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Betazok in hf_cm_eslides_21jun2010 full slides

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  • 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)
  • Transcript

    • 1. A Second Lookat Metoprolol Succinate in Heart Failure Gabriel B. Jocson III, MD
    • 2. Objectives1. Brief review of hormonal strategies in heart failure and treatment recommendations2. Discuss the zero order kinetics of Metoprolol Succinate3. Present the advantages of Metoprolol Succinate in heart failure4. 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 70s • 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
    • 4. Interplay between cardiac function and neurohormonal system in HF
    • 5. Pathophysiology of myocardial remodeling: Transition from compensated hypertrophy to HF
    • 6. Biologic effects of neurohormones coactivated in HF
    • 7. Diagnostic and prognostic significance of neuroendocrine factors in HF
    • 8. Β-blockade decreases TNF-α and natriuretic peptides in HF patients treated with ACEI NYHA class II or III. ≥6 months ACEI, diuretics, digitalis
    • 9. Biological response mediated by adrenergic receptors in the human heart
    • 10. Strategies to prevent/reverse HF progression
    • 11. Long-term β-blockade reduces oxidative stress in patients with HF
    • 12. Management of Heart Failure Assess LV Function EF < 40% Assess Volume status Fluid retention No Fluid retention ACE-I Aldactone Digoxin Diuretics B-blockerPacker and Cohn: Am J Cardiol 1999
    • 13. Advantages of MetoprololSuccinate in Heart Failure
    • 14. Metoprolol upregulates cardiac β1-receptor density in the failing heart
    • 15. MERIT-HF substudy: Effect of β-blockade on LV remodeling
    • 16. β-blockade restores LV geometry in patients with HF
    • 17. Role of β-blockade in prevention of sudden death
    • 18. Sudden death: Risk reduction with β-blockade
    • 19. Survival benefit of ACEI + β-blockade in HF
    • 20. Guidelines and TreatmentStrategies in Heart Failure
    • 21. Recommendations For Drugs In Patients With Symptomatic Systolic Dysfunction All patients (unless with Class I Recommended Class IACE Inhibitor contraindications) Level A Level A Level A ACE intolerant, persisting signs or Class I Recommended Class IARB Level A symptoms on ACEi/beta-blockade Level A Level A All patients (unless with Class I Recommended Class IΒ-blocker contraindications) Level A Level A Level AAldosterone Class I Recommended Class I Severe symptoms on ACE inhibitorantagonist Level B Level A Level B All patients with signs or symptoms of Class I Recommended Class IDiuretics congestion Level B Level A Level C Digitalis can be beneficial in patients with Class IIa Recommended Class IIaDigitalis current or prior symptoms of HF and reduced LVEF to decrease hospitalizations for HF. Level B Level C Level B
    • 22. ACC/AHA GUIDELINES FOR THERAPY IN 4 STAGES
    • 23. ACC/AHA guidelines for HF therapy:Stages A and B
    • 24. ACC/AHA guidelines for HF therapy:Stages C and D
    • 25. “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.
    • 26. Evidence -Based TreatmentAcross the Evidence-based Treatment Across the Continuum of Systolic LVD and HF Continuum of Systolic LVD and HFControl 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
    • 27. What choice of Beta Blocker?• Carvedilol• Metoprolol extended-release• Bisoprolol
    • 28. Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure MERIT-HFA 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
    • 29. 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
    • 30. 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
    • 31. 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 ODIf a patient did not tolerate increases in dose, temporary decrease was recommended MERIT-HF Study Group. Lancet 1999;353:2001-7
    • 32. Total MortalityPer cent20 Placebo 10.8%15 34% Risk Reduction10 Metoprolol CR/XL 7.2% NNT = 28 5 P=0.0062 (adjusted) P=0.00009 (nominal) 0 0 3 6 9 12 15 18 21 Months of follow-up MERIT-HF Study Group. Lancet 1999;353:2001-7
    • 33. Sudden DeathPer cent12 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
    • 34. Death From Worsening HeartPer cent Failure54 Placebo 2.9%3 49% Risk reduction Metoprolol CR/XL 1.5%2 NNT = 711 p=0.00230 0 3 6 9 12 15 18 21 Months of follow-up MERIT-HF Study Group. Lancet 1999;353:2001-7
    • 35. 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
    • 36. Total Mortality or Hospitalization for Worsening CHFPer 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
    • 37. MERIT-HF: Risk reductions in diabetic patients
    • 38. 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
    • 39. 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
    • 40. 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
    • 41. Start and target doses/ Titration scheme of Beta-blockers Beta Ist Wk1 Wk2 Wk3 Wk4 Wk5 Wk6 Wk7 Wk8 Wk1 Blocker dose – 2- (mg) Wk11 Wk16Metoprolol (MDC) 1 2 . 5 1 2 .5 25 25 50 50 100 10 0 200 200Bisoprolol(CIBIS II) 1.25 1.25 2.5 3.75 5 5 5 5 7 .5 10Carvedilol 3.12(US trials) - 5 6.26 1 2 .5 25 50
    • 42. WHEN TO START TREATMENT?• If no contraindication• Early use of β blockers risk of adverse reactionsWhich to use?• Carvedilol• Metoprolol extended-release• BisoprololHow to initiate and titrate β blockers doses?• Start low, go slow• Titration interval = 2-4 weeks• 2-3 hours observation period
    • 43. 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
    • 44. Dose Initiation In patients with clinically stable HF for 2-weeks with standard therapy (ACEI + diuretics) At very low dosesDose Titration Patients who tolerate slow upward Maximally tolerated initial doses dose adjustment target dosesTitration 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
    • 45. β-blockade in Heart Failure: Conclusion
    • 46. Limitations of β-Blockers Therapy in Chronic Heart Failure1. Contraindications in patients with • reactive airways disease • sinus node dysfunction2. 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
    • 47. Medications prescribed among Filipino patients discharged with heart failure Medications prescribed on Percent (n=969) discharge Diuretics 68 Cardiac Glycoside 56 ACE I 56 Vasodilator 50 Betablocker 38 Antithrombotic 32 Anticoagulant 26 ARBs 14 Calcium Antagonists 12 Antiarrhythmics 9 Inotropics 0.9 Jorge et al. PJC .2007; 35: 1 (January – June)
    • 48. “Withdrawal” or “reduced dose” VS “same dose”after an episode of decompensated heart failure: Results from COMETKaplan–Meier curves of mortality subsequent to discharge for thepatients who had an admission for HF, according to whether studymedication was withdrawn, the dose was dose reduced or the dosewas left unchanged (same dose). Metra, M et al. European Journal of Heart Failure. 2007;9 : 901–909
    • 49. 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
    • 50. 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 eliminatedevery hour: every hour:Hour 0:100 mg Hour 0:100 mgHour 1: 75 mg Hour 1: 92 mgHour 2: 56.2 mg Hour 2: 86 mgHour 3: 42.2 mg Hour 3: 78 mgHour 4: 31.7 mg Hour 4: 70 mgHour 5: 23.8 mg Hour 5: 62 mgHour 6: 17.8 mg Hour 6: 54 mgHour 7: 13.4 mg Hour 7: 46 mgHour 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 drugs concentration
    • 51. Metoprolol controlled release formulationMetoprolol 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 metoprololsuccinate (equivalent to 100 mg metoprolol tartrate) or400 – 450 pellets which contains 23.75 mg metoprolol succinate equivalent to 25 mgmetoprolol tartrate Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
    • 52. Fluid penetration and drug release from metoprolol CR/ZOK Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
    • 53. 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 succinatesalt 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.
    • 54. 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
    • 55. Plasma concentration of Metoprolol ZOKMean 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
    • 56. Pharmacokinetic variables Metoprolol Coventional Coventional CR/ZOK metoprolol metoprolol (100 mg) (100 mg) (50 mg b.d.)Cmax (nmol/l) 163 (117) 722 (337) 388 (207)C24 (nmol/l) 65 (90) 27 (31) 80 (93)AUC(0=24) (nmol h/l) 3068 (2323) 4645 (3215) 4532 (3391)★★ =AUC0=12 x 2. Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
    • 57. Heart rate reduction Metoprolol tartrate AtenololF.O.K. Metoprolol succinate ZOKZ.O.K. Percentage reductions in exercise heart-rate Kendall et al. J Clin Pharm and Ther. 1989; 14: 159-179
    • 58. Less peak-to-trough fluctuationin exercise heart rate with metoprololsuccinate/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 intervalMean ± SEM percentage reduction in exercise heart rate in healthyvolunteers after administration of 5 days of extended-release metoprololsuccinate 100 mg once daily (—■), immediate-release metoprololtartrate100 mg once daily (---●), or 50 mg twice daily (•••▲). Tangeman, H et al. Ann Pharmacother 2003;37:701-10.
    • 59. Reduction in blood pressure after 4 weeks Systolic BP Diastolic BP 0Reduction 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
    • 60. Mean change in FEV1 60 min after drug intake 0.5 Placebo Metoprolol CR/ZOK 100 mg Metoprolol CR/ZOK 200 mg Atenolol 100 mgΔ 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
    • 61. Advantages in Congestive Heart Failure
    • 62. 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
    • 63. Primary ObjectivesTo 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)
    • 64. 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
    • 65. 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 ODIf a patient did not tolerate increases in dose, temporary decrease was recommended MERIT-HF Study Group. Lancet 1999;353:2001-7
    • 66. Total MortalityPer cent20 Placebo 10.8%15 34% Risk Reduction10 Metoprolol CR/XL 7.2% NNT = 28 5 P=0.0062 (adjusted) P=0.00009 (nominal) 0 0 3 6 9 12 15 18 21 Months of follow-up MERIT-HF Study Group. Lancet 1999;353:2001-7
    • 67. Sudden DeathPer cent12 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
    • 68. Death From Worsening HeartPer cent Failure54 Placebo 2.9%3 49% Risk reduction Metoprolol CR/XL 1.5%2 NNT = 711 p=0.00230 0 3 6 9 12 15 18 21 Months of follow-up MERIT-HF Study Group. Lancet 1999;353:2001-7
    • 69. 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
    • 70. Total Mortality or Hospitalization for Worsening CHFPer 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
    • 71. MERIT-HF: Risk reductions in diabetic patients
    • 72. 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.
    • 73. 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. ofwithdrawals 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.
    • 74. MERIT-HF: Adverse events and Withdrawal Per cent 20 Placebo Metoprolol CR/XL 15 10 5 0 All-cause Adverse events Worsening HFNo. of -10% -17% -25%withdrawals 310/279 234/196 85/64 Hjalmarson A, et al. JAMA 2000;283:1295-302
    • 75. 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
    • 76. Comparison of withdrawals due to progression of heart failureClinical 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
    • 77. 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
    • 78. 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
    • 79. Death or need for heart transplantation MDC Waagstein et al. Lancet 1993;342:1441
    • 80. 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/BetaCIBIS II 84/65 752 III/IV 0.20 16.7MERIT - HF 72/45 795 III/IV 0.19 19.1COPERNICUS 190/130 2289 (III/IV)1 0.20 19.7Al 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.
    • 81. 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 CumulativeSurvival trial; CV = cardiovascular; HF = heart failure; MERIT-HF = Metoprolol CR/XL Randomized Intervention Trial inCongestive Heart Failure; NA = not available. Bauman,J et al. J Cardiovasc Pharmacol Ther 2004; 9; 117
    • 82. 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)
    • 83. CHF Admission or Clinic Diuretics + ACE-I or ARB + NO Class I or II Class III or IVMetoprolol succinate 25 mg OD Metoprolol succinate 12.5 mg OD 2 weeksMetoprolol succinate 50 mg OD Metoprolol succinate 25 mg OD 2 weeksMetoprolol succinate 100 mg OD Metoprolol succinate 50 mg OD 2 weeksMetoprolol succinate 200 mg OD Metoprolol succinate 100 mg OD 2 weeks Metoprolol succinate 200 mg OD
    • 84. 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
    • 85. Thank You

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