Antiadrenergic therapy in mild to moderate chronic heart failure Are there differences between b blo

1
Antiadrenergic therapy in mild to moderate
chronic heart failure Are there differences
between b blocking drugs?

• M Fowler, Stanford, USA

2
? adrenergic blocking drugs in mild-to-moderate
heart failure

• 9171 patients evaluated in long-term
  placebo-controlled clinical trials
• gt250 patients, gt6 months follow-up
• Improvement in cardiac function and symptoms
  equivocal effects on exercise tolerance
• Decrease in all-cause mortality by 3465
  (plt0.001) effect shown in 3 individual trials
• CIBIS-II, MERIT-HF, US Carvedilol Programme
• Decrease in combined risk of death and
  hospitalisation by 3540 (plt0.001) effect shown
  in 6 individual trials
• Effect shown in patients already receiving ACE
  inhibitors

3
?-adrenergic blocking drugs in mild to moderate
heart failure
Principal randomised trials more than 250
patients, greater than 6 months follow-up
Follow-up
Number of
NYHA class
Agent
patients
recruited
Aetiology
(months)
MDC
Metoprolol tartrate
383
IIIII
IDCM
15
CIBIS-I
Bisoprolol
641
IIIIV
mixed
23
ANZ
Carvedilol
415
(I) IIIII
IHD
19
US Carvedilol
Carvedilol
1,094
IIIV
mixed
7
CIBIS-II
Bisoprolol
2,647
IIIIV
mixed
15
12
MERIT-HF
Metoprolol succinate
3,991
IIIV
mixed
Early termination by Independent Data Safety
Board

4
Three drugs only responsible for the beneficial
clinical outcomes reported in the larger
randomised trials in mild to moderate heart
failure

• Metoprolol
• Bisoprolol
• Carvedilol

Beneficial effects published only in trial
populations with relatively low mortality and
systolic dysfunction
5
Sympathetic nervous system activation in heart
failure
Injury to heart
Sympathetic activation
?2 receptors
?1 receptors
?1 receptors
Metoprolol
Bisoprolol
Bucindolol
Carvedilol
Disease progression
6
Questions

• Are carvedilol, metoprolol or bisoprolol equally
  effective in mild to moderate heart failure?
• Can the beneficial results be extended to all
  ?-adrenergic blocking drugs?
• Do subpopulations respond differently to
  different agents?
• Are the dose response characteristics (benefit /
  risk) different with agents with different
  properties?

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Anti-adrenergic actions of ?-adrenergic blocking
drugs

• Primary properties
• ?1 adrenoceptor blockade
• relative affinity
• ?2 adrenoceptor blockade
• ? adrenoceptor blockade

• Secondary effects
• Up-regulation of ?1 adrenergic receptor density
• Influence on myocardial norepinephrine release
• Presence of intrinsic sympathomimetic activity

8
Antiadrenergic actions of b-adrenergic blocking
drugs

No Reduction
in ?1 ?2 ?1
upregulation myocardial
Noreceptor receptor receptor of ?1
receptor norepinephrine ISA
Metoprolol Bisoprolol
Carvedilol

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Are the pharmacological differences between
carvedilol and metoprolol or bisoprolol
clinically apparent?

• Between trial comparisons
• Meta-analyses
• Direct comparison trials

10
US Carvedilol Programme
Survival
1.0 0.9 0.8 0.7 0.6 0.5
? blockade in HF All-cause mortality
Carvedilol (n696)
Placebo (n398)
Risk reduction 65
plt0.001
Survival
CIBIS-II
1.00.80.6 0
Bisoprolol
0
50
100
150
200
250
300
350
400
Days
Packer et al (1996)
Mortality
MERIT-HF
20
Placebo
Risk reduction 34
Placebo
plt0.0001
15
Metoprolol CR/XL
10
0 200 400 600
800
Time after inclusion (days)
Risk reduction 34
5
CIBIS-II Investigators (1999)
p0.0062
0
0
3
6
9
12
15
18
21
Months of follow-up
The MERIT-HF Study Group (1999)
11
Anti-adrenergic therapy in HFNumber needed to
treat for one year to save one life
Cohort with MERIT-HF placebo group characteristics
NNT
29
30
27
25
20
15
15
10
5
0
Bisoprolol
Metoprolol
US Carvedilol
Calculated from CIBIS-II Investigators
(1999),MERIT-HF study group (1999), Packer et
al (1996)
12
Effect of ? blockade on hospitalisation Reduction
in number of hospitalisations
US Carvedilol
Reduction (odds ratio)
MERIT-HF
CIBIS-II
39
40
36
35
34
35
30
30
25
25
20
18
20
15
10
5
N/A
0
All-cause
Cardiovascular
Worsened HF
CIBIS-II Investigators (1999), Hjalmarson
(2000), and Fowler et al (in prep)
versus placebo
13
Effect of b blockade on all-cause mortality by
aetiology and NYHA class
NYHA II
NYHA III
NYHA IV
Ischaemic
Non-ischaemic
0
0.5
1
1.5
2
Relative risk and 95 confidence intervals
CIBIS-II
MERIT-HF
US Carvedilol Programme
14
Effect of b blockade on all-cause mortality by
gender and diabetic status
Diabetic
Non-diabetic
Male
Female
0
0.25
0.5
0.75
1
1.25
1.5
1.75
2
Relative risk and 95 confidence intervals
MERIT-HF
US Carvedilol Programme
15
Reduction in all-cause mortality by property of
b-blocking agentMeta analysis data

• Bonet (2000) 21 trials
• Vasodilating RR 0.55 (0.380.78)
• Non-vasodilating RR 0.73 (0.640.83)
• Lechat (1998) 18 trials
• Non-selective OR 0.51 (0.340.75)
• Selective OR 0.84 (0.611.16)
• Heidenreich (1997) 17 trials
• Carvedilol OR 0.54 (0.360.81)
• Non-carvedilol OR 0.82 (0.601.12)

p0.007
p0.049
p0.10
16
Randomised trials directly comparing metoprolol
with carvedilol

• DiLenarda et al (J Am Coll Cardiol, 1999) n30
• Kukin et al (Circulation, 1999) n67
• Sanderson et al (J Am Coll Cardiol, 1999) n51
• Metra et al (Circulation, 2000) n150

Small number of patients Survival outcome data
not generated
17
Effects of carvedilol in patients with persistent
LVD despite continuous metoprolol
? ? LVEF
10
Switched to carvedilol (n14) mean dose, 74 mg
5
Continued on metoprolol (n16) mean dose, 142 mg
()
p0.045
0
-5
Baseline
6 months
12 months

• At 12 months, carvedilol patients had mean EF
  increase of 7 units vs -0.8 units in metoprolol
  patients

Open-label randomised study of IDC patients with
EF lt40 on long-term metoprolol (gt1 year).
Patients receiving ACE inhibitors follow-up 12
months. Di Lenarda et al. J Am Coll Cardiol.
1999331926-1934.
18
Differential effects of b blockers in
HFComparison of long-term effects of metoprolol
vs carvedilol
Metra et al, Circulation 2000102,546-551
150 study patients (NYHA class II-IV, EF ?35)
Double-blind 11 randomisation
Metoprolol, 75 patients Carvedilol, 75 patients

• 28 withdrawals
• 11 deaths or urgent transplantation
• Lack of compliance, 12 patients
• Adverse reactions, 5 patients

Clinical and haemodynamic reassessment (after
1315 months) 122 patients
19
Absolute changes in LV ejection fraction and
volumes After long-term treatment with
metoprolol or carvedilol
LV ejection fraction
ml/m2
LV EDV
LV ESV
0
16
p0.038
-5
14

-10
12
-15
10

-20
8


-25
6
-30
4

-35
2

-40
plt0.01 (versus baseline) plt0.001 (versus
baseline)
0
Metoprolol
Carvedilol
Metra et al (2000)
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Comparison of long-term effects of metoprolol vs
carvedilol

Metra et al Circulation Aug 1, 2000

• NYHA class reduced by metoprolol and carvedilol
• Minnesota Q of L score equally reduced by both
  drugs
• Peak VO2 increased by 1.25ml/kg/min with
  metoprolol (plt0.05 vs carvedilol, plt0.01 vs
  baseline)
• 6-minute walk non-statistically significant
  increase, similar with metoprolol and carvedilol
• Greater decrease in PCW and PA pressure at rest
  and exercise with carvedilol than metoprolol (all
  plt0.05)
• 21 deaths or transplantation with metoprolol vs
  17 with carvedilol

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Comparison of long-term effects of metoprolol vs
carvedilol

• Risks of therapy (adverse
  reactions)

• 
  Metoprolol Carvedilol
• n () n ()
• Worsening heart failure 13 (17.3) 6
  (8.0)
• Hospitalisation for heart failure 6
  2
• Dizziness 1 (1.3) 11
  (14.7)

Metra et al (2000)
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Major trials of b blockade in heart failure
Mean dose Patients Target dose achieved
Effects on (n) (total/day) (total/day) outcom
es CIBIS 641 5 mg 3.8 mg All-cause
mortality NS CIBIS-II 2647 10 mg 7.5 mg
All-cause mortality ?34 (plt0.0001) MDC 383 1
00150 mg 108 mg Death or need for transplant
(NS) MERIT-HF 3991 200 mg 159 mg All-cause
mortality ?34 (p0.0062) US
Carv 1094 50100 mg 45 mg All-cause
mortality ?65 (p0.0001) ANZ Trial 415
50 mg 41 mg
Death or all-cause hospitalisation ?26
(p0.02)
23
Carvedilol dose-response trial (MOCHA) Effect on
LVEF and mortality
LVEF
Mortality
plt0.001
plt0.001
?
?
?
Mortality ()


LVEF (EF units)

Placebo
25
6.25
12.5
Placebo 6.25 12.5 25
Carvedilol (mg bid)
Carvedilol (mg bid)
Placebo (n84) carvedilol (n261) Patients
receiving diuretics, ACE inhibitors digoxin
follow-up 6 months
Bristow et al (1996)
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Dosing for b blockers in heart failure
The Medical Letter, June 26, 2000
Drug Starting dose Target dose Bisoprolol 1.25 mg
QD 10 mg QD Carvedilol 3.125 mg BID 6.2525 mg
BID Metoprolol 12.525 mg QD 200 mg
QD (extended-release)
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COMET Carvedilol or Metoprolol European Trial

• Rationale known differences in pharmacology
  might lead to differences in efficacy and safety
• Hypothesis COMET is powered to detect a 20
  difference in survival benefit between carvedilol
  and metoprolol
• gt 3000 patients with class II-IV heart failure
  due to ischaemic or non-ischaemic cardiomyopathy
• Randomised to carvedilol or metoprolol (in
  addition to usual therapy) for up to 3 years
• Primary endpoints - all-cause mortality-
  all-cause mortality / all-cause hospitalisation

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Conclusions

• Metoprolol (high dose succinate), bisoprolol
  (high dose), or carvedilol are the only ?
  blocking drugs shown to improve survival in mild
  to moderate heart failure
• Only carvedilol has been shown to be effective in
  lower doses
• Between trial comparisons and direct comparison
  trials suggest carvedilol may be more effective
  than metoprolol
• COMET is designed to test for differences in
  efficacy between metoprolol and carvedilol