Betazok in hf_cm_eslides_21jun2010 full slides

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


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


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


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


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


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


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


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


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: 159-179Betaloc 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


Mean plasma concentrations of metoprolol CR/ZOK 100 mg, metoprolol tablets 100 mg, and metoprolol tablets 50 mg

Pharmacokinetic variablesPharmacokinetic variables


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.


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


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

Thank YouThank You

Betazok in hf_cm_eslides_21jun2010 full slides

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