physician Concerns About Adding Physician Concerns About Adding
ββββββββ
--
Blockade in Hypertension Blockade in Hypertension
Metabolic Metabolic ►►
Wpceayhybo02I Wpceayhybo02I
►►
By?caveaCo By?caveaCo
ApoApo
BB
►►
7abv huaoaRRa? eopyo 7abv huaoaRRa? eopyo b;i?peaoSa vwp;heS b;i?peaoSa vwp;heS
►►
7abv huaoaRRa? eopyocayv;o 7abv huaoaRRa? eopyocayv;o w;ppCoR;pA w;ppCoR;pA
►►
,veLaConP(pb;P?aShv ,veLaConP(pb;P?aShv
Tolerability Tolerability ►►
Fatigue Fatigue
►►
Impotence Impotence
►►
Wahbn ohy?cavea Wahbn ohy?cavea
►►
Oach(nacv;ouvep?pye ch? hpyo Oach(nacv;ouvep?pye ch? hpyo z?p;Coa6 caSh haeN z?p;Coa6 caSh haeN
►►
Depression Depression
HCv( aCoRcpS9o%a;;o2.-odyCp?c Ocv? -ok111Ml9lkDlj-
Practice

58. Traditional  Traditional 
ββββββββ
--
Blocker Effects on Blocker Effects on
Peripheral Vasculature Peripheral Vasculature
Peripheral
Vasoconstriction
3u cusnuEtLy cpgsn r.sc
nrc%s utscustHyaJyltn"u.uas.
Lrn .ut%pctylnr.yl$LuEysauE
ulac#tp%t=.r pnu
vcu ay.ut3#n%rl aypl
3u cusnuEt4uls.
).ppEt:.pH
ol cusnuEtmpas.t<ucy&Jucs.
Resistance
Olp&&pnuEtα
1
stimulation
)u..t312btEndocrinologisabtdDD-,M-'MM.$Md-bt<s "uct5btProg Cardiovasc DisbtM00/,+M'-0$edbt5sltolRa Au.E BDbt Am J
HypertensbtM00/,M'0M$0.b
Practice

59. Tolerability / Cost Tolerability / Cost
►►
7aAo=ayacv hpyo%a vo%;p?Laco9oca;v hua;Po 7aAo=ayacv hpyo%a vo%;p?Laco9oca;v hua;Po bppCo p;acvy?aoo bppCo p;acvy?aoo
►►
d6 ayCaCo8a;aveaopco;pybonv;Ro;hRa d6 ayCaCo8a;aveaopco;pybonv;Ro;hRa
►►
IaeeoehCaodRRa?  IaeeoehCaodRRa? 
►►
ByoepSaoCcibegoCcibo?pe oheoeponhbn- ByoepSaoCcibegoCcibo?pe oheoeponhbn-
Practice

60. Cost effectiveness Cost effectiveness
Base case results 65 Base case results 65
--
yearyear
--
old male 2% annual CVD risk,  old male 2% annual CVD risk, 
Cost effectiveness plane Cost effectiveness plane
NI D C B A
9.809.90 10.00 10.10 10.20 10.30 10.40 10.50 10.60
,avyoaRRa? ozSHI3e (aco(acepygoChe?piy aCN
£4,000
£4,100
£4,200
£4,300
£4,400
£4,500
£4,600
£4,700
£4,800
£4,900
£5,000
,avyo?pe ozrttloYGoT (aco(acepyN
CCB
ACEI
Diuretics
BB
partial update of NICE Clinical Guideline
Practice

61. Conclusions Conclusions
►►
FnaoCpAybcvChybopRowa vow;p?Laceoveovo FnaoCpAybcvChybopRowa vow;p?Laceoveovo cpi hyaohyh hv;o nacv(PoRpconP(ac ayehpygo cpi hyaohyh hv;o nacv(PoRpconP(ac ayehpygo ae(a?hv;;Po ae(a?hv;;Po
atenolol atenolol
hyo(chSvcPo?vca-o%i goh oheo hyo(chSvcPo?vca-o%i goh oheo
iy?;avcoAna naco nheo?py?;iehpyov((;haeo pov;;o iy?;avcoAna naco nheo?py?;iehpyov((;haeo pov;;o betabeta
$$
blockers. blockers.
►►
7aAobayacv hpyowa vow;p?LaceonvuaobppCo 7aAobayacv hpyowa vow;p?LaceonvuaobppCo whp;pbh?ovyCoSa vwp;h?oauhCay?aegowi oo whp;pbh?ovyCoSa vwp;h?oauhCay?aegowi oo Ric naco?;hyh?v;opi ?pSaoe iCPoAh;;owaoyaaCaC- Ric naco?;hyh?v;opi ?pSaoe iCPoAh;;owaoyaaCaC-

62. Thank You for Your Attention

64. 66
$$
1onc1onc
77
$$
ktonc ktonc
0v;Ro;hRa 0v;Ro;hRa
renal renal
hepatic hepatic
d;hShyv hpyocpi a d;hShyv hpyocpi a
nono
yesyes
H? huaoSa vwp;h a H? huaoSa vwp;h a
~50%~50%
>90%>90%
Absorption Absorption
Pharmacokinetic Pharmacokinetic
nono
yesyes
DoseDose
$$
Ca(ayCay owhpvuvh;vwh;h Po Ca(ayCay owhpvuvh;vwh;h Po
~40%~40%
~30%~30%
%hpvuvh;vwh;h Po %hpvuvh;vwh;h Po
weakweak
moderate moderate
Ih(hCoep;iwh;h Po Ih(hCoep;iwh;h Po
6o)6o)
6ol6ol
$$
1010
Interpt Interpt
-ouvchv hpyopRo(;-o -ouvchv hpyopRo(;-o
concconc
Elimination EliminationPharmacodynamics Pharmacodynamics
++++
∅∅
ββ
11
$$
selectivity selectivity
x1x1
x10x10
ββ
11
$$
%;v?LvCao(p ay?P %;v?LvCao(p ay?P
yesyes
nono
2cibov??iSi;v hpyohyocayv;o 2cibov??iSi;v hpyohyocayv;o
dsds
..
∅∅
++++
MembMemb
e vwh;h+hybov? huh P e vwh;h+hybov? huh P
∅∅
∅∅
ISAISA
Atenolol Atenolol
Carvedilol Carvedilol
Carvedilol’PDs, PKsand Elimination

65. Beta Blocker Classification Beta Blocker Classification

66. ++
00
00
1.01.0
Propranolol Propranolol
++++
00
++++
10.010.0
Nebivolol Nebivolol
00
00
++++
1.01.0
Metoprolol Metoprolol
00
+?+?
00
0.30.3
Labetalol Labetalol
++++
00
00
10.010.0
Carvedilol Carvedilol
00
00
++++
10.010.0
Bisoprolol Bisoprolol
00
00
++++
1.01.0
Atenolol Atenolol
Ancillary  Ancillary 
Effect Effect
ISAISA
RELATIVE  RELATIVE 
ββββββββ
11
SELECTIVITY SELECTIVITY
ββββββββ
11
--
BLOCKADE POTENCY  BLOCKADE POTENCY 
RATIO(PROPRANOLOL=1) RATIO(PROPRANOLOL=1)
DRUG  DRUG 
Beta Blocker Classification Beta Blocker Classification

67. Adverse metabolic  Adverse metabolic 
effects of beta blockers effects of beta blockers
►►
Oach(nacv;ouvep?pye ch? hpy9ohy?caveaCo Oach(nacv;ouvep?pye ch? hpy9ohy?caveaCo hyei;hyocaehe vy?a hyei;hyocaehe vy?a
►►
Bynhwh hpyopRoIOIo Bynhwh hpyopRoIOIo
ff
hy?caveaohyo hy?caveaohyo
 chb;P?achCaovyCoeSv;;oCayeaoI2I  chb;P?achCaovyCoeSv;;oCayeaoI2I
►►
Bynhwh hpyopRoIfHFo Bynhwh hpyopRoIfHFo
ff
Ca?caveaohyo02I Ca?caveaohyo02I
Bell DSH.  Bell DSH. 
CurrCurr
Med Res  Med Res 
OpnOpn
2005;21:1191 2005;21:1191
--
12001200

68. Effect of Stimulating αααα-and 
ββββ‐‐‐‐adrenoreceptors

69. COMET : Risk of Death COMET : Risk of Death

70. BetaBeta
--
blockers are no longer preferred as a  blockers are no longer preferred as a 
routine initial therapy for hypertension routine initial therapy for hypertension
►►
BetaBeta
--
blockers may be considered in : blockers may be considered in :
--
younger women of child younger women of child
--
bearing potential bearing potential
--
patients with HTN & evidence of increased sympathetic  patients with HTN & evidence of increased sympathetic  drive drive
--
intolerance / contra intolerance / contra
--
indication to ACEI and  indication to ACEI and 
ARBsARBs
►►
In these circumstances, if initial therapy is with  a BB and  In these circumstances, if initial therapy is with  a BB and 
a second drug is required, add DHP CCB rather than a  a second drug is required, add DHP CCB rather than a  thiazide thiazide
--
type diuretic to reduce the risk of developing  type diuretic to reduce the risk of developing 
diabetes.  diabetes. 
partial update of NICE Clinical Guideline18