- The document summarizes the history of beta-blocker treatment for heart failure, from early studies in the 1970s showing potential benefits to large randomized controlled trials in the 1990s and 2000s firmly establishing mortality reduction. - Key trials included MDC (1993) showing reduced mortality and heart transplantation, CIBIS-II (1999) showing reduced mortality with bisoprolol, MERIT-HF (1999) showing reduced mortality with metoprolol CR/XL, and COPERNICUS (2001) showing reduced mortality, hospitalizations, and worsening heart failure with carvedilol. - Meta-analyses demonstrated a consistent mortality reduction of approximately 35% associated with beta-blocker use in

1. The success of neurohormonal blockade:
looking back – looking forward:
Beta-blockers
Karl Swedberg
Senior professor of Medicine
University of Gothenburg
Professor of Cardiology
Imperial College, London
Disclosures:
Honoraria/Consultancy: Amgen, Astrazeneca, Novartis,
Pfizer, Servier, Vifor
Research grants: Amgen, Servier

2. Treatment of heart failureTreatment of heart failure
From two textbooks 1929 and 1974From two textbooks 1929 and 1974
”…and for all this there is only
digitalis and rest…”
Paul Dudley White: Textbook in Cardiology, 1929
Moderately severe heart failure
Decrease physical activity
Institute digitalis
Give thiazide every day plus potassium
If not enough use furosemide and
if insufficient, combine them
J W Hurst: The Heart 3rd edition, 1974
J Willis Hurst
1920-2011

3. Importance of adrenergic supportImportance of adrenergic support
Am J Medicine 1963; 39:442Am J Medicine 1963; 39:442
”These data suggest that the adrenergic nervous system
plays an important compensatory role in the circulatory
adjustments of patients to congestive heart failure, and
emphasize the need for caution in the use of highly
effective antiadrenergic drugs in the treatment of patients
with limited cardiac reserve”

4. Myocardial norepinephrine depletionMyocardial norepinephrine depletion
Thus, norepinephrine depletion interferes with the abilityThus, norepinephrine depletion interferes with the ability
of the adrenergic nervous system to support the failingof the adrenergic nervous system to support the failing
myocardium and in this manner it may intensify themyocardium and in this manner it may intensify the
congestive heart failure state.congestive heart failure state.
Circ Research 1966; 21:51Circ Research 1966; 21:51

5. Beta-blockers in heart failure 1973Beta-blockers in heart failure 1973
Hjalmarson and Waagstein had postulated:Hjalmarson and Waagstein had postulated:
●● A simple working hypothesis - energy starvationA simple working hypothesis - energy starvation
●● High heart rate and sympathetic stimulation mayHigh heart rate and sympathetic stimulation may
facilitate development of heart failurefacilitate development of heart failure
●● Heart failure is a potential reversible conditionHeart failure is a potential reversible condition
●● Bedside observations: beta-blockers wereBedside observations: beta-blockers were
antiischemic and well toleratedantiischemic and well tolerated

6. Waagstein et al. Br Heart J 1975; 37:1022Waagstein et al. Br Heart J 1975; 37:1022
First report ofFirst report of  blockers in HFblockers in HF

7. Effect of beta-blockade on ejection fraction
by echocardiography
0 6 12 24 >24
Months
0:4
0:5
0:1
0:2
0:3
0:4
0:5
0:6
Swedberg et al Br Heart J 1980

8. Effect of beta-blocker withdrawal
During -Blocker
B A
p<0.1
(Circ/s)
0.2
0.4
0.6
0.8
1.0
Mean VCF
Withdrawal
B A
p<0.01
0.1
0.2
0.3
0.4
0.5
0.6
0.7
(Ratio)
EF
During -Blocker Withdrawal
Swedberg et al Br Heart J 1980

9. Effect of beta-blockade on survival in dilated
cardiomyopathy
1 2 3 4 5
10
20
30
40
50
60
70
80
90
100
24 23 21 19 15 14 13 11 7 5
12
11
10
9
8
7
6
5
4
3
2
1
Years
Digitalis, diuretics
AND a beta-blocker
Digitalis and diuretics ONLY
Survival(%)
Swedberg et al Lancet 1979

10. NorepinephrineNorepinephrine
12001200
800800
400400
00
ArterialArterial
pp<0.001<0.001
Coronary SinusCoronary Sinus
pp<0.001<0.001
CHF n = 30CHF n = 30
No HF n = 25No HF n = 25
Swedberg et al. Am J Cardiol 1984Swedberg et al. Am J Cardiol 1984
Myocardial Catecholamine Balance in Heart FailureMyocardial Catecholamine Balance in Heart Failure
Myocardial norepinephrine releaseMyocardial norepinephrine release

11. MDC Trial (Metoprolol in DilatedMDC Trial (Metoprolol in Dilated
Cardiomyopathy)Cardiomyopathy)
ll Multicenter trial in 33 centers in EuropeMulticenter trial in 33 centers in Europe
and North America. Coordinated fromand North America. Coordinated from
Göteborg (Coordinator: Finn Waagstein)Göteborg (Coordinator: Finn Waagstein)
ll Primary objective: Death or need for heartPrimary objective: Death or need for heart
transplanttransplant
ll Randomized, double-blind,Randomized, double-blind,
placebo/metoprolol 50 mg 2-3 times dailyplacebo/metoprolol 50 mg 2-3 times daily
ll 383 patients with idiopathic dilated383 patients with idiopathic dilated
cardiomyopathy, EF <40%, followed for 12-cardiomyopathy, EF <40%, followed for 12-
18 months.18 months.
Waagstein et al Lancet 1993; 342: 1491Waagstein et al Lancet 1993; 342: 1491

12. placebo
metoprolol
Risk reduction
34% (95% CI 62 to -6)
Risk reduction
34% (95% CI 56 to 0)
MDC-trialMDC-trial
Deaths or heart transplantationsDeaths or heart transplantations
(primary outcome)(primary outcome)
Waagstein F et al Lancet 1993, Andersson B et al Lancet 1998;351:1180

13. placebo (189)
metoprolol (194)
Risk reduction
0.4 (95% CI 0.16-0.97)
Prevention of cardiac transplantationPrevention of cardiac transplantation
in the MDC trialin the MDC trial
Waagstein F. Lancet 1993; Andersson B. Lancet 1998;351:1180

14. ACC/AHA Guidelines for theACC/AHA Guidelines for the
management of CHF 1995management of CHF 1995

15. ACC/AHA Guidelines 1995
• ” use of beta-blockers for the treatment of chronic heart
failure remains investigational, but the official status of beta-
blockers may change as recent data are reviewed. Hence,
physicians might consider the use of a beta-blocker in
selected patients with chronic heart failure.”

16. Carvedilol
(n=696)
Placebo
(n=398)
Survival
Days
0 50 100 150 200 250 300 350 400
1.0
0.9
0.8
0.7
0.6
0.5
Risk reduction = 65%
p<0.001
Packer et al (1996)Packer et al (1996)
CIBIS-II Investigators (1999)CIBIS-II Investigators (1999)
0 200 400 600 800
Bisoprolol
Placebo
Time after inclusion (days)
p<0.0001
Survival
Risk reduction = 34%
The MERIT-HF Study Group (1999)The MERIT-HF Study Group (1999)
US Carvedilol Programme
CIBIS-II
0.8
1.0
0.6
0
Months of follow-up
Mortality
(%)
0 3 6 9 12 15 18 21
20
15
10
5
0
Placebo
Metoprolol CR/XL
p=0.0062
Risk reduction = 34%
MERIT-HF
COPERNICUS:COPERNICUS:
MonthsMonths
00
00
33 66 99 1212 1515 1818 2121
100100
9090
8080
6060
7070
CarvedilolCarvedilol
PlaceboPlacebo
Risk reduction = 35%
p = 0.00013p = 0.00013
Survival
Packer et al (2001)

17. Cumulative Metaanalysis of Beta blockerCumulative Metaanalysis of Beta blocker
Effects on Mortality in CHFEffects on Mortality in CHF
RR (95% CI)
0.91 (0.37-2.26
0.76 (0.30-1.16)
0.70 (0.27-1.80)
0.70 (0.27-1.82)
0.99 (0.61-1.59)
0.78 (0.60-1.02)
0.79 (0.61-1.02)
0.63 (0.50-0.80)
0.64 (0.52-0.80)
0.64 (0.52-0.80)
0.66 (0.58-0.74)
0.65 (0.58-0.73
0.74 (0.64-0.80)
0 0.5 1 1.5 2
Year
1985
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
Accum.
No. of patients
102
156
205
215
622
1516
1625
2760
3266
3338
10058
10984
16077
Skoglund, Swedberg 2003

18. Beta-blocker Trials in Heart FailureBeta-blocker Trials in Heart Failure
Effects on MortalityEffects on Mortality
Beta-blockerBeta-blocker
WorseWorseBetterBetter
1.01.00.50.5 0.250.25
TotalTotal
0.910.91
CIBIS IICIBIS II
MERITMERIT
BESTBEST
0.670.67
0.680.68
0.640.64
0.740.74
PreviousPrevious
COPERNICUSCOPERNICUS
0.650.65
ResolvdResolvd
Metaanalysis incl.Metaanalysis incl.
15202 patients15202 patients
2243 deaths2243 deaths

19. Meta-analysis of 22 beta-blocker studies inMeta-analysis of 22 beta-blocker studies in
CHFCHF
Brophy et al Ann Int Med 2001

20. Mechanism?Mechanism?
ll Why and how do treatment with a beta-Why and how do treatment with a beta-
blocker work?blocker work?

21. 23 trials in 19 209 HF patients with beta23 trials in 19 209 HF patients with beta--blocker (mean EF=17%-36%)blocker (mean EF=17%-36%)
McAlister et al. Ann Intern Med. 2009;150:78
BetaBeta-blocker dose and heart rate reduction-blocker dose and heart rate reduction
in chronic HF patientsin chronic HF patients
Results of 13 univariable meta-regressions evaluating the effect of individual
covariates on mortality benefits of beta-blockers in heart failure

22. ESC Guidelines for the Diagnosis and
Treatment of Acute and Chronic Heart Failure
Which beta-blocker dose?
Beta-blocker
First dose
(mg) Increments
(mg/day)
Target dose
(mg/day)
Titration
period
Bisoprolol 1.25 2.5, 3.75, 5,
7.5, 10
10 Weeks-
month
Metoprolol
succinate/CR
12.5/25 25, 50, 100,
200
200 Weeks-
month
Carvedilol 3.125 6.25, 12.5,
25, 50
50 Weeks-
month
Nebivolol 1.25 2.5, 5, 10 10 Weeks-
month

23. Randomised
3029
Carvedilol
1511
Metoprolol
1518
Assigned to drug
and received at least one tablet
Withdrew consent 10
Lost to follow-up 3
Withdrew consent 18
Lost to follow-up 2
Flow chart of patients
Poole-Wilson et al Lancet 2003

24. Time (years)
Mortality (%)
0
10
20
30
40
0 1 2 3 4 5
Metoprolol
Carvedilol
hazard ratio 0.83,
95% CI 0.74-0.93, p=0.0017
Primary endpoint of mortality
Number at risk
Carvedilol 1511 1367 1259 1155 1002 383
Metoprolol 1518 1359 1234 1105 933 352
Poole-Wilson et al Lancet 2003

25. Heart rate (beats.min-1)
Metoprolol
Carvedilol
Time (years)
70
75
80
0 1 2 3 4 5
60
90
** ** *
Change of heart rate
* p<0.05, ** p<0.01
Error bars represent 1 standard error
Poole-Wilson et al Lancet 2003

26. ESC Guidelines for the Diagnosis and
Treatment of Acute and Chronic Heart Failure
Which beta-blocker dose?
Beta-blocker
First dose
(mg) Increments
(mg/day)
Target dose
(mg/day)
Titration
period
Bisoprolol 1.25 2.5, 3.75, 5,
7.5, 10
10 Weeks-
month
Metoprolol
succinate/CR
12.5/25 25, 50, 100,
200
200 Weeks-
month
Carvedilol 3.125 6.25, 12.5,
25, 50
50 Weeks-
month
Nebivolol 1.25 2.5, 5, 10 10 Weeks-
month

27. •883 patients with CHF at 41 centres, naive to BB or on a low dose.
•Randomised to carvedilol or bisoprolol
•Forced titrated to target doses according to ESC Guidelines

28. CIBIS-ELDCIBIS-ELD
Achieved dose levelsAchieved dose levels
Dose level Bisoprolol n=431
%
Carvedilol n=445
%
12.5% 11 10
25% 25 22
50% 23 25
100% 31 32
> 50% 54 54
Dungen et al EJHF 2011

29. Primary endpoint:Primary endpoint:
Tolerability and target doseTolerability and target dose
Düngen et al EJHF 2011

30. International Journal of Cardiology 155 (2012) 160–166

31. Heart Rate by Dose LevelHeart Rate by Dose Level
Gelbricht et al. IJC 2012.

32. SummarySummary
·· Treatment of chronic systolic heart failureTreatment of chronic systolic heart failure
with a beta-blocker is the most effectivewith a beta-blocker is the most effective
pharmacological therapy.pharmacological therapy.
·· From the first report of beneficial effects, itFrom the first report of beneficial effects, it
took around 25 years for general acceptance.took around 25 years for general acceptance.
·· There is still a major under-treatment inThere is still a major under-treatment in
clinical practiseclinical practise