1 1 Do Do third third generation generation beta beta blockers blockers work work better better in in cardiovascular cardiovascular treatment treatment ? ? Ceyhun CEYHAN Prof. MD, FESC Ceyhun CEYHAN Prof. MD, FESC Adnan Menderes Adnan Menderes University University Facult Facult of of Medicine Medicine Department Department of of Cardiology Cardiology , Ayd , Ayd ı ı n, n, Turkey Turkey
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11
Do Do thirdthird generationgeneration
beta beta blockersblockers workwork
betterbetter in in cardiovascularcardiovascular
treatmenttreatment??Ceyhun CEYHAN Prof. MD, FESCCeyhun CEYHAN Prof. MD, FESC
WY et al. WY et al. DiabetDiabet MedMed. 1994;11(2):137. 1994;11(2):137--144. 144. 2. 2. FonarowFonarow
GC. GC. Am J MedAm J Med. 2004;116(Suppl 5A):76S. 2004;116(Suppl 5A):76S--88S. 88S. 3. Bell DS. 3. Bell DS. The EndocrinologistThe Endocrinologist. 2003;13:116. 2003;13:116--123.123.
Cardiac Benefits of Beta-BlockadeAntiatherogenic—reduces inflammation, shear
stress, endothelial dysfunction and risk for plaque rupture1,2,3
(not marketed because of BEST)(not marketed because of BEST)•• Produces vasodilatation by ? Produces vasodilatation by ? cGMPcGMP--dependent dependent mechanism mechanism
CarvedilolCarvedilol, , labetalollabetalol::
due to due to 11
--blockadeblockade
CeliprololCeliprolol::
due to due to 22
--adrenergic receptor adrenergic receptor agonismagonism (not marketed in US, due to hepatic dysfunction)(not marketed in US, due to hepatic dysfunction)
*N=25; parameters at 2 weeks*N=25; parameters at 2 weeksAt 2 weeks; *P<0.05 At 2 weeks; *P<0.05 vsvs
pretreatment. Change in SBP/DBP was pretreatment. Change in SBP/DBP was --19/12 mm Hg for 19/12 mm Hg for nebivololnebivololAdapted from Adapted from KampKamp
O et al. Am J O et al. Am J CardiolCardiol. 2003;92:344. 2003;92:344--348348
-15-10
-50
510
1520
25
Heart rateHeart rate((bpmbpm))
Beat
s pe
r minut
eBe
ats
per
minut
e
1818
1919
Myocardial Infarction: Is there a Class Effect?
Freemantle
N, et al. BMJ 1999;318:1730-7.FreemantleFreemantle
N, et al. N, et al. BMJ BMJ 1999;318:17301999;318:1730--7.7.
Total Mortality Reduction after Myocardial InfarctionTotal Mortality Reduction after Myocardial InfarctionTotal Mortality Reduction after Myocardial InfarctionAcebutololAcebutololAcebutolol
AlprenololAlprenololAlprenolol
AtenololAtenololAtenolol
Carvedilol
*CarvedilolCarvedilol
**
MetoprololMetoprololMetoprolol
OxprenololOxprenololOxprenolol
PindololPindololPindolol
PractololPractololPractolol
PropranololPropranololPropranolol
SotalolSotalolSotalol
TimololTimololTimolol
XamoterolXamoterolXamoterol|0||00
|1||11
|2||22
|3||33
|4||44
|5||55
|6||66
Odd Ratio of DeathOdd Ratio of DeathOdd Ratio of Death
n = 54,234n = 54,234n = 54,234
*
Meta-analysis did NOT include CAPRICORN Trial (Lancet 2001;357:1385-90), which showed 23%
in all-cause mortality (Hazard ratio = 0.77 [95% Confidence interval = 0.60-0.98], p=0.03)
**
MetaMeta--analysis did NOT include CAPRICORN Trial analysis did NOT include CAPRICORN Trial (Lancet 2001;357:1385(Lancet 2001;357:1385--90), which showed 23%90), which showed 23%
in allin all--cause mortality (Hazard ratio = 0.77 [95% cause mortality (Hazard ratio = 0.77 [95% Confidence interval = 0.60Confidence interval = 0.60--0.98], p=0.03) 0.98], p=0.03)
••••••
•••
•••
•••
•••
•••
•••
•••
•••••••••
2020
CAPRICORN Study Design
Dargie
HJ, et al. Eur J Heart Fail 2000;2:325-332.
PlaceboPlacebo
6.25 mg BID6.25 mg BID
BaselineBaseline
12.5 mg BID12.5 mg BID
33––10 10 DaysDays
33––10 10 DaysDays
633633EventsEvents
Visits Every 3Visits Every 3––4 4 MonthsMonths
CarvedilolCarvedilol25 mg BID25 mg BID
Encouraged adjunctive therapy
Receiving ACE inhibitor 48 hrs
Clinically stable, but may have had pulmonary edema or cardiogenic
shock during index infarction
Encouraged adjunctive therapy
Receiving ACE inhibitor 48 hrs
Clinically stable, but may have had pulmonary edema or cardiogenic
shock during index infarction
2121
CAPRICORN:All-Cause Mortality
The CAPRICORN Investigators.The CAPRICORN Investigators.
MERIT-HF. Lancet 1999;353:2001-2007; CIBIS-II. Lancet 1999;353:9-13; Packer M, et al. N Engl J Med 2001;344:1651-1658; BEST. N Engl J Med 2001;344:1659-1667.
MERITMERIT--HF. HF. LancetLancet 1999;353:20011999;353:2001--2007; CIBIS2007; CIBIS--II. II. LancetLancet 1999;353:91999;353:9--13; Packer M, et 13; Packer M, et al. al. N N EnglEngl J Med J Med 2001;344:16512001;344:1651--1658; BEST. 1658; BEST. N N EnglEngl J MedJ Med 2001;344:16592001;344:1659--1667.1667.
Relative risk and 95% confidence intervalsRelative risk and 95% confidence intervalsRelative risk and 95% confidence intervals
MD, et al. MD, et al. EurEur Heart J Heart J 2005; 26:2152005; 26:215--225.225.
2128 patients 2128 patients ≥≥
70 years 70 years heart failure historyheart failure history (admission < 1 year or known EF (admission < 1 year or known EF ≤≤35%) 35%) to to nebivololnebivolol, titrated to 10 mg QD, or placebo, titrated to 10 mg QD, or placebo
Median 21 monthsMedian 21 months
2525
SexualSexual DysfunctionDysfunction
Decreased blood flow in the Corpora Decreased blood flow in the Corpora CavernosaCavernosa
due to Vasoconstrictiondue to Vasoconstriction
2626
2727
Effect of Effect of NebivololNebivolol
and and MetoprololMetoprolol on Sexual Function: IIEFon Sexual Function: IIEF
2828
28
Nebivolol
and erectile function Prevalence of erectile dysfunction
Doumas M, et al. Asian J Androl 2006; 8:177-82.
Before nebivolol After nebivololSevere
Moderate
Mild
None
Severity of ED
9% 59%
5%
27%34%
18%30%
18%
44 patients treated previously with beta-blockers switched to nebivolol
Vasoconstriction causes decrease in Vasoconstriction causes decrease in micromicro--vascular surface area invascular surface area in
skeletal skeletal
muscle causing reduction in the insulinmuscle causing reduction in the insulin-- mediated glucose entry and metabolism.mediated glucose entry and metabolism.
Baseline SBP/BP was 153/92 mm Hg and 155/95 mm Hg in the Baseline SBP/BP was 153/92 mm Hg and 155/95 mm Hg in the nebivololnebivolol
and and metroprololmetroprolol
groups, respectively. Following groups, respectively. Following 6 months of therapy. BP was 131/79 mm Hg and 129/82 mm Hg in the6 months of therapy. BP was 131/79 mm Hg and 129/82 mm Hg in the
nebivololnebivolol
and and metroprololmetroprolol
groups, respectively. groups, respectively. HOMA=homeostasis model assessment insulin resistance.HOMA=homeostasis model assessment insulin resistance.CelikCelik
T et al. T et al. J J HypertensHypertens 2006;24:5912006;24:591--596596
3232
Insulin Resistance
-12,2
-21,6-25
-20
-15
-10
-5
0
5
Nebivolol2.5-5 mg QD
Atenolol50-100 mg QD
Perc
enta
ge C
hang
e
p<0.01p<0.01
PoirerPoirer
L, et al. L, et al. J J HypertensHypertens 2001;19:14292001;19:1429--1435.1435.
Insulin Sensitivity IndexInsulin Sensitivity Index
Compare effects of -blockers with different pharmacologic properties on glycemic
and metabolic control in patients
with diabetes and hypertension receiving RAAS blockade
Participants:1235 patients
Treatment:
Carvedilol
6.25 mg to 25 mg bid (n = 498) or Metoprolol
tartrate
50 mg to 200 mg bid
(n = 737) Follow-up:
35 weeks
Objective:Objective:
Compare effects of Compare effects of --blockers with blockers with different pharmacologic properties on different pharmacologic properties on glycemicglycemic
and metabolic control in patients and metabolic control in patients
with diabetes and hypertension receiving with diabetes and hypertension receiving RAAS blockadeRAAS blockade
6.25 mg to 25 mg bid (n = 6.25 mg to 25 mg bid (n = 498) or 498) or MetoprololMetoprolol
tartratetartrate
50 mg to 200 mg bid 50 mg to 200 mg bid
(n = 737)(n = 737)FollowFollow--up:up:
35 weeks35 weeks
GlycemicGlycemic
Effects in diabetes Mellitus: Effects in diabetes Mellitus: carvedilolcarvedilol--metoprololmetoprolol comparison IN comparison IN hypertensiveshypertensives
studystudy
Bakris
GL, et al. JAMA 2004;292:2227-2236.
GEMINI
3434
Metoprolol tartrate Carvedilol
% (SD) P % (SD) P
HbA1c0.15
(0.04) <0.001 0.02 (0.04) 0.65
Insulin sensitivity –2.0 0.48 –9.1 0.004
GEMINI: Change in HbA1c
and Insulin Sensitivity
EndpointEndpoint(mean (mean ))
BakrisBakris
GL, et al.GL, et al.
JAMAJAMA 2004;292:22272004;292:2227--36.36.
3535
GEMINI GEMINI Progression to Progression to microalbuminuriamicroalbuminuria
Bakris
GL. American Heart Association Scientific Sessions 2004.
Nov 7-10, 2004; New Orleans, LA.
End pointEnd point MetoprololMetoprolol CarvedilolCarvedilol Odds ratio Odds ratio (95% CI)(95% CI)
p p
Progression to Progression to microalbuminuriamicroalbuminuria
in Elderly and Obese Patientsin Elderly and Obese Patients
3939
SSiigngniiffiicant cant NNoteote
1/3 of1/3 of
heartheart--failure patients are failure patients are
receiving BB in clinical practice, because receiving BB in clinical practice, because clinical trials have generally included clinical trials have generally included younger patients (average age 61), younger patients (average age 61),
HoweverHowever
the average age of heartthe average age of heart--
failure patients in the real world was failure patients in the real world was 76. 76.
4040
Elderly PatientsElderly Patients
Decreased density of Decreased density of ßß receptors receptors results in decreased efficacy in the results in decreased efficacy in the elderly.elderly.
VasodilatingVasodilating
BB do not just work by BB do not just work by
blocking the blocking the ßß rreceptorseceptors..
4141
4242
Obese patientsObese patients
Traditional Beta Blockers results in Traditional Beta Blockers results in 1.2 Kg/Yr weight gain due to reduced 1.2 Kg/Yr weight gain due to reduced resting energy expenditure, and resting energy expenditure, and thermogenesisthermogenesis
•Obesity defined as body mass index >30 kg/m2. •Data on file, Forest Laboratories, Inc. New York, NY
Placebo DBP Placebo SBPPlacebo DBP Placebo SBP
DoseDose
PlaceboPlacebo
5 mg5 mg
10 mg10 mg
20 mg20 mg
Efficacy of Efficacy of NebivololNebivolol
in Obesein Obese Patients:Patients:
4444
2006 AACE Hypertension
Guidelines►
ß-blocker use recommended as 2nd
or 3rd
line
in hypertension Because the major adverse effects of BBs
may be
mediated by peripheral vasoconstriction and increasing insulin resistance, the use of the new third-generation ß-blockers (such as nebivolol)
or drugs that block both
α
and ß
receptors (such as carvedilol) may prove to be particularly beneficial. These agents cause vasodilatation and an increase in insulin sensitivity.
►►
ßß--blocker use recommended as 2blocker use recommended as 2ndnd
or 3or 3rdrd
line line in hypertensionin hypertensionBecause the major adverse effects of Because the major adverse effects of BBsBBs
may be may be
mediated by peripheral vasoconstriction and increasing mediated by peripheral vasoconstriction and increasing insulin resistance, the use of the insulin resistance, the use of the new thirdnew third--generation generation ßß--blockers (such as blockers (such as nebivololnebivolol))
or drugs that block both or drugs that block both
αα
and and ßß
receptors (such as receptors (such as carvedilolcarvedilol) may prove to be ) may prove to be particularly beneficial. particularly beneficial. These agents cause These agents cause vasodilatation and an increase in insulin sensitivity.vasodilatation and an increase in insulin sensitivity.
They differ in their indications and their effectiveness for various disorders
Selective, vasodilatory
-blockers are:
●
Indicated for hypertension
●
Proven for heart failure and myocardial infarction
●
Offer advantages in patients with diabetes mellitus
●
Are well tolerated
--blockers are a diverse class of drugsblockers are a diverse class of drugs
They differ in their indications and their They differ in their indications and their effectiveness for various disorderseffectiveness for various disorders
Selective, Selective, vasodilatoryvasodilatory
--blockers are: blockers are:
●●
Indicated for hypertensionIndicated for hypertension
●●
Proven for heart failure and myocardial Proven for heart failure and myocardial infarctioninfarction
●●
Offer advantages in patients with diabetes Offer advantages in patients with diabetes mellitusmellitus