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A Second Look at Metoprolol Succinate
in Heart Failure
A Second Look at Metoprolol Succinate
in Heart Failure
Gabriel B. Jocson III, MD
ObjectivesObjectives
1.1. Brief review of hormonal strategies in heart Brief review of hormonal strategies in heart failure and treatment recommendationsfailure and treatment recommendations
2.2. Discuss the zero order kinetics of Metoprolol Discuss the zero order kinetics of Metoprolol SuccinateSuccinate
3.3. Present the advantages of Metoprolol Present the advantages of Metoprolol Succinate in heart failureSuccinate in heart failure
4.4. Show guides in preventing decompensation or Show guides in preventing decompensation or deterioration in using beta-blockers in heart deterioration in using beta-blockers in heart failurefailure
HF: The Disease BurdenHF: 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
*US Census Bureau, International Data Base, 2004
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)
Interplay between cardiac function and neurohormonal system in HF
Biologic effects of neurohormones coactivated in HF
Packer and Cohn: Am J Cardiol 1999
Assess Volume status
Fluid retention
Diuretics
No Fluid retention
ACE-I
Digoxin
Assess LV FunctionAssess LV Function
EF EF << 40% 40%
Management of Heart FailureManagement of Heart Failure
Aldactone
B-blocker
Advantages of Metoprolol Succinate in Heart FailureAdvantages of Metoprolol Succinate in Heart Failure
Metoprolol upregulates cardiac β1-receptor density in the failing heart
MERIT-HF substudy: Effect of β-blockade on LV remodeling
β-blockade restores LV geometry in patients with HF
Role of β-blockade in prevention of sudden death
Sudden death: Risk reduction with β-blockade
Survival benefit of ACEI + β-blockade in HF
Guidelines and Treatment Strategies in Heart FailureGuidelines and Treatment Strategies in Heart Failure
Recommendations For Drugs In Patients With Symptomatic Systolic Dysfunction
ACE InhibitorAll patients (unless with contraindications)
Class I Level A
Recommended Level A
Class I Level A
ARB ACE intolerant, persisting signs or symptoms on ACEi/beta-blockade
Class ILevel A
Recommended Level A
Class I Level A
Β-blockerAll patients (unless with contraindications)
Class ILevel A
Recommended Level A
Class I Level A
Aldosterone antagonist
Severe symptoms on ACE inhibitor Class ILevel B
Recommended Level A
Class I Level B
Diuretics All patients with signs or symptoms of congestion
Class ILevel B
Recommended Level A
Class I Level C
DigitalisDigitalis can be beneficial in patients withcurrent or prior symptoms of HF and reduced LVEF to decrease hospitalizations for HF.
Class IIa Level B
Recommended Level C
Class IIa Level B
What choice of Beta Blocker?
• Carvedilol• Metoprolol extended-release• Bisoprolol
MERIT-HF Study Group. Lancet 1999;353:2001-7
MERIT-HFMERIT-HFA Double-Blind, Placebo-Controlled Survival Study A Double-Blind, Placebo-Controlled Survival Study
With Metoprolol CR/XL in Patients With With Metoprolol CR/XL in Patients With Decreased Ejection Fraction (Decreased Ejection Fraction (0.40) 0.40)
and Symptoms of Heart Failure (NYHA II–IV)and Symptoms of Heart Failure (NYHA II–IV)
Metoprolol CR/XL Randomized Intervention Trial
in Congestive Heart Failure
Metoprolol CR/XL Randomized Intervention Trial
in Congestive Heart Failure
* 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.
Single-blind
Double-blind
Weeks
Titrated from12.5 mg/25 mg
to 200 mg once dailyover 6 to 8 weeks* n=1990
MetoprololCR/XL
n=2001Placebo
211812 15963-2
PlaceboRun-in
Months
MERIT – HF Study DesignMERIT – HF Study Design
MERIT-HF Study Group. Lancet 1999;353:2001-7
Inclusion CriteriaInclusion 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
Dosing Simplicity Dosing Simplicity
Starting dose at 12.5 mg or 25 mg OD
(half a 25 mg tablet recommended for patients who were NYHA III/IV)
2 weeks
Increased to 50 mg OD
2 weeks
Increased to 100 mg OD
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
2 weeks
Months of follow-up
Per cent
0 3 6 9 12 15 18 21
20
15
10
5
0
Placebo 10.8%
Metoprolol CR/XL 7.2%
P=0.0062 (adjusted)P=0.00009 (nominal)
34% Risk Reduction34% Risk Reduction
Total MortalityTotal Mortality
MERIT-HF Study Group. Lancet 1999;353:2001-7
NNT = 28
12
9
6 Metoprolol CR/XL 3.9%
p=0.0002
Sudden DeathSudden Death
0 3 6 9 12 15 18 21Months of follow-up
Per cent
Placebo 6.6%
41% Risk reduction41% Risk reduction
3
0
MERIT-HF Study Group. Lancet 1999;353:2001-7
NNT = 38
5
4
3
1
Placebo 2.9%
Metoprolol CR/XL 1.5%
p=0.0023
2
Death From Worsening Heart Failure
Death From Worsening Heart FailurePer cent
0 3 6 9 12 15 18 21Months of follow-up
0
49%49% Risk reductionRisk reduction
MERIT-HF Study Group. Lancet 1999;353:2001-7
NNT = 71
Total Mortality or All-Cause Hospitalization(Time to First Event)
Total Mortality or All-Cause Hospitalization(Time to First Event)Per cent
60
50
30
Placebo
Metoprolol CR/XL
p=0.00012
40
20
10
19% Risk reduction19% Risk reduction
00 3 6 9 12 15 18 21
Months of follow-upHjalmarson A, et al. JAMA 2000;283:1295-302
Total Mortality or Hospitalization for Worsening CHF(Time to First Event)
Total Mortality or Hospitalization for Worsening CHF(Time to First Event)
Months of follow-up
Per cent
0 3 6 9 12 15 18 21
40
30
20
10
0
Placebo
Metoprolol CR/XL
p<0.00001
31% Risk reduction31% Risk reduction
Hjalmarson A, et al. JAMA 2000;283:1295-302
MERIT-HF: Risk reductions in diabetic patients
DosingDosing
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
DosingDosing
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
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Start and target doses/ Titration scheme ofStart and target doses/ Titration scheme of
Beta-blockersBeta-blockers
Limitations of β-Blockers Therapy in Chronic Heart Failure
Limitations of β-Blockers Therapy in Chronic Heart Failure
Circulation Circulation 2000;101;558-5692000;101;558-569
1.1. Contraindications in patients with Contraindications in patients with
reactive airways disease reactive airways disease sinus node dysfunctionsinus node dysfunction
2.2. Reluctance to initiate in Reluctance to initiate in
advanced heart failure *advanced heart failure * decompensated heart failure*decompensated heart failure*
3.3. Initiation and uptitration may be difficult (target doses Initiation and uptitration may be difficult (target doses are not achieved)are not achieved)
4.4. Beta-Blocker resistance (unclear reasons)Beta-Blocker resistance (unclear reasons)
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
“Withdrawal” or “reduced dose” VS “same dose”after an episode of decompensated heart failure:
Results from COMET
Beta-Blocker with Z.O.K.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.
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 timeDrug elimination is independent of the drug's concentration
1st order:25% is eliminated every hour:Hour 0:100 mg Hour 1: 75 mgHour 2: 56.2 mgHour 3: 42.2 mgHour 4: 31.7 mgHour 5: 23.8 mgHour 6: 17.8 mgHour 7: 13.4 mgHour 8: 3.4 mg
ZERO order:8 mg is eliminated every hour:Hour 0:100 mg Hour 1: 92 mgHour 2: 86 mgHour 3: 78 mgHour 4: 70 mgHour 5: 62 mgHour 6: 54 mgHour 7: 46 mgHour 8: 38 mg
Metoprolol controlled release Metoprolol controlled release formulationformulation
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
Metoprolol CR (ZOK) is a divisible tablet consisting of a multitude of small subunits (pellets) Metoprolol CR (ZOK) is a divisible tablet consisting of a multitude of small subunits (pellets) embedded in an inert tablet mass.embedded in an inert tablet mass.
Each tablet contains about 1,600 to 1,800 pellets which contains 95 mg of metoprolol Each tablet contains about 1,600 to 1,800 pellets which contains 95 mg of metoprolol succinate (equivalent to 100 mg metoprolol tartrate) or succinate (equivalent to 100 mg metoprolol tartrate) or
400 – 450 pellets which contains 23.75 mg metoprolol succinate equivalent to 25 mg 400 – 450 pellets which contains 23.75 mg metoprolol succinate equivalent to 25 mg metoprolol tartratemetoprolol tartrate
Fluid penetration and drug release from metoprolol CR/ZOK
Fluid penetration and drug release from metoprolol CR/ZOK
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179Betaloc Prescribing Information, AstrazZeneca, Data on File
Betazok Prescribing Information, AstrazZeneca, Data on FileTangeman, H et al. Ann Pharmacother 2003;37:701-10.
Pharmacology: Conventional metoprolol tartrate vs metoprolol succinate
Pharmacology: Conventional metoprolol tartrate vs metoprolol succinate
ParametersParameters Metoprolol TartrateMetoprolol Tartrate Metoprolol SuccinateMetoprolol Succinate
AbsorptionAbsorption Rapid and completeRapid and complete SLOW and completeSLOW and complete
11stst pass metabolism pass metabolism extensiveextensive extensiveextensive
MetabolismMetabolism Liver CYP2D6Liver CYP2D6 Liver CYP2D6Liver CYP2D6
PeakPeak 1.5- 2 hour1.5- 2 hour 6-12 hours6-12 hours
DurationDuration 6-12 hours6-12 hours 24 hours24 hours
Solubility Solubility aqueousaqueous LipophilicLipophilic
Food interactionFood interaction May increase systemic May increase systemic availability by 30-40%availability by 30-40%
nonenone
BioavailabilityBioavailability 50%-70%*50%-70%* 20-30%20-30%
Protein BindingProtein Binding 5-10%5-10% 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
Advantages of Z.O.K.Advantages of Z.O.K.
1.1. Continuous and even Continuous and even ββ11-Blockade with once -Blockade with once daily dosingdaily dosing
2.2. Reduce adverse effects associated with HIGH Reduce adverse effects associated with HIGH peak plasma concentrationspeak plasma concentrations
3.3. Increases the amount of time the plasma Increases the amount of time the plasma concentrations are in the therapeutic rangeconcentrations are in the therapeutic range
4.4. Helps achieve simplicity, efficacy, and Helps achieve simplicity, efficacy, and tolerability especially in patients with heart tolerability especially in patients with heart failurefailure
Plasma concentration of Metoprolol ZOK
Plasma concentration of Metoprolol ZOK
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
Mean plasma concentrations of metoprolol CR/ZOK 100 mg, metoprolol tablets 100 mg, and metoprolol tablets 50 mg
Pharmacokinetic variablesPharmacokinetic variables
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
MetoprololCR/ZOK(100 mg)
Coventionalmetoprolol(100 mg)
Coventionalmetoprolol
(50 mg b.d.)
CCmaxmax (nmol/l) (nmol/l)
CC2424 (nmol/l) (nmol/l)
AUCAUC(0=24) (0=24) (nmol h/l)(nmol h/l)
163 (117)163 (117)65 (90)65 (90)
3068 (2323)3068 (2323)
722 (337)722 (337)27 (31)27 (31)
4645 (3215)4645 (3215)
388 (207)388 (207)80 (93)80 (93)
4532 (3391)4532 (3391)★★
★★=AUC=AUC0=120=12 x 2. x 2.
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
Heart rate reductionHeart rate reduction
Percentage reductions in exercise heart-ratePercentage reductions in exercise heart-rate
Metoprolol tartrateMetoprolol tartrate
Metoprolol succinate ZOKMetoprolol succinate ZOK
AtenololAtenolol
F.O.K.
Z.O.K.
Reduction in blood pressure after 4 weeks
Reduction in blood pressure after 4 weeks
Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
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
0
10
20
Red
uctio
n in
sup
ine
BP
(m
mH
g)
Systolic BP Diastolic BP
*
Well Tolerated in Severe Heart Failure
Well Tolerated in Severe Heart Failure
Goldstein et al. J Am Coll Cardiol. 2001 Oct;38(4):932-8.
Total Number of HospitalizationsPost-hoc Subgroup analysis of Patients with Severe Heart Failure
400
300
200
100
0
p = 0.0037
p = 0.0005
p < 0.0001
All-cause-27%
CV cause-34%
Heart failure-45%
Placebo
Metoprolol CR/XL
TolerabilityTolerability
Goldstein et al. J Am Coll Cardiol. 2001 Oct;38(4):932-8.
Withdrawal of Study MedicinePost-hoc Subgroup analysis of Patients with Severe Heart
Failure
25
20
10
5
0
p = 0.027
p = 0.018
p = 0.012
All-cause-31%
Adverse events-39%
Wors. CHF-49%
Placebo
Metoprolol CR/XL
15
No. of withdrawals 86/62 66/42 34/18
Percent
0
5
10
15
20
All-cause-10%
310/279
Adverse events-17%
234/196
Worsening HF-25%
85/64
MERIT-HF: Adverse events and WithdrawalMERIT-HF: Adverse events and Withdrawal
Per cent
No. ofwithdrawals
PlaceboMetoprolol CR/XL
Hjalmarson A, et al. JAMA 2000;283:1295-302
Comparison of withdrawals due to progression of heart failure
Comparison of withdrawals due to progression of heart failure
Waagstein F, et al. Lancet. 1993 Dec 11;342(8885):1441-6MERIT-HF Study Group*. Lancet 1999; 353: 2001–07Packer M et al. N Engl J Med. 2001;344: 1651-8
Clinical TrialClinical Trial
MDCMDC
MERIT HFMERIT HF
COPERNICUSCOPERNICUS
Withdrawal inWithdrawal inPlacebo ArmPlacebo Arm
(n)(n)
13 (6.7%)13 (6.7%)
85 (4.2%)85 (4.2%)
(24.2%)(24.2%)
Withdrawal inWithdrawal inBeta blocker ArmBeta blocker Arm
(n)(n)
7 (3.7%)7 (3.7%)
64 (3.2%)64 (3.2%)
(17.5%)(17.5%)
pp
(p = 0.14)(p = 0.14)
(p = 0.08)(p = 0.08)
----
SummarySummary
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
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