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Role of beta blockers in the management of cardiovascular diseases

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Role of beta blockers in the management of cardiovascular diseases

  1. 1. Role of beta-blockers in the management of cardiovascular diseases
  2. 2. The Cardiovascular Continuum in Hypertension and the Relative Preventive Effect of BP Lowering and Ancillary Actions of Antihypertensive Agents BP  + Specific Ancillary Actions BP  + Specific Ancillary Actions BP  + Specific Ancillary Actions BP  + Specific Ancillary Actions Metabolic Syndrome Dyslipidemia LVH IMT Microalb. Mild Renal Disease Recent Diabetes Endothelial Dysfunction MI Stroke CHF ESRD Angina TIA Claudicatio Proteinuria Moderate Renal Disease Established Diabetes Subclinical Organ Damage Risk Factors Clinical Disease Cardio- vascular Event Death Hypertension Zanchetti J Hypertens 2005;23:1113-20
  3. 3. Kaplan’s clinical hypertension
  4. 4. Opie LH. Drug for the Heart. Elsevier Saunders 2005, 6th ed p.21
  5. 5. Poldermans D et al. NEJM 1999; 341: 1789-94 Zaugg M. Der Anaesthesist 2000; 49: 570-585 Reduce sympathetic nervous system activation (heart rate and myocardial contractility); balance the myocardial oxygen supply/demand ratio Increase the threshold for ventricular fibrillation in the presence of ischemia May increase the stability of coronary atherosclerotic plaques May reduce myocardial oxygen consumption by suppressing lipolysis, causing the myocardium to metabolize more glucose instead of fatty acids Cardioprotective mechanisms of beta-blockers
  6. 6. Indications for ß-Blockade & US FDA-Approved Drugs Opie LH. Drug for the Heart. Elsevier Saunders 2005, 6th ed p.2 Bisoprolol, atenololPerioperarive ischemia Propranolol, timolol, metoprolol, carvedilolAMI, follow-up Atenolol, metoprololAMI, early phase NoneSilent ischemia Propranolol, nadolol, atenolol, metoprololAngina pectoris 1. Ischemic Heart Disease US FDA-Approved DrugsIndications for ß-Blockade
  7. 7. Opie LH. Drug for the Heart. Elsevier Saunders 2005, 6th ed p.2 2. Hypertension Hypertension, systemic Acebutolol, atenolol, bisoprolol, labetalol, metoprolol, nadolol, pindolol, propranolol, timolol Hypertension, severe, urgent Labetalol Hypertension with LVH Prefer angiotensin receptor blocker Hypertension, isolated systolic No outcome studies, prefer diuretic, CCB Pheochromocytoma( already receiving ˆ blockade) Propranolol Hypertension, severe, perioperative Esmolol Indications for ß-Blockade US FDA-Approved Drugs Indications for ß-Blockade & US FDA-Approved Drugs
  8. 8. 3. Arrhythmias Excess urgent sinus tachycardia Esmolol Tachycardias (sinus, SVT &VT) Propranolol Supraventricular, perioperative Esmolol Recurrences Of Afib, Afl Sotalol Control of ventricular rate in Afib,Afl Propranolol Digitalis-induced tachyarrhythmias Propranolol Anesthetic arrhythmias Propranolol PVC control Acebutolol, propranolol Serious ventricular tachycardia Sotalol Indications for ß-Blockade US FDA-Approved Drugs Indications for ß-Blockade & US FDA-Approved Drugs Opie LH. Drug for the Heart. Elsevier Saunders 2005, 6th ed p.2
  9. 9. 4 Congestive Heart Disease Carvedilol, metoprolol (bisoprolol) 5. Cardiomyopathy Hypertrophic obstructive cardiomyopathy Propranolol 6. Other cardiovascular indications Neurocardiogenic syncope, aortic dissection (Propranolol; ? all) Marfan’s syndrome, mitral valve prolapse, congenital QT prolongation Tetralogy of Fallot, fetal tachycardia 7. Central indications Anxiety (Propranolol) Opie LH. Drug for the Heart. Elsevier Saunders 2005, 6th ed p.2 Indications for ß-Blockade US FDA-Approved Drugs Indications for ß-Blockade & US FDA-Approved Drugs
  10. 10. - Chobanian AV et al. JNC 7. JAMA 2003 ; 289 : 2560-2572 - ESH Guidelines Committee. J Hypertens 2003 ; 21 : 1011-1053 Compelling indications for beta-blockade Hypertension /Heart Failure Hypertension /post MI Hypertension /high CAD risk Hypertension /Diabetes Mellitus Hypertension /arrhythmias Hypertension /angina pectoris
  11. 11. MECHANISMS OF PRIMARY (ESSENTIAL) HYPERTENSION BRAUNWALD'S HEART DISEASE
  12. 12. BRAUNWALD'S HEART DISEASE renal juxtaglomerular Renin-Angiotensin Mechanism ACEI ARB Beta-blocker
  13. 13. Beta-blocker therapy should be started and continued for 3 years in all patients with normal LV function after MI or ACS. Beta-blocker therapy should be used in all patients with LV systolic dysfunction (EF ≤40%) with heart failure or prior MI, unless contraindicated. (Use should be limited to carvedilol, metoprolol succinate, or bisoprolol, which have been shown to reduce risk of death.) Beta blockers may be considered as chronic therapy for all other patients with coronary or other vascular disease. I IIa IIb III I IIa IIb III I IIa IIb III Beta-Blocker Therapy
  14. 14. Beta Blockers Beta blockers are indicated for all patients recovering from UA/NSTEMI unless contraindicated. (For those at low risk, see Class IIa on the next slide). Treatment should begin within a few days of the event, if not initiated acutely, and should be continued indefinitely. Patients recovering from UA/NSTEMI with moderate or severe LV failure should receive beta-blocker therapy with a gradual titration scheme. III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
  15. 15. Beta Blockers It is reasonable to prescribe beta blockers to low-risk patients (i.e., normal LV function, revascularized, no high-risk features) recovering from UA/NSTEMI in the absence of absolute contraindications. III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
  16. 16. 18 b-Blocker Saves Lives in Heart Failure? b–blocker is the most important progress in Heart Failure Rx in the last 5 years
  17. 17. Effect of medical therapies that affect the natural history of heart failure based on the primary site of action. CRT-(D) indicates cardiac resynchronization therapy plus defibrillator; ACEIs, angiotensin-converting enzyme inhibitors; and Aldo, aldosterone
  18. 18. Volume Overload Pressure Overload Loss of Myocardium Impaired Contractility LV Dysfunction EF < 40%  Cardiac Output Hypoperfusion  End Systolic Volume  End Diastolic Volume Pulmonary Congestion Left Ventricular Dysfunction
  19. 19. 22 Effect of BetaBlockadeonOutcome inPatientsWithHFandPost-MI LVD ↓23%mortality(p=.031)25BIDpost-MI LVD carvedilolCAPRICORN5 ↓35%mortality(p=.0014)25BIDseverecarvedilolCOPERNICUS4 ↓34%mortality(p=.0062)200QDmild/ moderate metoprolol succinate MERIT-HF3 ↓34%mortality(p<.0001)10QDmoderate/ severe bisoprololCIBIS-II2 ↓48%diseaseprogression (p=.007) 6.25- 25BID mild/ moderate carvedilolUSCarvedilol1 Outcome Target Dose(mg) HF SeverityDrugStudy 1.Colucci WSet al. Circulation1196;94:2800-6. 2. CIBISII Investigators. Lancet 1999;353:9-13. 3. MERIT-HFStudyGroup. Lancet 1999;353:2001-7. 4. Packer Met al. NEngl JMed2001;3441651-8. 5. TheCAPRICORNInvestigators. Lancet 2001;357:1385-90.
  20. 20. Placebo-controlled randomised European trial Objectives:  Mortality  Tolerability of beta-blockade by bisoprolol in heart failure Lechat Ph et al. Circulation 1994; 90: 1765–1773 C I B I S I Cardiac Insufficiency Bisoprolol Study
  21. 21. • Reduction of mortality with bisoprolol in patients ... ... in total (n = 641) – 20% p = 0.22 ... without myocardial infarction – 47% p = 0.01 ... with dilated cardiomyopathy – 53% p = 0.01 ... with a ventricular rate of over 80 beats/minute – 42% p < 0.05 • Reduction by one NYHA class in patients receiving ... ... bisoprolol 21% p = 0.04 ... placebo 15% • Reduction in heart failure decompensation – 32% p < 0.01 requiring hospitalisation Lechat Ph at the CIBIS investigators’ meeting at the Journées Européennes de la Société Française de Cardiologie, Paris, 1994 CIBIS I: Main results
  22. 22. • Double-blind, placebo-controlled, randomised trial • 2,647 patients included (NYHA III + IV) • Bisoprolol administered on top of standard therapy (diuretic + ACE inhibitor) CIBISIIInvestigatorsandCommittees.Lancet1999;353:9–13 CIBIS II Cardiac Insufficiency Bisoprolol Study
  23. 23. • Ambulatory patients with stable CHF of all aetiologies • NYHA functional class III or IV • Stable on ACE inhibitor and diuretic • Aged 18 – 80 years • Left ventricular ejection fraction ≤ 35% CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 CIBIS II Main inclusion criteria
  24. 24. In the bisoprolol-treated group of patients there was a reduction in • All-cause mortality (independent of aetiology) by 34% (p<0.0001) • Sudden death by 44% (p<0.0011) • All-cause hospital admissions by 20% (p<0.0006) • Hospital admissions due to worsening heart failure by 36% (p<0.0001) CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13 CIBIS II Main results at a glance
  25. 25. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001; 22: 1527-60 Chronic heart failure:  Still a major clinical and public health problem  Current pharmacological therapy:  ACE-inhibitors  Beta-blockers  Diuretics  Aldosterone antagonists  Digitalis glycosides C I B I S III Cardiac Insufficiency Bisoprolol Study
  26. 26. Background  Guidelines universally recommend that treatment of patients with chronic heart failure (CHF) should be initiated with an angiotensin-converting enzyme inhibitor (ACEi) to which a β-blocker should be added as second step therapy.  These recommendations are not based on evidence.  No study has examined the safety and efficacy of initiating CHF treatment with an ACEi versus a β-blocker.  Several mechanistic reasons support choosing beta- blockade as first therapy in CHF. Willenheimer et al., Circulation 2005; 112: 2426-35
  27. 27. Background (conti…) • Sympathetic nervous system is activated prior to RAAS in CHF. • In the early course of CHF, sudden death is the most prevalent mode of death. • β-blockers in contrast to ACEi are proven highly effective in reducing sudden death. • From the pathophysiological point of view it may be appropriate to start with a β-blocker first. Willenheimer et al., Circulation 2005; 112: 2426-35
  28. 28. PoldermansDetal.NEJM1999;341:1789-94 ZauggM.DerAnaesthesist2000;49:570-585 reduce sympathetic nervous system activation (heart rate and myocardial contractility); balance the myocardial oxygen supply/demand ratio increase the threshold for ventricular fibrillation in the presence of ischemia may increase the stability of coronary atherosclerotic plaques may reduce myocardial oxygen consumption by suppressing lipolysis, causing the myocardium to metabolize more glucose instead of fatty acids Cardioprotective mechanisms of beta-blockers
  29. 29. Beta-blockade: • Renoprotective in patients with CHF, reduce the risk of worsening renal function which is frequently observed with ACE-inhibitors 1,2  pretreatment with beta-blockers protective against the potential development of renal impairment with ACE-inhibitors • More effective in reducing sudden cardiac death than ACE-inhibitors 3-7  up to 40-60% of patients with CHF die from sudden cardiac death (mainly in early stages of CHF) 4,7,8 1.KnightELetal.AmHeartJ1999;138:849-552.BartBA.AmHeartJ1999;138:801-33.CIBISIIInvestigators Committees.Lancet1999;353:9-134.MERIT-HFStudyGroup.Lancet1999;353:2001-7 5.PackerMetal.NEnglJMed2001;344:1651-586.GargRetal.JAMA1995;273:1450-56 7.AliotEetal.EurHeartJ2002:4(SupplD);D31-D428.UretskyBFetal.JACC1997;30:1589-97 CIBIS III Rationale
  30. 30. Sudden Death In Chronic Heart Failure 50-80 30-50 5-30 5-15 20-50 30-70 II III IV Sudden Death(%)Annual Mortality (%)NYHA Functional Class These data summarize mortality estimates from the published data Uretsky and Sheahan JACC 1997;30 : 1589-97
  31. 31. • ACE-inhibitors: mortality reduction of about 25%1 • ACE-inhibitors + beta-blockers: further reduction of 30-35%2-5 1.GargRetal.JAMA1995;273:1450-562.ShibataMCetal.EurJHeartFailure2001;3:351-57 3.CIBISIIInvestigatorsCommittees.Lancet1999;353:9-134.MERIT-HFStudyGroup.Lancet1999; 353:2001-75.PackerMetal.NEnglJMed2001;344:1651-586.ExnerDVetal.JACC1999;33:916-23  beta-blockers more effective than ACE-inhibitors in CHF?6 CIBIS III Rationale
  32. 32. • Age ≥ 65 years • Mild to moderate CHF (NYHA class II or III) • LVEF ≤ 35% • Stable CHF since ≥ 7 days (without clinically relevant fluid retention/diuretic adjustment) Willenheimeretal.,Circulation2005;112:2426-35 Cardiac Insufficiency Bisoprolol Study III Inclusion criteria
  33. 33. Bisoprolol-first (o.d.) Enalapril-first (b.i.d.) Bisoprolol o.d. Enalapril b.i.d. Bisoprolol o.d. Enalapril b.i.d week Study end 1 - 2.5 years 0 2 4 6 8 10 26 28 30 32 34 36week Study end 1 - 2.5 years First up-titration First up-titration Second up-titration Second up-titrationMaintenance period Maintenance period Second maintenance period 22-100 weeks Second maintenance period 16-94 weeks 1.25 2.5 3.75 5.0 7.5 1.25 2.5 3.75 5.0 7.5 2.5 5.0 2.5 5.0 * * * * * * * * * * * * * * * * ……….……. * * * * * * = visits 10.0 mg 10.0 mg 10.0 mg 10.0 mg Bisoprolol o.d. Enalapril b.i.d 0 2 4 6 8 10 26 28 30 32 34 36 * * * * * * * * * * * * * * * * ……….……. * * * * * Willenheimeretal.,Circulation2005;112:2426-35 Study design Cardiac Insufficiency Bisoprolol Study III
  34. 34. In terms of combined mortality / hospitalization Bisoprolol-first was non-inferior to enalapril-first in the ITT sample Bisoprolol-first was close to non-inferior to enalapril-first in the PP sample Willenheimer et al., Circulation 2005; 112: 2426-35 Intention-to-treat (ITT) Per-protocol (PP) Cardiac Insufficiency Bisoprolol Study III Conclusions
  35. 35. There was no difference in safety between the two strategies, showing that a bisoprolol-first strategy does not cause concerns Willenheimer et al., Circulation 2005; 112: 2426-35 Cardiac Insufficiency Bisoprolol Study III Conclusions
  36. 36. The CIBIS III result supports a free choice of initial treatment for CHF - enalapril or bisoprolol - based on the physician’s individual judgment in each patient Willenheimer et al., Circulation 2005; 112: 2426-35 Clinical implication
  37. 37. MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure Purpose To determine whether metoprolol controlled/extended release (CR/XL) once daily, in addition to standard therapy, can lower mortality in patients with decreased ejection fraction and symptoms of heart failure Reference MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–7.
  38. 38. MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure - TRIAL DESIGN - Design Randomized, double-blind, placebo-controlled Patients 3991 patients with left ventricular ejection fraction <0.40 and NYHA class II-IV heart failure, stabilized by optimum standard therapy (any combination of diuretics + ACE inhibitor) Follow up and primary endpoint Aim 2.4 years follow up. Primary endpoint all-cause mortality Treatment Patients assigned metoprolol received 12.5 (NYHA III-IV) or 25 mg (NYHA II) once daily, increasing over 8 weeks to maximum target dose 200 mg once daily
  39. 39. MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure - RESULTS - • Study halted at mean follow up of 1 year on recommendation of independent safety committee because predefined criteria met and exceeded: —All-cause mortality significantly lower in metoprolol CR/XL group (145 vs. 217, 34% risk reduction, P=0.0062) —Significantly fewer cardiovascular deaths (128 vs. 203), sudden deaths (79 vs. 132) and death from worsening heart failure (30 vs. 58) • Drug well tolerated, as defined by permanent early discontinuation of treatment (13.9% of metoprolol CR/XL group versus 15.3% placebo)
  40. 40. MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure - RESULTS continued - MERIT-HF Study Group. Lancet 1999;353:2001–7. No patients lost to follow up MERIT-HF trial profile 3991 patients randomized 2001 patients placebo 217 patient deaths 1784 patients alive 1539 patients on treatment 145 patient deaths 1990 patients metoprolol CR/XL 1845 patients alive 1614 patients on treatment
  41. 41. MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure - RESULTS continued - Cumulative all-cause mortality MERIT-HF Study Group. Lancet 1999;353:2001–7. Follow up (months) P = 0.0062 (adjusted for interim analysis) P = 0.00009 (nominal) 0 0 3 6 9 12 16 18 21 5 10 15 20 Placebo Metoprolol CR/XL Cumulative mortality (%)
  42. 42. MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure - RESULTS continued - MERIT-HF Study Group. Lancet 1999;353:2001–7. 0 0.5 1.0 1.5 Relative risk for mortality Relative risk (95% CI) Mortality Metoprolol CR/XL better Risk reduction (%) Total mortality Cardiovascular mortality Sudden death Death from worsening heart failure 34 38 41 49 0.0062 0.00003 0.0002 0.0023 P
  43. 43. MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure - SUMMARY - Metoprololol CR/XL once daily in addition to optimum standard therapy: • Was well tolerated and did not increase risk in any of subgroups analyzed • Improved survival in clinically stable patients, equating to prevention of 1 death per 27 patients treated per year
  44. 44. Effect of carvedilol, bisoprolol and metoprolol on mortality in CHF • 1094 patients with class II–IV CHF randomised to placebo or carvedilol for up to 15 months • 65% in all-cause mortality (stopped by DSMB) US Carvedilol Heart Failure Program CIBIS II trial • 2647 patients with class III–IV CHF randomised to placebo or bisoprolol for up to 3 years • 34% in all-cause mortality (stopped by DSMB) MERIT-HF trial • 3991 patients with class III–IV CHF randomised to placebo or metoprolol for up to 3 years • ~34%  in all-cause mortality (stopped by DSMB) Packer (1996); CIBIS-II (1999); MERIT-HF (1997)
  45. 45. Multicentre trials of b-blocker effects on morbidity and mortality in CHF Study Effect on Effect on Effect on pre-specified endpoint mortality morbidity MDC  Morbidity/mortality  Non-significant  In risk of worsening by 34% (p=0.058) in mortality heart failure CIBIS-I  Mortality by Mortality by 20%  Hospitalisations 20% (p=0.22) (especially non-ischaemic) for heart failure by 34% ANZ Carvedilol  Morbidity/mortality  Mortality by 25–35%  Cardiovascular by 26% (p=0.02) (ischaemic only) hospitalisations by 25–30% US Carvedilol  Mortality by Mortality by 65%  Cardiovascular 65% (p=0.001) (ischaemic and hospitalisations by 26% non-ischaemic) ANZ, Australia–New Zealand Cooperative Study CIBIS-I, Cardiac Insufficiency Bisoprolol Study MDC, Metoprolol in Dilated Cardiomyopathy Study US Carvedilol, US Carvedilol Heart Failure Program
  46. 46. b-adrenergic blocking drugs in heart failure Principal randomized trials - more than 250 patients, greater than 6 months follow-up Annualized mortality rate Placebo mortality rate (annualized %) b-blocker mortality rate (annualized %) US Carvedilol 15%* 6%* CIBIS-II 13.2% 8.8% MERIT-HF 11.0% 7.2% *estimated from 7 month data
  47. 47. Carvedilol vs placebo in patients with mild, moderate and severe CHF The US Study Program protocol • Patient population – 1094 patients with chronic CHF – CHF  3 months – LVEF 35% despite  2 months treatment with diuretics + ACE-I • Planned study duration – 6–12 months (prematurely terminated because of a significant effect of carvedilol on survival) • Exclusion criteria – active ventricular tachycardia – HR <68 bpm – systolic BP <85 mmHg or >160 or diastolic BP > 100 mmHg • Primary outcomes – death from cardiovascular causes • Secondary outcomes – frequency of hospitalisation for cardiovascular reasons Packer (1996)
  48. 48. Effect of carvedilol on morbidity and mortality The US Study Program ACE inhibitor Digitalis Diuretic Packer (1996) Mortality Hospital days –52% –65% Carvedilol
  49. 49. Cause and incidence of death in the US Carvedilol Heart Failure Program Cause of death Progressive heart failure Sudden death Myocardial ischaemia Other cardiovascular causes Noncardiovascular causes Placebo Carvedilol (n=398) (n=696) No. (%) 13 (3.3) 5 (0.7) 15 (3.8) 12 (1.7) 2 (0.5) 1 (0.1) 1 (0.3) 2 (0.3) 0 2 (0.3) Packer (1996)
  50. 50. US Carvedilol Heart Failure Program Most frequent adverse reactions leading to discontinuation of treatment Adverse event* Heart failure Fatigue Myocardial infarction Bradycardia Dyspnoea Dizziness Hypotension Syncope Nausea Abnormal liver function Worsening renal function Depression Placebo Carvedilol (n=398) (n=696) no. (%) 9(2.3) 11(1.6) 3(0.8) 5(0.7) 4(1.0) 3(0.4) 0 6(0.9) 4(1.0) 2(0.3) 0 3(0.4) 1(0.3) 2(0.3) 1(0.3) 2(0.3) 0 3(0.4) 1(0.3) 2(0.3) 1(0.3) 2(0.3) 1(0.3) 2(0.3) *Patients may have had more than one reaction leading to withdrawal of placebo or carvedilol Packer (1996)
  51. 51. Patient subgroup Placebo Carvedilol (%) (%) Mild heart failure 3.7 0.9 Moderate heart failure 7.6 4.5 Severe heart failure 5.7 2.9 Age<59 years 5.8 2.0 Age59 years 9.6 4.3 Male 7.2 3.2 Female 9.6 3.1 Ischaemic cause 9.0 3.9 Non-ischaemic cause 6.7 2.5 US Carvedilol Heart Failure Program % deaths in patient subgroups Packer (1996)
  52. 52. US Carvedilol Heart Failure Program Effects in patient subgroups Patient subgroup* Protocol Mild heart failure Moderate heart failure Dose-ranging Severe heart failure Age (yr) <59 59 Gender Male Female Left ventricular ejection fraction <0.23 0.23 Placebo Carvedilol 5/134 2/232 11/145 6/133 13/84 12/261 2/35 2/70 11/190 7/350 20/208 15/346 22/304 17/534 9/94 5/162 20/209 10/334 11/189 12/360 No of deaths/total no Hazard ratio (98% Cl)† 0.22 (0.04–1.14) 0.57 (0.21–1.54) 0.27 (0.12–0.60) 0.53 (0.07–3.76) 0.30 (0.11–0.80) 0.38 (0.19–0.77) 0.41 (0.22–0.80) 0.23 (0.07–0.69) 0.25 (0.11–0.56) 0.49 (0.21–1.14) * For continuous variables, medians were used to define the subgroups. The type of heart failure was not recorded for one patient in the placebo group and two in the carvedilol group. The ejection fraction was not recorded for two patients in the carvedilol group. Packer (1996) †CI denotes confidence interval
  53. 53. * For continuous variables, medians were used to define the subgroups. The type of heart failure was not recorded for one patient in the placebo group and two in the carvedilol group. The ejection fraction was not recorded for two patients in the carvedilol group. Patient subgroup* 6-minute walk (m) <396 396 Cause of heart failure Ischaemic Non-ischaemic Systolic blood pressure (mm Hg) <115 115 Heart rate (bpm) <82 82 Placebo Carvedilol 20/202 17/345 11/196 5/351 17/189 13/332 14/208 9/362 19/210 13/337 12/188 9/359 10/186 11/354 21/212 11/342 No of deaths/total no Hazard ratio (98% Cl)† 0.49 (0.25–0.93) 0.25 (0.09–0.71) 0.35 (0.16–0.73) 0.35 (0.15–0.83) 0.34 (0.17–0.70) 0.38 (0.15–0.95) 0.61 (0.25–1.49) 0.26 (0.12–0.55) †CI denotes confidence interval US Carvedilol Heart Failure Program Effects in patient subgroups Packer (1996)
  54. 54. 58 Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure A randomised, double-blind, placebo-controlled phase III study SENIORSSENIORS
  55. 55. 59 • 296 (54%) Male • Median age 76 years (90% range 55-89) • 161 (29%) Clinic: 391 (71%) Hospital • NYHA Class: II - 8%; III - 33%; IV - 59% Hillingdon study results baseline characteristics BackgroundSENIORSSENIORS
  56. 56. 60 • To evaluate the effect of nebivolol compared to placebo on mortality and morbidity in elderly CHF patients Study objectiveSENIORSSENIORS
  57. 57. 61 • Primary Outcome – Time to composite of all cause mortality or cardiovascular hospital admissions • Secondary Outcomes – Time to all cause mortality – Time to cardiovascular hospital admissions – Time to cardiovascular mortality – Time to all cause hospital admissions – Time to composite of all cardiovascular mortality or cardiovascular hospital admissions – Functional capacity by NYHA class and by 6 minute walk test SENIORS - Outcome measuresSENIORSSENIORS
  58. 58. 62 • Age  70 years • A clinical diagnosis of chronic heart failure (HF) and either of: a) documented LVEF  35% within previous 6 months or b) hospital admission within previous 1 year for congestive HF • Written consent prior to enrolment into the study Inclusion criteriaSENIORSSENIORS
  59. 59. 63 • New drug therapy for heart failure • Any change in cardiovascular drug therapy in the 2 weeks prior to randomisation • Heart failure due primarily to valvular heart disease • Contra-indication or previous intolerance to beta blockers • Heart rate < 60 beats per minute • Systolic blood pressure < 90mmHg Main exclusion criteriaSENIORSSENIORS
  60. 60. 64 2135 randomised 1067 assigned to nebivolol 1061 assigned to placebo Patients not in ITT: 7 6 from excluded centre 1 error in randomisation 2128 evaluable Patient flowSENIORSSENIORS
  61. 61. 65 IV 19 (1.8) 24 (2.3) Age (mean, yrs) Male (n, %) Nebivolol 76.1 657 (61.6) Placebo 76.1 686 (64.7) LVEF  35 % (n, %)* 683 (64.3) 686 (64.8) LVEF (mean, %) 36.0 36.0 NYHA Class (n, %) I 32 (3.0) 29 (2.7) II 603 (56.5) 597 (56.3) III 413 (38.7) 411 (38.7) * 7 patients with missing LVEF at baseline Baseline characteristics 1SENIORSSENIORS
  62. 62. 66 Aldosterone Antag. 298 (27.9) 272 (25.6) Prior Revascularisation (n, %) PTCA Nebivolol 47 (4.4) Placebo 34 (3.2) CABG 101 (9.5) 94 (8.9) Medication for Heart Failure (n, %) ACE Inhibitors 880 (82.5) 884 (83.3) Diuretics 916 (85.9) 910 (85.8) Cardiac Glycosides 415 (38.9) 420 (39.6) Aetiology of Heart Failure (n %) Ischaemic 812 (76.1) 809 (76.3) Idiopathic 166 (15.6) 167 (15.7) Antiarrhythmics 91 (8.3) 119 (11.2) Baseline characteristics 2SENIORSSENIORS
  63. 63. 67 Mean ± SD > 5 mg Nebivolol 7.7 ± 3.6 815 (76.4%) Placebo 8.5 ± 3.1 881 (83.0%) On 10 mg 688 (64.5%) 805 (75.9%) Maintenance dose achievedSENIORSSENIORS
  64. 64. 68 • Nebivolol significantly reduced death or hospitalisation in elderly heart failure patients • The effect was similar regardless of ejection fraction, age or gender ConclusionsSENIORSSENIORS
  65. 65. 69 • Advanced age should not be considered a contra-indication to beta blockade in chronic heart failure • The SENIORS study indicates that beta blockade can be recommended for heart failure regardless of ejection fraction • Nebivolol is an effective agent for elderly heart failure patients Clinical implicationsSENIORSSENIORS

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