Α Reapraisal on the Use of β-blockers

Transcription

1 Α Reapraisal on the Use of β-blockers Athanasios J. Manolis MD, FACC, FESC, FAHA Director of Cardiology Dept, Asklepeion General Hospital, Athens Greece. Adj. Ass. Professor, Hypertension Section, Boston University, MA, USA Adj. Professor of Medicine, Emory University, Atlanta, USA

2 Disclosures Research Grants, Honoraria, Advisory Boards SERVIER ABBOTT MENARINI RECORDATI NOVARTIS FERRER PFIZER AMGEN GSK BOERINGHER INGHELHEIM BAYER

3 Zanchetti J Hypertens 2005;23: 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 Clinical Disease BP + Specific Ancillary Actions BP + Specific Ancillary Actions Risk Factors Hypertension Subclinical Organ Damage LVH IMT Microalb. Mild Renal Disease Recent Diabetes Endothelial Dysfunction Metabolic Syndrome Dyslipidemia Angina TIA Claudicatio Proteinuria Moderate Renal Disease Established Diabetes MI Stroke CHF ESRD Cardiovascular Event Death

4 β- blockers in CV Continuum Heart Failure Stable Coronary Artery Disease Hypertension

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8 2013 ESH/ESC Hypertension Guidelines Drugs To Be Preferred In Specific Conditions

9 β- blockers in CV Continuum Heart Failure Stable Coronary Artery Disease Hypertension

10 2013 ESH/ESC Hypertension Guidelines Choice Of Antihypertensive Drugs - Conclusions From 2013 (And 2003 And 2007) Guidelines The main benefits of antihypertensive treatment are due to lowering BP per se and are largely independent of the drug employed Although meta-analyses occasionally claim superiority of one class for some outcomes this largely depends on selection bias of trials. The largest meta-analyses do not show clinically relevant between-class differences Current Guidelines reconfirm that the following drugs classes are all suitable for initiation and maintenance of antihypertensive treatment either as monotherapy or in some combinations with each other (IA) Diuretics (thiazides / chlorthalidone / indapamide) Beta-blockers Calcium antagonists ACE-inhibitors Angiotensin receptor blockers

11 The NICE/BHS Approach to Sequencing Antihypertensive Drug Classes Choosing drugs for patients newly diagnosed with hypertension Abbreviations: A, ACE inhibitor (consider Ag-II receptor antagonist if ACE-I intolerant) C, calcium-channel blocker D, thiazide-type diuretic Younger than 55 years A 55 years or older or black patients of any age A + C or A + D C or D Step 1 Step 2 A + C + D Step 3 Black patients are those of African or Caribbean descent, and not mixedrace, Asian, or Chinese patients Add further diuretic therapy or alpha-blocker or beta-blocker Consider seeking specialist advice Step 4

12 Incidence of CV Events with Different Treatments -Effects of Age ACE-I vs D/BB CA vs D/BB ACE-I vs CA ARB vs Others Age < 65 (n = 22088) Age 65 (n = 25342) Age < 65 (n = 43594) Age 65 (n = 46185) Age < 65 (n = 10049) Age 65 (n = 16310) Age < 65 (n = 1464) Age 65 (n = 6338) SBP/DBP difference (mmhg) +1.3/ / / / / / / /-1.2 Favours first Favours second Risk Ratio Risk Ratio (95% CI) 1.05 ( ) 1.01 ( ) 1.06 ( ) 1.02 ( ) 0.91 ( ) 0.98 ( ) 0.89 ( ) 0.91 ( ) p for trend BPLTTC Br Med J 2008;336:1121

13 Relative Risk of CV Events - Comparing Drugs with Control and Other Drugs Thiazides -blockers ACEI ARB CA-channel blockers CHD RR (95% CI) CHF RR (95% CI) Stroke RR (95% CI) BP diff. (mmhg) Drug vs any other SBP DBP Specified drug better Control better CHD RR (95% CI) RR Specified drug better Control better CHF RR (95% CI) RR Specified drug better Control better Stroke RR (95% CI) RR Thiazides -blockers ACEI ARB CCB Specified drug Specified drug better worse Specified drug Specified drug better worse 0.7 Specified drug better Specified drug worse Law et al., BMJ 2009; 338: b1665

14 Β-blockers as Initial Treatment for HTN: All Cause Mortality Wiysonge CS et al. JAMA 2013:310;1851

15 ESH/ESC NICE vs vs NICE ESH and Guidelines JNC-8 Guidelines

16 2013 ESH/ESC Hypertension Guidelines Maintenance Of β-blockers As Possible Choice For Antihypertensive Treatment(As In Guidelines)the Law / Collaborative Trialist Groups Meta-analyses Equally effective compared to all other drugs on CHD prevention Highly protective in patients with a recent MI or with CHF Incidence of CV outcomes similar for BBs with/without D compared to other drugs Slightly lower effectiveness (shared with ACEI) in stroke prevention but only vs CA

17 A Class Effect? MRC elderly study LIFE ASCOT ALLHAT Carlberg meta-analysis Atenolol

18 Pharmacologic Properties of Various β-blockers Bradycardia Negative inotropy BP ß 1 - SELECTIVE Less bronchospasm Fewer peripheral effects Metabolic effects Circulatory NONSELECTIVE (ß 1 ß 2 ) Similar cardiac and antihypertensive effects More marked pulmonary and peripheral effects

19 2009 ESH Reappraisal and 2013 ESH/ESC Guidelines on Hypertension Management when discussing β-blockers, however, it should not be ignored that they are no homogeneous class, and that vasodilating β-blockers such as carvedilol and nebivolol appear not to share some of the negative properties described for other compounds

20 Mechanisms of Action of Nebivolol in CV System

21 Beta-Blockers in Hypertension Disadvantages Less effective in BP reduction Unfavorable metabolic effects Less protection against subclinical OD Less effective in central BP reduction Less prevention of stroke Less CVD protection in the elderly Side effects and reduced compliance

22 2013 ESH/ESC Guidelines: Goals of Antihypertensive Treatment BP reduction

23 Beta-Blockers in Hypertension Disadvantages Less effective in BP reduction Unfavorable metabolic effects Less protection against subclinical OD Less effective in central BP reduction Less prevention of stroke Less CVD protection in the elderly Side effects and reduced compliance

24 mmhg (MAP) Van Nueten L. Clinical Research Report Single Dose Control of Blood Pressure over 24 hours with Nebivolol Placebo Nebivolol 5 mg o.d Start 6 hrs 12 hrs 18 hrs 24 hrs T/P ratio 89% Time from last dose: 7 am Afternoon Evening Night Early morning

25 2013 ESH/ESC Guidelines Combinations between Some Classes of Antihypertensive Drugs Thiazide diuretics Thiazide diuretics ß- blockers AT 1 - receptor antagonists ACCOMPLISH ADVANCE HYVET ASCOT ONTARGET AT 1 - receptor antagonists α-blockers Calcium antagonists Calcium antagonists ACE inhibitors ACE inhibitors Pronounced antihypertensive effect CV protection Optimal tolerability

26 Change in mmhg Nebivolol plus HCTZ: DBP and SBP Reductions in Patients not Responding to Monotherapy 0 SBP DBP Nebivolol + HCTZ 5/12.5 mg (n=9) Nebivolol + HCTZ 5/25 mg (n=16) Malacco E. High Blood Press, Cardiovasc Prev 2008; 15:76-84

27 2013 ESH/ESC Hypertension Guidelines The Diuretic / BB Combination A beta-blocker / diuretic combination was as effective as other combinations in several trials and more effective than placebo in three trials (SHEP / Coope-Warrender / STOP I) This combination elicits more cases of NOD in susceptible individuals, compared to other combinations

28 Mean change from baseline (mm Hg) Mean change from baseline (mm Hg) Giles TG et al. Lancet 2014, 383: Efficacy and Safety of Nebivolol and Valsartan as Fixed- Dose Combination in Hypertension: a Randomized, Multicentre Study 8-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallelgroup trial at 401 US sites, participants. Diastolic blood pressure, baseline to week 8(primary endpoint) PL /80 10/320 20/320 Systolic blood pressure, baseline to week 8(key secondary endpoint) PL /80 20/320 10/320

29 Goals of Antihypertensive Treatment Nebivolol vs other β-blockers BP reduction Risk Factors HT Prevention NOD Prevention TOD regression/ prevention AF Prevention LVH IMT Microalbuminaria Arterial stiffness Endotheliadysfunction Cardiacfibrosis ESRD CHD CHF Stroke Cognitive Dysfunction Dementia

30 Beta-Blockers in Hypertension Disadvantages Less effective in BP reduction Unfavorable metabolic effects Less protection against subclinical OD Less effective in central BP reduction Less prevention of stroke Less CVD protection in the elderly Side effects and reduced compliance

31 Potential Adverse Metabolic Effects of β-blockers Insulin-resistance P-insulin levels P-glucose levels LDL/HDL Triglycerides

32 Celik et al. J Hypertens 2006 Change in Insulin and HOMA Index Induced by Nebivolol and Metoprolol after 24 Wks in HTN Insulin μu/ml HOMA index 18 * p< * p< Placebo Nebivolol Placebo Metoprolol Placebo Nebivolol Placebo Metoprolol

33 From Elliott WJ, Lancet 2007; 369: 201 Results of a Meta-analysis for Incident Diabetes 22 Clinical Trials of 143,153 HTN Patients Prevalence of HF in elderly diabetics is 39% Elderly diabetics have 1.3 fold greater risk of developing HF than non diabetics ARB ACE inhibitor CCB Placebo Beta-blocker Diuretic 0.57 ( ) p < ( ) p < ( ) p = ( ) p = ( ) p = 0.30 Referent Odds ratio of incident diabetes Incoherence =

34 % event rates Agabiti et al. Drugs 2007; 67:1-11 New Onset Diabetes in the SENIORS trial % 1.8% Placebo Nebivolol 0 Placebo Nebivolol

35 New diabetes (%) COMET Trial: New Onset Diabetes 15 Relative Risk Reduction 22%, P = Metoprolol 5 Carvedilol Number at risk Time (years) Metoprolol 1, Carvedilol 1,151 1,

36 Pesant et al. Amer J Therap 1999 Changes in Lipids Induced by Nebivolol and Atenolol after 24 Wks in HTN 20 TC LDL-C LDL-C/HDL-C TG % Nebivolol (5 mg) -20 Atenolol (50 mg)

37 Beta-Blockers in Hypertension Disadvantages Less effective in BP reduction Unfavorable metabolic effects Less protection against subclinical OD Less effective in central BP reduction Less prevention of stroke Less CVD protection in the elderly Side effects and reduced compliance

38 Cumulative atherosclerotic lesion area Anti-atherosclerotic Effect of Nebivolol, a New NO-releasing β-blocker, in Cholesterol-fed Rabbits % p< Controls Carvedilol 12.5 mg/day Nebivolol 5 mg/day Napoli C, Ignarro LJ

39 Mean % percentage decrease from baseline Comparison Between Nebivolol and Ramipril in Patients with Hypertension and LVH: a Randomized Open Blinded Eend-point (PROBE) Trial 0 LVM LVMI LVM LVMI LVM LVMI N R P<0.001 P< Ramipril 2.5 mg P<0.001 Ramipril 2.5mg vs Nebivolol 5 mg Nebivolol 5 mg Caglar N et al Eur Rev Med Pharmacol Sci; 2011;12:1359

40 Assessment of Effect of Irbesartan and Nebivolol on LA Volume and Deformation in Patients with Mild-to-Moderate HTN Degirmenci H. et al Eur Rev Med Pharmacol Sci 2014;18:781

41 Beta-blockers in Patients with Intermittent Claudication and Arterial Hypertension: Results from the Nebivolol or Metoprolol in Arterial Occlusive Disease Trial Results: After a 48-week treatment period, ABI and absolute claudiacation distance improved significantly in both groups (p<0.05 for both) A significant increase 39% of initial claudication distance was found in Nebivolol group (p< 0.003) vs 16.6% in Metoprolol group (p: NS) Espinola-Klein C et al. Hypertension 2011; June ahead print

42 Beta-Blockers in Hypertension Disadvantages Less effective in BP reduction Unfavorable metabolic effects Less protection against subclinical OD Less effective in central BP reduction Less prevention of stroke Less CVD protection in the elderly Side effects and reduced compliance

43 Differential Effect of β-bl/d and ACE-I/CCB s On BP in ASCOT CAFÉ Study Circulation 2006

44 A Comparison of Atenolol and Nebivolol in Isolated Systolic Hypertension Nebivolol and atenolol have similar effects on brachial blood pressure and aortic stiffness. However nebivolol reduces aortic pulse pressure more than atenolol, which may be related to a less pronounced rise in augmentation index and bradycardia Dhakam Z et al. J Hypertens 2008;26:351 Effect of Nebivolol or Irbesartan in Combination with HCTZ on Vascular Function in Hypertensive pts: The NINFE study There was no inferiority of nebivolol compared with irbesartan on endothelial function, arterial stiffness and central hemodynamic parameters. Marazzi VC et al. Int J Cardiol 2012;155:279

45 PWV (m/sec) McEniery, et al. Hypertension 2004; 44:305 Nebivolol but not Atenolol Reduces Arterial Stiffness * ** 6% Atenolol Nebivolol * p<0.05 vs baseline ** p<0.01 vs baseline 25% improvement in survival Saline Dose (nmol/min)

46 Beta-Blockers in Hypertension Disadvantages Less effective in BP reduction Unfavorable metabolic effects Less protection against subclinical OD Less effective in central BP reduction Less prevention of stroke Less CVD protection in the elderly Side effects and reduced compliance

47 Relative Risk of CV Events - Comparing Drugs with Control and Other Drugs Thiazides -blockers ACEI ARB CA-channel blockers CHD RR (95% CI) CHF RR (95% CI) Stroke RR (95% CI) BP diff. (mmhg) Drug vs any other SBP DBP Specified drug better Control better CHD RR (95% CI) RR Specified drug better Control better CHF RR (95% CI) RR Specified drug better Control better Stroke RR (95% CI) RR Thiazides -blockers ACEI ARB CCB Specified drug Specified drug better worse Specified drug Specified drug better worse 0.7 Specified drug better Specified drug worse Law et al., BMJ 2009; 338: b1665

48 Β-blockers as Initial Treatment for HTN: All Cause Mortality Wiysonge CS et al. JAMA 2013:310;1851

49 Beta-Blockers in Hypertension Disadvantages Less effective in BP reduction Unfavorable metabolic effects Less protection against subclinical OD Less effective in central BP reduction Less prevention of stroke Less CVD protection in the elderly Side effects and reduced compliance

50 Heart failure and Chronic Obstructive Pulmonary Disease The Quandary of Beta-blockers and Beta-agonists COPD (even moderate or severe) is not a contraindication to beta-blockers. Low dose initiation and gradual up-titration is recommended. Cardioselectivity is paramount, metoprolol, bisoprolol and nebivolol are candidates. Hawkins NM et al. J Am Coll cardiol 2011;57:2127

51 Heart failure and Chronic Obstructive Pulmonary Disease The Quandary of Beta-blockers and Beta-agonists COPD (even moderate or severe) is not a contraindication to beta-blockers. Low dose initiation and gradual up-titration is recommended. Cardioselectivity is paramount, metoprolol, bisoprolol and nebivolol are candidates. Hawkins NM et al. J Am Coll cardiol 2011;57:2127

52 1-selectivity Bucindolol Carvedilol Metoprolol Bisoprolol Nebivolol Brixius K. Br J Pharmacol 2001; 193: Cardioselectivity of Different beta-blockers

53 Proportion having an event (%) SENIORS Trial: All Cause Mortality or CV Hospital Admission Primary Outcome Nebivolol Placebo Hazard Ratio 0.86 [0.74;0.99] 10 p = Time in study (months) No. of events: Nebivolol 332 (31.1%) Placebo 375 (35.3%)

54 Protective Effects of Nebivolol Against Anthracycline-induced Cardiomyopathy: 6 months Baseline 204 P< Placebo Nebivolol P< P< P< LVESD LVEDD NT-pro-BNP LVESD LVEDD NT-pro-BNP EF% post treatment

55 Nebivolol Induces Distinct Changes in Profibrosis MicroRNA Expression Compared with Atenolol, in SHR Nebivolol substantially attenuated cardiac remodeling, hypertrophy and fibrosis more than atenolol Hongmel Ye et al. Hypertension 2013 on line Differential Effect of Nebivolol vs Metoprolol on Functional Sympatholysis in Hypertensive Humans In young healthy humans sympathetic vasoconstriction is markedly blunted during exercise. This phenomenon known as functional Sympatholyis is impaired in hypertensives. Nebivolol restored functional sympatholysis in hypertensive humans Price A et al. Hypertension 2013; on line Investigation of Nebivolol as a Novel Therapeutic Agent in the Treatment of Alzheimer s Disease Nebivolol significantly reduce amyloid neuropathology in the brain, which could be one of the most important parameters for primary prevention of AD Wang J et al. J Alzheimer s Dis 2013; on line

56 Beta-Blockers in Hypertension Disadvantages Less effective in BP reduction Unfavorable metabolic effects Less protection against subclinical OD Less effective in central BP reduction Less prevention of stroke Less effective vascular protection Less CVD protection in the elderly Side effects and reduced compliance

57 Ambrosioni E et al. J Hypertens 2000;18:1691 Patterns of Hypertension Management in Italy 66% discontinuation of the treatment or switching to another drug 60% 30% 0% Inadequate Blood Pressure control Side effects Newer and better agent available Drug interactions Other

58 Man survives earthquakes, epidemics, terrible illnesses, and every kind of spiritual suffering, but always the most poignant tragedy was, is, and ever will be, the tragedy of the bedroom. Leo Tolstoy ( )

59 Hypertension and Sexual Dysfunction

60 Sexual intercourse/month Nebivolol and sexual activity Nebivolol and Sexual Activity Baseline vs 12 weeks 10 8 * * * Atenolol 50 mg o.d. Nebivolol 5 mg o.d. Atenolol + Chlorothalidone 50 Boydak B, et al. Clin Drug Invest 2005;25:409-16

61 Erectile Function Score Switch from b-blockers to Nebivolol 30 p= ,09 17, Before After Doumas et al, Asian J Androl 2006

62 Traditional Beta-blockers vs Nebivolol Advantages (+) / Disadvantages (-) Β-blockers Nebivolol BP reduction CV event reduction CHD prevention CHF prevention CHF treatment CHD treatment Subclinical OD PAD COPD (moderate/severe) Dysmetabolic effects New onset diabetes Central BP NO release Side effects profile Sexual dysfunction ? Manolis AJ Future Cardiology 2014: in press

63 Which Which β-blocker β-blocker?? NO - vasodilating properties Old Generation

64 Christiane B: Sailing in Ionian Sea