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Betazok in hf_cm_eslides_21jun2010 full slides
1. A Second Look
at Metoprolol Succinate
in Heart Failure
Gabriel B. Jocson III, MD
2. Objectives
1. Brief review of hormonal strategies in heart
failure and treatment recommendations
2. Discuss the zero order kinetics of Metoprolol
Succinate
3. Present the advantages of Metoprolol
Succinate in heart failure
4. Show guides in preventing decompensation or
deterioration in using beta-blockers in heart
failure
3. HF: The Disease Burden
• Prevalence of Congestive Heart Failure in the USA:
• 4.8 million Americans (NHLBI); 2% age 40-59; 5% age
60-69; 10% over 70's
• Prevalence Rate for Congestive Heart Failure:
• approx 1 in 56 or 1.76% or 4.8 million people in USA
Prevalence of Congestive Heart Failure in the Philippines:
(extrapolated from USA data)
1,521,912 of 86,241,697* population (1.76%)
(Prevalence Rate:1 in 56)
*US Census Bureau, International Data Base, 2004
12. Management of Heart Failure
Assess LV Function
EF < 40%
Assess Volume status
Fluid retention No Fluid retention
ACE-I Aldactone
Digoxin
Diuretics B-blocker
Packer and Cohn: Am J Cardiol 1999
22. Recommendations For Drugs In Patients With
Symptomatic Systolic Dysfunction
All patients (unless with Class I Recommended Class I
ACE Inhibitor contraindications) Level A Level A Level A
ACE intolerant, persisting signs or Class I Recommended Class I
ARB Level A
symptoms on ACEi/beta-blockade Level A Level A
All patients (unless with Class I Recommended Class I
Β-blocker contraindications) Level A Level A Level A
Aldosterone Class I Recommended Class I
Severe symptoms on ACE inhibitor
antagonist Level B Level A Level B
All patients with signs or symptoms of Class I Recommended Class I
Diuretics congestion Level B Level A Level C
Digitalis can be beneficial in patients with
Class IIa Recommended Class IIa
Digitalis current or prior symptoms of HF and reduced
LVEF to decrease hospitalizations for HF. Level B Level C Level B
26. “The single most significant addition to the
pharmacological management of heart failure since the
publication of previous guidelines [ACC/AHA] involves
the use of beta-receptor antagonists.”
-Heart Failure Society of America (1999)
Heart Failure Society of America (HFSA) Practice Guidelines. J Cardiac Fail. 1999;5:357-382.
27. Evidence -Based TreatmentAcross the
Evidence-based Treatment Across the
Continuum of Systolic LVD and HF
Continuum of Systolic LVD and HF
Control Volume Improve Clinical Outcomes
ACEI Aldosterone
Diuretics β Blocker
Renal Replacement or ARB Antagonist
Therapy* or ARB
CRT ±
an ICD*
HDZN/ISDN*
*In selected patients
Treat Residual Symptoms
Digoxin
28. What choice of Beta Blocker?
• Carvedilol
• Metoprolol extended-release
• Bisoprolol
29.
30. Metoprolol CR/XL Randomized Intervention Trial
in Congestive Heart Failure
MERIT-HF
A Double-Blind, Placebo-Controlled Survival Study
With Metoprolol CR/XL in Patients With
Decreased Ejection Fraction (≤ 0.40)
and Symptoms of Heart Failure (NYHA II–IV)
MERIT-HF Study Group. Lancet 1999;353:2001-7
31. MERIT – HF Study Design
Titrated from
12.5 mg/25 mg
to 200 mg once daily Metoprolol
over 6 to 8 weeks* CR/XL n=1990
Placebo
Run-in
Placebo n=2001
-2 3 6 9 12 15 18 21
Weeks Months
Single-
Double-blind
blind
* The recommended starting dose is 12.5 mg of blind medicine in patients with
NYHA functional class III–IV heart failure and 25 mg in functional class II
heart failure.
MERIT-HF Study Group. Lancet 1999;353:2001-7
32. Inclusion Criteria
• Men and women aged 40–80 years
• NYHA functional class II–IV for ≥3 months
before randomisation despite optimal standard
therapy
• EF ≤40%
• Supine resting heart rate ≥68 bpm
MERIT-HF Study Group. Lancet 1999;353:2001-7
33. Dosing Simplicity
Starting dose at 12.5 mg or 25 mg OD
(half a 25 mg tablet recommended for
2 weeks patients who were NYHA III/IV)
Increased to 50 mg OD
2 weeks
Increased to 100 mg OD
2 weeks
Increased up to 200 mg OD
If a patient did not tolerate increases in dose, temporary decrease was recommended
MERIT-HF Study Group. Lancet 1999;353:2001-7
35. Sudden Death
Per cent
12
Placebo 6.6%
9
41% Risk reduction
6 Metoprolol CR/XL 3.9%
NNT = 38
3
p=0.0002
0
0 3 6 9 12 15 18 21
Months of follow-up
MERIT-HF Study Group. Lancet 1999;353:2001-7
36. Death From Worsening Heart
Per cent Failure
5
4 Placebo 2.9%
3 49% Risk reduction
Metoprolol CR/XL 1.5%
2
NNT = 71
1
p=0.0023
0
0 3 6 9 12 15 18 21
Months of follow-up
MERIT-HF Study Group. Lancet 1999;353:2001-7
37. Total Mortality or All-Cause Hospitalization
Per cent
(Time to First Event)
60
50 Placebo
19% Risk reduction
40 Metoprolol CR/XL
30
20
10
p=0.00012
0
0 3 6 9 12 15 18 21
Months of follow-up
Hjalmarson A, et al. JAMA 2000;283:1295-302
38. Total Mortality or Hospitalization
for Worsening CHF
Per cent (Time to First Event)
40
Placebo
30
31% Risk reduction
Metoprolol CR/XL
20
10
p<0.00001
0
0 3 6 9 12 15 18 21
Months of follow-up
Hjalmarson A, et al. JAMA 2000;283:1295-302
40. Myths about β-blockade in HF
• Difficult to initiate
• Difficult to up-titrate to maximal
doses
• Contraindicated in patients with
advanced heart failure
• Not effective in diabetic patients
41. Dosing
• Therapy should be begun in very low
doses
• dose doubled at regular intervals (eg,
every two to three weeks) until
• the target dose is reached
• or symptoms become limiting
42. Dosing
• Initial and target doses
• Carvedilol : 3.125 mg twice daily with target
dose of 25 to 50 mg twice daily
• metoprolol succinate: 12.5 or 25 mg daily
with target dose of 200 mg/day
• Bisoprolol: 1.25 mg once daily with target
dose of 5 to 10 mg once daily
44. WHEN TO START TREATMENT?
• If no contraindication
• Early use of β blockers risk of adverse reactions
Which to use?
• Carvedilol
• Metoprolol extended-release
• Bisoprolol
How to initiate and titrate β blockers doses?
• Start low, go slow
• Titration interval = 2-4 weeks
• 2-3 hours observation period
45. Titration of beta-blockers in HF
Careful initial upward dose adjustment
ensures favourable minimizes adverse
clinical management events
• Eligible candidates: Non hospitalized patients with
HF (NYHA class II or III), stable with standard HF
therapy
46. Dose Initiation
In patients with clinically stable HF for 2-weeks with standard
therapy (ACEI + diuretics)
At very low doses
Dose Titration
Patients who tolerate slow upward Maximally tolerated
initial doses dose adjustment target doses
Titration interval: > 2 weeks
Upward titration is delayed until any adverse effects observed with lower
doses have resolved
Careful b-blockade early in treatment may prevent the need for treatment
delays during later stages of therapy
49. Limitations of β-Blockers Therapy in
Chronic Heart Failure
1. Contraindications in patients with
• reactive airways disease
• sinus node dysfunction
2. Reluctance to initiate in
• advanced heart failure *
• decompensated heart failure*
3. Initiation and uptitration may be difficult (target doses
are not achieved)
4. Beta-Blocker resistance (unclear reasons)
Circulation 2000;101;558-569
51. “Withdrawal” or “reduced dose” VS “same dose”
after an episode of decompensated heart failure:
Results from COMET
Kaplan–Meier curves of mortality subsequent to discharge for the
patients who had an admission for HF, according to whether study
medication was withdrawn, the dose was dose reduced or the dose
was left unchanged (same dose).
Metra, M et al. European Journal of Heart Failure. 2007;9 : 901–909
52. Deterioration in some patients
• Natural course of the disease
• Co-morbidities (infections, kidney disease, anemia)
• May depend on titration
• Food interactions
• Drug interactions
• Pharmacokinetics of the beta-blockers being
used
53. Beta-Blocker with Z.O.K.
It should be evident that when a drug is being metabolized with zero-order kinetics that
the half life becomes longer as the concentration (or dose) increases.
1st order: ZERO order:
25% is eliminated 8 mg is eliminated
every hour: every hour:
Hour 0:100 mg Hour 0:100 mg
Hour 1: 75 mg Hour 1: 92 mg
Hour 2: 56.2 mg Hour 2: 86 mg
Hour 3: 42.2 mg Hour 3: 78 mg
Hour 4: 31.7 mg Hour 4: 70 mg
Hour 5: 23.8 mg Hour 5: 62 mg
Hour 6: 17.8 mg Hour 6: 54 mg
Hour 7: 13.4 mg Hour 7: 46 mg
Hour 8: 3.4 mg Hour 8: 38 mg
First Order Kinetics:
A constant fraction of the drug in the body is eliminated per unit time.
The rate of elimination is proportional to the amount of drug in the body.
majority of drugs are eliminated in this way.
Zero order kinetics:
a constant amount of drug is eliminated per unit time
Drug elimination is independent of the drug's concentration
54. Metoprolol controlled release
formulation
Metoprolol CR (ZOK) is a divisible tablet consisting of a multitude of small subunits (pellets)
embedded in an inert tablet mass.
Each tablet contains about 1,600 to 1,800 pellets which contains 95 mg of metoprolol
succinate (equivalent to 100 mg metoprolol tartrate) or
400 – 450 pellets which contains 23.75 mg metoprolol succinate equivalent to 25 mg
metoprolol tartrate
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
55. Fluid penetration and drug release
from metoprolol CR/ZOK
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
56. Pharmacology: Conventional metoprolol
tartrate vs metoprolol succinate
Parameters Metoprolol Tartrate Metoprolol Succinate
Absorption Rapid and complete SLOW and complete
1st pass metabolism extensive extensive
Metabolism Liver CYP2D6 Liver CYP2D6
Peak 1.5- 2 hour 6-12 hours
Duration 6-12 hours 24 hours
Solubility aqueous Lipophilic
Food interaction May increase systemic none
availability by 30-40%
Bioavailability 50%-70%* 20-30%
Protein Binding 5-10% 5-10%
The solubility profile of the succinate salt is more suitable for an ER preparation than a tartrate salt. Therefore, the succinate
salt was used in the ER formulation in place of the tartrate salt used in the metoprolol IR formulation
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
Betaloc Prescribing Information, AstrazZeneca, Data on File
Betazok Prescribing Information, AstrazZeneca, Data on File
Tangeman, H et al. Ann Pharmacother 2003;37:701-10.
57. Advantages of Z.O.K.
· Continuous and even β1-Blockade with once
daily dosing
· Reduce adverse effects associated with HIGH
peak plasma concentrations
· Increases the amount of time the plasma
concentrations are in the therapeutic range
· Helps achieve simplicity, efficacy, and
tolerability especially in patients with heart
failure
58. Plasma concentration
of Metoprolol ZOK
Mean plasma concentrations of metoprolol CR/ZOK 100 mg, metoprolol tablets 100 mg,
and metoprolol tablets 50 mg
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
60. Heart rate reduction
Metoprolol tartrate Atenolol
F.O.K.
Metoprolol succinate ZOK
Z.O.K.
Percentage reductions in exercise heart-rate
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
61. Less peak-to-trough fluctuation
in exercise heart rate with metoprolol
succinate/CR than metoprolol tartrate
Metoprolol tartrate 100 mg
Metoprolol tartrate 50 mg BD
Metoprolol succinate 100 mg
Stable effect on exercise heart rate throughout the dosage interval
Mean ± SEM percentage reduction in exercise heart rate in healthy
volunteers after administration of 5 days of extended-release metoprolol
succinate 100 mg once daily (—■), immediate-release metoprolol
tartrate100 mg once daily (---●), or 50 mg twice daily (•••▲).
Tangeman, H et al. Ann Pharmacother 2003;37:701-10.
62. Reduction in blood pressure
after 4 weeks
Systolic BP Diastolic BP
0
Reduction in supine BP
(mmHg)
10
20
*
Systpolic and diastolic blood pressures were decreased after 4 weeks
treatment with metoprolol in conventional tablets (100 mg ) and CR/
ZOK (100 mg ).
Blood pressures were recorded 24 hours after dosing. *P<0.05
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
63. Mean change in FEV1 60 min
after drug intake
0.5 Placebo
Metoprolol CR/ZOK 100 mg
Metoprolol CR/ZOK 200 mg
Atenolol 100 mg
Δ FEV1 (litres)
0
- 0.5
Mean change in FEV, (SEM) 60 min after drug intake
in eight asthmatic subjects
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
65. MERIT – HF Study Design
Titrated from
12.5 mg/25 mg
to 200 mg once daily Metoprolol
over 6 to 8 weeks* CR/XL n=1990
Placebo
Run-in
Placebo n=2001
-2 3 6 9 12 15 18 21
Weeks Months
Single-
Double-blind
blind
* The recommended starting dose is 12.5 mg of blind medicine in patients with
NYHA functional class III–IV heart failure and 25 mg in functional class II
heart failure.
MERIT-HF Study Group. Lancet 1999;353:2001-7
66. Primary Objectives
To determine whether metoprolol CR/XL reduces:
• Total mortality
• The combined end point of all-cause mortality and all-
cause hospitalization (time to first event)
Secondary Objectives
• All-cause mortality and hospitalisations for
heart failure (time to first event)
• Death due to cardiovascular causes with cause-specific mortality for
heart failure and sudden death
• Change in functional status (NYHA class)
• Quality of life (sub-study)
67. Inclusion Criteria
• Men and women aged 40–80 years
• NYHA functional class II–IV for ≥3 months
before randomisation despite optimal standard
therapy
• EF ≤40%
• Supine resting heart rate ≥68 bpm
MERIT-HF Study Group. Lancet 1999;353:2001-7
68. Dosing Simplicity
Starting dose at 12.5 mg or 25 mg OD
(half a 25 mg tablet recommended for
2 weeks patients who were NYHA III/IV)
Increased to 50 mg OD
2 weeks
Increased to 100 mg OD
2 weeks
Increased up to 200 mg OD
If a patient did not tolerate increases in dose, temporary decrease was recommended
MERIT-HF Study Group. Lancet 1999;353:2001-7
70. Sudden Death
Per cent
12
Placebo 6.6%
9
41% Risk reduction
6 Metoprolol CR/XL 3.9%
NNT = 38
3
p=0.0002
0
0 3 6 9 12 15 18 21
Months of follow-up
MERIT-HF Study Group. Lancet 1999;353:2001-7
71. Death From Worsening Heart
Per cent Failure
5
4 Placebo 2.9%
3 49% Risk reduction
Metoprolol CR/XL 1.5%
2
NNT = 71
1
p=0.0023
0
0 3 6 9 12 15 18 21
Months of follow-up
MERIT-HF Study Group. Lancet 1999;353:2001-7
72. Total Mortality or All-Cause Hospitalization
Per cent
(Time to First Event)
60
50 Placebo
19% Risk reduction
40 Metoprolol CR/XL
30
20
10
p=0.00012
0
0 3 6 9 12 15 18 21
Months of follow-up
Hjalmarson A, et al. JAMA 2000;283:1295-302
73. Total Mortality or Hospitalization
for Worsening CHF
Per cent (Time to First Event)
40
Placebo
30
31% Risk reduction
Metoprolol CR/XL
20
10
p<0.00001
0
0 3 6 9 12 15 18 21
Months of follow-up
Hjalmarson A, et al. JAMA 2000;283:1295-302
75. Well Tolerated in Severe Heart
Failure
Placebo
Metoprolol CR/XL
400 p = 0.0037
p = 0.0005
300
p < 0.0001
200
100
0
All-cause CV cause Heart failure
-27% -34% -45%
Total Number of Hospitalizations
Post-hoc Subgroup analysis of Patients with Severe Heart Failure
Goldstein et al. J Am Coll Cardiol. 2001 Oct;38(4):932-8.
76. Tolerability
Percent
25 p = 0.027 Placebo
20 Metoprolol CR/XL
p = 0.018
15
p = 0.012
10
5
0
All-cause Adverse events Wors. CHF
-31% -39% -49%
No. of
withdrawals 86/62 66/42 34/18
Withdrawal of Study Medicine
Post-hoc Subgroup analysis of Patients with Severe Heart
Failure
Goldstein et al. J Am Coll Cardiol. 2001 Oct;38(4):932-8.
77. MERIT-HF: Adverse events and Withdrawal
Per cent
20
Placebo
Metoprolol CR/XL
15
10
5
0
All-cause Adverse events Worsening HF
No. of -10% -17% -25%
withdrawals 310/279 234/196 85/64
Hjalmarson A, et al. JAMA 2000;283:1295-302
78. Comparison of withdrawals
from different trials
Clinical Trial Withdrawal in Withdrawal in
Placebo Arm Beta blocker Arm
n (%) n(%)
CIBIS II 14.05% 11.5%
MDC 8% 6%
MERIT HF 15.3% 13.9 %
COPERNICUS 18.5 % 14.8 %
CAPRICORN 8.9% 9.8%
CIBIS-II Investigators and Committees. Lancet. 1999 Jan 2;353(9146):9-13
Waagstein F, et al. Lancet. 1993 Dec 11;342(8885):1441-6
MERIT-HF Study Group*. Lancet 1999; 353: 2001–07
Packer M et al. N Engl J Med. 2001;344: 1651-8
The CAPRICORN Investigators*. Lancet 2001; 357: 1385–90
79. Comparison of withdrawals due to
progression of heart failure
Clinical Trial Withdrawal in Withdrawal in
Placebo Arm Beta blocker Arm p
(n) (n)
MDC 13 (6.7%) 7 (3.7%) (p = 0.14)
MERIT HF 85 (4.2%) 64 (3.2%) (p = 0.08)
COPERNICUS (24.2%) (17.5%) --
Waagstein F, et al. Lancet. 1993 Dec 11;342(8885):1441-6
MERIT-HF Study Group*. Lancet 1999; 353: 2001–07
Packer M et al. N Engl J Med. 2001;344: 1651-8
80. Metoprolol in Dilated Cardiomyopathy (MDC)
Adverse events and withdrawals
Metoprolol Placebo p
(n = 194) (n = 189)
Total no. of withdrawals 24 31 0.29
Progressive heart failure 7 13 0.14
Non-compliance 12 11 0.96
Other adverse events 4 7 0.32
Withdrawal during 5 6
titration phase
Waagstein et al. Lancet 1993;342:1441
81. Titration scheme for metoprolol
tartrate in MDC
• Week 1 10 mg / day
• Week 2 15 mg / day
• Week 3 30 mg / day
• Week 4 50 mg / day
• Week 5 75 mg / day
• Week 6 100 mg/ day
• Week 7 150 mg/ day
Waagstein et al. Lancet 1993;342:1441
82. Death or need for heart
transplantation MDC
Waagstein et al. Lancet 1993;342:1441
83. Pooling of Patients with Severe Heart Failure
NYHA Functional Class III/IV and EF < 0.25
Total Mortality Yearly
Randomized NYHA EF Placebo Risk
No. Class Mean Deaths/Pat. Yrs
Plac/Beta
CIBIS II 84/65 752 III/IV 0.20 16.7
MERIT - HF 72/45 795 III/IV 0.19 19.1
COPERNICUS 190/130 2289 (III/IV)1 0.20 19.7
Al pooled 346/240 3836
0.0 1.0 1
NYHA Class not recorded in COPERNICUS
Relative risk and 95% Cl but placebo mortality indicates III/IV
Goldstein et al. J Am Coll Cardiol. 2001 Oct;38(4):932-8.
84. Relative Risk Reductions
in Three Major Trials of β-Blockers
in Heart Failure
Relative Risk Reduction in Trial*
Endpoint MERIT-HF (%) CIBIS - II(%) COPERNICUS(%)
All-cause mortality 34 34 35
HF death 49 26 NA
Sudden death 41 44 44
All hospitalization 18 20 20
CV hospitalization 25 NA 28
HF hospitalization 35 32 33
All deaths/hospitalization 19 NA 24
*Compared to placebo.
CIBIS-II = Cardiac Insufficiency Bisoprolol Study II; COPERNICUS = Carvedilol Prospective Randomized Cumulative
Survival trial; CV = cardiovascular; HF = heart failure; MERIT-HF = Metoprolol CR/XL Randomized Intervention Trial in
Congestive Heart Failure; NA = not available.
Bauman,J et al. J Cardiovasc Pharmacol Ther 2004; 9; 117
85. COMET: Dosing Issues
Metoprolol-Tartrate (immediate release)
COMET Target dose: 2 x 50 mg tartrate ~78 mg Metoprolol
Metoprolol-Succinate (CR/XR/ZOK)
MERIT-HF Target dose: 1 x 190 mg succinate ~155 mg
Metoprolol (achieved mean dose in MERIT-HF ~130 mg)
86. CHF Admission or Clinic
Diuretics + ACE-I or ARB + NO
Class I or II Class III or IV
Metoprolol succinate 25 mg OD Metoprolol succinate 12.5 mg OD
2 weeks
Metoprolol succinate 50 mg OD Metoprolol succinate 25 mg OD
2 weeks
Metoprolol succinate 100 mg OD Metoprolol succinate 50 mg OD
2 weeks
Metoprolol succinate 200 mg OD Metoprolol succinate 100 mg OD
2 weeks
Metoprolol succinate 200 mg OD
87. Summary
• Metoprolol succinate , via zero order kinetics, provides
– continuous and even β1-blockade with once daily
dosing while
– reducing adverse effects and
– increases the amount of time the plasma
concentrations are in the therapeutic range
• Treatment with metoprolol succinate once daily added
to standard heart-failure therapy improves survival and
reduces the need for hospital admission due to
worsening heart failure
Good Evening dear collegues and thank you for being here. Our topic is a review of metoprolol and its benefit on heart failure but we will talk about is not our commonly used metoprolol tartrate which is the short acting one but rather metoprolol succinate, or shall I say the better metoprolol because not only is it long acting but also it this metorpolol that was used in the large trials of betablocker and heart failure
With that we will be discussing first hormonal strategies in heart failure and why metorpololol succinate whith zero order kinetics pose certain advantages over the metorpolol tartrate in CHF
We know the disease burden world wide of heart failure such that 1 out of 56 filipinos may may CHF
The neurohormonal system specifically the sympathetic nervous system, RAAS and with certain hormones and cytokines Is activated in both acute and chronic, and these neurohormonal axis is the target of treatment of heart failure
This slide will illustrate that at the molecular level, betablockade results in lowering of surrogate markets of heart failure which are your TNF Alpha, ANP and BNP. This is before betablockade and this is after and the degree of lowering is significant
This double-blind, placebo-controlled, randomised study was preceded by a single-blind, 2-week placebo run-in period. The study was approved by local ethical committees. All patients gave written informed consent. Randomisation was balanced for investigational site, age, sex, ethnic origin, cause of heart failure, previous acute myocardial infarction, time since last myocardial infarction, diabetes mellitus, ejection fraction, and NYHA functional class. With a target enrolment of 1600 patients in each group and an average follow-up of 2.4 years, MERIT-HF would have at least 80% power to detect a 30% relative-risk reduction in all-cause mortality (20% on intention to treat). The primary statistical analyses included log-rank test for the comparison of the two randomisation groups and Cox proportional hazards model for relative risk. Prespecified subgroup analyses were to be performed in any subgroup in which at least 180 total deaths in the two randomisation groups had occurred. With 180 deaths there was at least a 70% power to detect a 30% increase in risk.
Men and women aged 40–80 years were eligible for enrolment. Patients had to have symptomatic heart failure, defined as NYHA functional class II–IV. Standard therapy was defined as any combination of diuretics and an angiotensin-converting enzyme (ACE) inhibitor. If an ACE inhibitor was not tolerated, hydralazine/long-acting nitrate, or an angiotensin receptor blocker (ARB) could be used. Digitalis could also be prescribed. Patients had to have a ventricular ejection fraction of 40% or less within 3 months of recruitment. Patients with ejection fraction between 36% and 40% were eligible only if their maximum walking distance during a 6-minute walk test was 450 meters or less. Patients had to have a resting supine heart rate of at least 68 beats per minute.
The Kaplan-Meier plot of death from any cause in the MERIT-HF trial showed that the benefit provided by metoprolol CR/XL is initially seen at approximately 3 months after initiation of treatment and increases over time. There were145 deaths in the metoprolol CR/XL group (7.2%) and 217 in the placebo group (11%), corresponding to a relative risk of 0.66 (95% CI = 0.53 – 0.81; P =0.00009 nominal and 0.0062 adjusted). There was a statistically significant decrease in mortality in the metoprolol CR/XL group compared with placebo. The risk reduction was 34% (3.8% absolute reduction) in the metoprolol CR/XL group.
In this Kaplan-Meier plot of sudden death in the MERIT-HF trial, the benefit of metoprolol CR/XL could be seen very early, as the curves begin to separate before 2 months of treatment. In the metoprolol CR/XL group, there were 79 sudden deaths (4%) as opposed to 132 sudden deaths (6.6%) in the placebo group, corresponding to a relative risk of 0.59 (95% CI = 0.45 – 0.78; P =0.0002). This translates into a 41% risk reduction (2.6% absolute reduction) in the metoprolol CR/XL group.
Death from worsening heart failure occurred in 30 patients in the metoprolol CR/XL group (1.5%) and in 58 patients in the placebo group (2.9%), corresponding to a relative risk of 0.51 (95% CI = 0.33 – 0.79; P =0.0023). This translates into a 49% risk reduction (1.4% absolute reduction) in the metoprolol CR/XL group.
The combined end point of total mortality or all-cause hospitalisations (prespecified as the second of the primary end points) occurred in 641 patients in the metoprolol CR/XL group (32.2%) and in 767 patients in the placebo group (38.3%), corresponding to a relative risk reduction of 19% (95% CI =10 – 27; P =0.00012) and to a 6.1% absolute risk reduction.
The combined end point of total mortality or hospitalisations due to worsening heart failure occurred in 311 patients in the metoprolol CR/XL group (15.6%) and in 439 patients in the placebo group (21.9 %), corresponding to a relative risk reduction of 31% (95% CI =20–40; P <0.00001) and to a 6.3% absolute risk reduction.
ß-Blockade in HF Content Points: Care of HF has evolved dramatically over the past decade with the availability of treatment that changes the underlying biology of the failing heart. ß-Blockers have emerged as an important intervention for a broad range of patients as part of treatment that aims both to forestall development of HF and prevent the inexorable progression of the disease. 57 Current guidelines for the management of HF recommend the use of ß-blockers in the majority of patients, ranging from patients at high risk of developing HF to patients with asymptomatic and symptomatic disease.
Despite their proven efficacy in mild to moderate heart failure in patients with primary or secondary dilated cardiomyopathies, it is important to emphasize that b-blockers have limitations in their general application in heart failure populations. First and foremost is that many heart failure patients have contraindications to b-blockade, such as reactive airways disease, sinus node or conduction system disease with bradycardia, and advanced heart failure with hemodynamic decompensation. Another problem is that even in mild to moderate heart failure, initiation of therapy and uptitration of b-blocking agents can be difficult, requiring both persistence and knowledge of management maneuvers70 that allow target doses to be achieved. A third problem is that for reasons that are not yet clear, some individuals do not respond to b-blockade in terms of favorable effects on myocardial function, and these individuals may have a worse outcome than patients treated with placebo.62 Some but not all of these problems might be overcome by the development of heart failure– designed “fourth-generation” b-blockers,57 other effective types of antiadrenergic therapy, or b-blockers combined with positive inotropic agents.117 The importance of the b-blocker data set is not that it demonstrates a “cure” for chronic heart failure but rather that it has shown that in some patients, prognosis can be substantially improved by medical therapy. This observation should provide the impetus to develop further types of treatment that improve the biological properties of the failing heart
the distribution of oral medications prescribed among 969 patients who were registered and discharged during the pilot expansion phase of the DEAR Heart Program.
the relationship between the changes in beta-blocker dose and outcome of the HF patients studied in COMET. Hospitalisations for HF were associated with a high mortality. The patients who were withdrawn from betablocker therapy or who had a dose reduction had a higher mortality compared with those who had their dose unchanged, independent of prognostic variables assessed at baseline and at the visit before hospitalisation.
Each microcapsule acts as a diffusion cell designed to deliver metoprolol succinate at a near constant rate for approximately 20 h independent of food intake, pH, and other physiologic factors such as peristalsis (5,6). The consistent delivery system of once-daily ER metoprolol succinate reduces the peak-to-trough variability observed when subjects take the IR form of metoprolol
ER metoprolol was associated with significantly less peak-to-trough fluctuation in exercise heart rate than immediate- release metoprolol, as evidenced by a relatively stable effect on exercise heart rate throughout the dosage interval
This double-blind, placebo-controlled, randomised study was preceded by a single-blind, 2-week placebo run-in period. The study was approved by local ethical committees. All patients gave written informed consent. Randomisation was balanced for investigational site, age, sex, ethnic origin, cause of heart failure, previous acute myocardial infarction, time since last myocardial infarction, diabetes mellitus, ejection fraction, and NYHA functional class. With a target enrolment of 1600 patients in each group and an average follow-up of 2.4 years, MERIT-HF would have at least 80% power to detect a 30% relative-risk reduction in all-cause mortality (20% on intention to treat). The primary statistical analyses included log-rank test for the comparison of the two randomisation groups and Cox proportional hazards model for relative risk. Prespecified subgroup analyses were to be performed in any subgroup in which at least 180 total deaths in the two randomisation groups had occurred. With 180 deaths there was at least a 70% power to detect a 30% increase in risk.
This large-scale study was designed to investigate the effect of metoprolol CR/XL once daily in addition to standard therapy in patients with decreased ejection fraction and symptoms of heart failure (New York Heart Association (NYHA) functional class II–IV). The primary end points were total mortality and the combined end point of all-cause mortality and all-cause hospitalisation. Randomisation began February 14, 1997 and ended April 14, 1998. The Independent Safety Committee was to monitor total mortality at approximately 25%, 50%, and 75% of the total number of expected deaths. On September 21, 1998, the Independent Safety Committee undertook the secondary interim analysis of the MERIT-HF data. The Committee found that the previously defined criteria for termination of the study for mortality reduction had been met and exceeded (z = 3.807 versus 2.98 as defined in the protocol). The study was closed prematurely on October 31, 1998, because of significant benefit in the metoprolol CR/XL arm.
Men and women aged 40–80 years were eligible for enrolment. Patients had to have symptomatic heart failure, defined as NYHA functional class II–IV. Standard therapy was defined as any combination of diuretics and an angiotensin-converting enzyme (ACE) inhibitor. If an ACE inhibitor was not tolerated, hydralazine/long-acting nitrate, or an angiotensin receptor blocker (ARB) could be used. Digitalis could also be prescribed. Patients had to have a ventricular ejection fraction of 40% or less within 3 months of recruitment. Patients with ejection fraction between 36% and 40% were eligible only if their maximum walking distance during a 6-minute walk test was 450 meters or less. Patients had to have a resting supine heart rate of at least 68 beats per minute.
The Kaplan-Meier plot of death from any cause in the MERIT-HF trial showed that the benefit provided by metoprolol CR/XL is initially seen at approximately 3 months after initiation of treatment and increases over time. There were145 deaths in the metoprolol CR/XL group (7.2%) and 217 in the placebo group (11%), corresponding to a relative risk of 0.66 (95% CI = 0.53 – 0.81; P =0.00009 nominal and 0.0062 adjusted). There was a statistically significant decrease in mortality in the metoprolol CR/XL group compared with placebo. The risk reduction was 34% (3.8% absolute reduction) in the metoprolol CR/XL group.
In this Kaplan-Meier plot of sudden death in the MERIT-HF trial, the benefit of metoprolol CR/XL could be seen very early, as the curves begin to separate before 2 months of treatment. In the metoprolol CR/XL group, there were 79 sudden deaths (4%) as opposed to 132 sudden deaths (6.6%) in the placebo group, corresponding to a relative risk of 0.59 (95% CI = 0.45 – 0.78; P =0.0002). This translates into a 41% risk reduction (2.6% absolute reduction) in the metoprolol CR/XL group.
Death from worsening heart failure occurred in 30 patients in the metoprolol CR/XL group (1.5%) and in 58 patients in the placebo group (2.9%), corresponding to a relative risk of 0.51 (95% CI = 0.33 – 0.79; P =0.0023). This translates into a 49% risk reduction (1.4% absolute reduction) in the metoprolol CR/XL group.
The combined end point of total mortality or all-cause hospitalisations (prespecified as the second of the primary end points) occurred in 641 patients in the metoprolol CR/XL group (32.2%) and in 767 patients in the placebo group (38.3%), corresponding to a relative risk reduction of 19% (95% CI =10 – 27; P =0.00012) and to a 6.1% absolute risk reduction.
The combined end point of total mortality or hospitalisations due to worsening heart failure occurred in 311 patients in the metoprolol CR/XL group (15.6%) and in 439 patients in the placebo group (21.9 %), corresponding to a relative risk reduction of 31% (95% CI =20–40; P <0.00001) and to a 6.3% absolute risk reduction.
Permanent withdrawal of study drug due to any cause during the study occurred in 279 patients in the metoprolol CR/XL group and 310 patients in the placebo group (risk reduction for withdrawal decreased by 10% in the metoprolol CR/XL group; 95% CI, -5- 24%; P =0.18). Permanent withdrawal of study drug due to any adverse event occurred in 196 patients in the metoprolol CR/XL group and 234 patients in the placebo group (risk reduction, 17%; 95% CI, -1- 31%; P =0.06). Worsening heart failure was the main reason for withdrawal in 64 patients (3.2%) in the metoprolol CR/XL group and 85 (4.2%) in the placebo group (risk reduction, 25%; 95% CI, -4- 46%; P =0.08).
CIBIS II- (N= 2647) table above shows patients died or permanent treatment withdrawal; treatment withdrawn early = 28 (1%) for placebo, 41(1.5%) for metoprolol MDC- (N= 383) The definition of withdrawal was met when study medication was withdrawn more than 7 days before a subject reached a primary endpoint MERIT-HF: Study drug was permanently stopped early in 13·9% of the metoprolol CR/XL group and in 15·3% of the placebo group (0·90 [0·77–1·06]) COPERNICUS: the cumulative withdrawal rates at one year for the total cohort were 18.5 percent in the placebo group and 14.8 percent in the carvedilol group CAPRICORN: (N=1959) withdrew permanently COMET: The study drug was permanently stopped for reasons other than death in 481 (32%) patients in the carvedilol group and in 483 (32%) in the metoprolol group Reference: CIBIS-II Investigators and Committees. Lancet. 1999 Jan 2;353(9146):9-13 Waagstein F, et al. Lancet . 1993 Dec 11;342(8885):1441-6 MERIT-HF Study Group *. Lancet 1999; 353: 2001–07 Packer M et al. N Engl J Med. 2001;344: 1651-8 The CAPRICORN Investigators *. Lancet 2001; 357: 1385–90 Poole-Wilson PA , et al. Lancet. 2003 Jul 5;362(9377):7-13 A_Mabunay_MD_14May2010
85 (4.2%) in the placebo group (risk reduction, 25%; 95% CI, -4- 46%; P =0.08). Reference: CIBIS-II Investigators and Committees. Lancet. 1999 Jan 2;353(9146):9-13 Waagstein F, et al. Lancet . 1993 Dec 11;342(8885):1441-6 MERIT-HF Study Group *. Lancet 1999; 353: 2001–07 Packer M et al. N Engl J Med. 2001;344: 1651-8 The CAPRICORN Investigators *. Lancet 2001; 357: 1385–90 Poole-Wilson PA , et al. Lancet. 2003 Jul 5;362(9377):7-13 A_Mabunay_MD_14May2010
Withdrawal due to progressive heart failure was 7 metoprolol-group and 13 placebo-group (p=0.14)
