Ο ΡΟΛΟΣ ΤΩΝ ΝΕΩΤΕΡΩΝ β ΑΠΟΚΛΕΙΣΤΩΝ ΣΤΗΝ ΥΠΕΡΤΑΣΗ ΚΑΙ ΚΑΡΔΙΑΚΗ ΑΝΕΠΑΡΚΕΙΑ

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1 Ο ΡΟΛΟΣ ΤΩΝ ΝΕΩΤΕΡΩΝ β ΑΠΟΚΛΕΙΣΤΩΝ ΣΤΗΝ ΥΠΕΡΤΑΣΗ ΚΑΙ ΚΑΡΔΙΑΚΗ ΑΝΕΠΑΡΚΕΙΑ ΤΣΟΡΜΠΑΤΖΟΓΛΟΥ ΚΑΤΙΦΕΝΙΑ ΚΑΡΔΙΟΛΟΓΟΣ Ιπποκράτειες Ηµέρες Καρδιολογίας 6/4/2013

2 !!! ΔΕΝ!ΕΧΩ!ΟΙΚΟΝΟΜΙΚΑ!ΣΥΜΦΕΡΟΝΤΑ!ΑΠΟ ΚΑΜΙΑ!ΦΑΡΜΑΚΕΥΤΙΚΗ!ΕΤΑΙΡΕΙΑ

3 ! β-αποκλειστεσ ΣΤΗΝ ΑΡΤΗΡΙΑΚΗ ΥΠΕΡΤΑΣΗ

4 3 ΓΕΝΙΕΣ ββ 1ης ΓΕΝΙΑΣ ΜΗ ΕΚΛΕΚΤΙΚΟΙ (αγγειοσύσπαση) 2ης ΓΕΝΙΑΣ ΕΚΛΕΚΤΙΚΟΙ (µη αγγειοσύσπαση) 3ης ΓΕΝΙΑΣ ΑΓΓΕΙΟΔΙΑΣΤΑΛΤΙΚΟΙ (αγγειοδιαστολή)

5 Control%of%Blood%Pressure Blood%pressure%%%%%=%%%%%Cardiac%output%%%%%x%%%%%Peripheral resistance Hypertension%%%%%=%%%%%Increased%CO%%%%%and/or%%%%%Increased PR Excess sodium intake Preload Fluid volume Renal%sodium retention Genetic factors Contractilit y Heart rate Sympathetic nervous%system Vasoconstrictio n ReninC angiotensinc aldosterone system Kaplan%NM.%Curr%Opin%Nephrol%Hypertens%1994

6 Trials in Hypertensive Patients in Whom BB Not Inferior or Better than Comparators Trial Patients Comparator CV events IPPPSH HAPPHY STOP I INVEST UKPDS UKPDS (long-term) Non-BB Non-BB ACEI or CCB CCB+ACEI ACEI ACEI = = = = Less with BB Less with BB M #

7 Relative Risk of CHD Events in Single Drug BP Difference Trials according to Drug ( -blocker or Other), Presence of CHD, and for -blockers according to Acute MI on Entry No. of trials No. of events Relative Risk (95% CI) Relative Risk Trials of -blockers People with history of CHD Entry after acute MI Entry after long term CHD People with no history of CHD Trials of drugs other than - blockers 37 People with history of CHD 24 People with no history of CHD 64 All trials except ones of - blockers in people with history of CHD M Treatment Placebo better better Law et al., BMJ 2009; 338: b

8 Relative Risk of CHD and CHF - Comparing Drugs with Control and Other Drugs Thiazides -blockers ACEI ARB CA-channel blockers CHD RR (95% CI) CHF RR (95% CI) 0. 5 Specified drug better Control better 0. 5 Specified drug better Control better M Drug vs any other Thiazides - blockers ACEI ARB CCB BP diff. SBP (mmhg) DBP CHD RR (95% CI) 1. 0 RR Specified drug Specified drug 1.0 better worse 0 * CHD events in trials of -blockers in CAD patients excluded Specified drug better CHF RR (95% CI) 1. 0 RR Specified 1.2drug worse 2 Law et al., BMJ 2009; 338:

9 Relative Risk of Stroke (Meta-analysis) in Drug Comparison Trials on BP Lowering Drugs HR BB vs all others BB vs ACEI / ARB / D (exclusion of CA) CA vs all others 1.18 ( ) 1.11 ( ) P = 0.02 P = 0.40 Ca vs ACE / ARB / D (exclusion of BB) Favours 1st drug Favours others 0.91 ( ) 0.93 ( ) P = 0.01 P = M Law et al., BMJ 2009; 338: b

10 No systematic analysis has been made of the possible role of a smaller BP reduction by BB-based treatment in those trials in which BBs appeared to have a smaller effect on stroke M ESH Task Force Document, J Hypertens

11 Left ventricular hypertrophy regression % Diuretics - 6 % - 11 % - 10 % - 13 % β-blockers CCBs ACE I ARBs Schmieder R E et al. Am J Med 2003;115:41-46

12 BB and Subclinical Organ Damage BBs have been shown to be less powerful than other agents in studies using subclinical organ damage as an endpoint Increased LVM Carotid IMT thickening Aortic stiffness Increased small artery wall/lumen ratio M ESH Task Force Document, J Hypertens

13 Beta-blockers CHD Prevention Superior to other drugs in CHD patients Similar to other drugs in patients with no CHD Stroke Prevention Inferior to CA Similar to other drugs CHF Prevention Superior to CA Similar to other drugs M Law et al., BMJ 2009; 338:

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

15 Results of a Meta-analysis for Incident Diabetes - Twenty-two Clinical Trials of 143,153 Hypertensive Patients ARB ACE inhibitor CCB Placebo Beta-blocker Diuretic 0.57 ( ) p < ( ) p < ( ) p = ( ) p = ( ) p = 0.30 Referent Odds ratio of incident diabetes Incoherence = From Elliott WJ, Lancet 2007; 369:

16 Beta-Blockers in Hypertension Plusses Adequate BP reduction CV event reduction - Placebo-controlled trials - Comparison trials Effective protection against CHD/CHF (primary prevention) Superior CHD protection in CAD patients Treatment of angina / CHF Minuses Dysmetabolic effects Protection against subclinical OD Side effects Less central BP reduction? Less prevention of stroke? Less BP reduction / CVD protection in the elderly? M

17 Beta)Blocker/Therapy/in/Hypertension: A/Need/to/Pause/and/Reflect!! Thomas/D./Giles,/George/L./Bakris/and/Michael/A./Weber! JACC$Vol.$51,$No.$4,$2008:$51338! M

18 2007 ESH/ESC Guidelines BBs questioned from results of two large randomized trials (LIFE / ASCOT) They have strongly influenced a recent meta-analysis conclusion that BBs are inferior to others in stroke prevention but not in prevention of MI / mortality Based on a meta-analysis NICE* in has adviced the use of BBS only as 4th-line antihypertensive drugs These conclusions must be considered with care but also with a critical mind * National (UK) Institute of health and Clinical Excellence 12000

19 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 A + C or A + D 55 years or older or black patients of any age 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 M

20 All Drugs may Have Pros & Cons If BBs banned because less effective in preventing stroke why the same not recommended for: Diuretics widely used with BB stroke more common when added to BB (ASCOT) ACEIs less effective on stroke than CCBs ARBs less effective on MI than ACEIs CCBs less effective on CHF prevention But the type of event which should be preferentially prevented is obviously unknown M Mancia G & Zanchetti A, J Hypertens 2008; 26: 164-

21 Choice of Antihypertensive Drugs Each drug class has contraindications as well favourable effects in specific clinical settings. The choice of drugs should be made according to this evidence The traditional ranking of drugs into first / second / third and subsequent choice, with an average patient as reference, has now little scientific and practical justification and should be avoided M ESH Task Force, J Hypertens

22 2007 ESH/ESC Hypertension Guidelines CV protection majorly depends on BP lowering per se Each drug class effective in a fraction of the hypertensive population The greater the options the greater the chance of achieving BP control M

23 2007 ESH/ESC Hypertension Guidelines First Choice Drug Treatment Diuretics * ACE-inhibitors Calcium antagonists Angiotensin receptor antagonists Beta-blockers * * Not to be initially preferred in patients at high risk of developing diabetes The BB/Diuretic combination should not be used in patients with MS or at high risk of diabetes M

24 2007 ESH/ESC Guidelines Conditions favouring Use of Some Antihypertensive Drugs versus Others Thiazide diuretics Isolated systolic hypertension (elderly) Heart failure Hypertension in blacks ACE inhibitors Heart failure LV dysfunction Post-MI Diabetic nephropathy Non-diabetic nephropathy LV hypertrophy Carotid atherosclerosis Proteinuria / Microalbuminuria Atrial fibrillation Metabolic syndrome Beta-blockers Angina pectoris Post-MI Heart failure Tachyarrhythmias Glaucoma Pregnancy Angiotensin receptor antagonists Heart failure Post-MI Diabetic nephropathy Proteinuria / Microalbuminuria LV hypertrophy Atrial fibrillation Metabolic syndrome ACEI-induced cough Calcium antagonists (dihydropyridines) Isolated systolic hypertension (elderly) Angina pectoris LV hypertrophy Carotid/Coronary Atherosclerosis Pregnancy Hypertension in blacks Diuretics (antialdosterone) Heart failure Post-MI Calcium antagonists (verapamil/diltiazem) Angina pectoris Carotid atherosclerosis Supraventricular tachycardia Loop diuretics End stage renal disease Heart failure 11817

25 2007 ESH/ESC Guidelines : Combinations Thiazide diuretics Thiazide diuretics ß-blockers AT1-receptor antagonists AT1-receptor antagonists α-blockers Calcium antagonists Calcium antagonists ACE inhibitors ACE inhibitors Ø Ø Ø Pronounced antihypertensive effect CV protection Optimal tolerability

26 ΝΕΩΤΕΡΟΙ Β-ΑΠΟΚΛΕΙΣΤΕΣ (3ης ΓΕΝΙΑΣ) ΣΤΗΝ ΑΡΤΗΡΙΑΚΗ ΥΠΕΡΤΑΣΗ

27 Vasodilator BBs BBs are not a homogeneous class Vasodilator BBs (celiprolol / nebivolol / carvedilol) do not share some of the negative properties described for other compounds M ESH Task Force Document, J Hypertens

28 Effects of b Blockers on Insulin Sensitivity Carvedilol Pindolol Metoprolol Atenolol Propranolol Between these agents the difference on IS is ~25-45%, which is similar to the metabolic effects of the insulin-sensitisers Percentage change (%) 20 Jacob S et al. Am J Hypertens 1998

29 New Onset Diabetes 15 Relative Risk Reduction 22%, P = 0.04 N e w di ab et es ( % ) 10 5 Metoprolol Carvedilol Number at risk Time (years) Metoprolol 1, Carvedilol 1,151 1, ESC 2003

30 GEMINI (pts with HT and DM) CARVEDILOL VS METOPROLOL HAD LESS ADVERSE EFFECTS ON: n GLYCOSYLATED HEMOGOBIN n TOTAL CHOLESTEROL n TRIGLYCERIDES Bakris GL JAMA 2004

31 GEMINI (pts with HT and DM) CARVEDILOL VS METOPROLOL LESS CASES OF MICROALBUMINOURIA PROGRESSION TO PROTEINURIA Bakris GL JAMA 2004

32 New onset diabetes in the SENIORS trial % % e v e n t r a t e s 0 1.8% Placebo Nebivolol Placebo Nebivolol Agabiti et al. Drugs 2007; 67:1-11

33 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 Celik et al. J Hypertens 2006

34 Nebivolol but not Atenolol Reduces Arterial Stiffness P W V ( m /s e c ) * ** Atenolol Nebivolol * p<0.05 vs baseline ** p<0.01 vs baseline n= Saline Dose (nmol/min) McEniery, et al. Hypertension 2004;44:305

35 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

36 A Comparison of Atenolol and Nebivolol in Isolated Systolic Hypertension Ø Nebivolol and atenolol have similar effects on brachial blood pressure and aortic stiffness. Ø 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

37 Vasodilator BBs - Favourable Effects Less bradycardia Aortic stiffness Central BP Less NOD than classical BBs (GEMINI) NOD similar to placebo (SENIORS) Less adverse effects on HbA1c / lipid profile Greater antiproteinuric effect Improvement of coronary flow reserve in HT Reduction of death / hospitalization in CHF M ESH Task Force Document, J Hypertens

38 Vasodilator BBs Inconveniences reported for classical BBs limited / absent Outcome reduction in CHF (randomized trials) No outcome trials in HT M ESH Task Force, J Hypertens

39 Reappraisal of European Guidelines on Hypertension Management: an ESH Task Force Document 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!! Journal of Hypertension 2009

40 Reappraisal of European Guidelines on Hypertension Management: an ESH Task Force Document ΧΡΕΙΑΖΟΝΤΑΙ ΠΕΡΙΣΣΟΤΕΡΕΣ ΜΕΛΕΤΕΣ ΓΙΑ ΝΕΩΤΕΡΟΥΣ β-αποκλειστεσ ΣΤΗΝ ΑΡΤ. ΥΠΕΡΤΑΣΗ ESH Task Force, J Hypertens 2009

41 β- ΑΠΟΚΛΕΙΣΤΕΣ ΣΤΗΝ ΚΑΡΔΙΑΚΗ ΑΝΕΠΑΡΚΕΙΑ

42 β ΥΠΟΔΟΧΕΙΣ ΣΤΟ Κ.Α. ΣΥΣΤΗΜΑ ΣΤΗΝ ΚΑΡΔΙΑ β1, β2, β3, β4 - α1 ΣΤΑ ΑΓΓΕΙΑ β2 α1 ΣΤΟΥΣ ΒΡΟΓΧΟΥΣ β2

43 Β ΥΠΟΔΟΧΕΙΣ ΣΤΗΝ ΚΑΡΔΙΑ

44 β ΥΠΟΔΟΧΕΙΣ ΣΤΟ Κ.Α. ΣΥΣΤΗΜΑ ΦΥΣΙΟΛΟΓΙΚΗ ΚΑΡΔΙΑ β1/β2 = 70-80/30-20 ΑΝΕΠΑΡΚΟΥΣΑ ΚΑΡΔΙΑ β1/β2/α1 = 2/1/1

45 β ΥΠΟΔΟΧΕΙΣ ΣΤΟ Κ.Α. ΣΥΣΤΗΜΑ ΝΟΡΕΠΙΝΕΦΡΙΝΗ Συγγένεια: β1 / β2 = 20 β1 / α1 = 10

46 ΣΤΗΝ ΚΑΡΔΙΑΚΗ ΑΝΕΠΑΡΚΕΙΑ ΝΟΡΕΠΙΝΕΦΡΙΝΗ: ΒΟΜΒΑΡΔΙΣΜΟΣ ΤΩΝ β1 ΥΠΟΔΟΧΕΩΝ

47 ΚΑΡΔΙΑΚΗ ΑΝΑΔΙΑΜΟΡΦΩΣΗ! N"Engl"J"Med"332:"100,"1990

48 VBWG Important pathophysiologic mechanisms in HF Cardiac abnormalities Struct ural Functi onal Myocardium or myocyte Myocardial relaxation Abnormal excitationcontraction coupling -Adrenergic desensitization Hypertrophy Necrosis Fibrosis Apoptosis Left ventricular chamber Remodeling Dilation Increased sphericity Aneurysmal dilatation or wall thinning Concentric hypertrophy Coronary arteries Obstruction Inflammation Mitral regurgitation Intermittent ischemia or hibernating myocardium Induced arterial and ventricular arrhythmias Altered ventricular interaction Modified from Jessup M, Brozena S. N Engl J Med. 2003;348:

49 !!

50 β ΥΠΟΔΟΧΕΙΣ ΣΤΟ Κ.Α. ΣΥΣΤΗΜΑ ΦΥΣΙΟΛΟΓΙΚΗ ΚΑΡΔΙΑ β1/β2 = 70-80/30-20 ΑΝΕΠΑΡΚΟΥΣΑ ΚΑΡΔΙΑ β1/β2/α1 = 2/1/1 (DOWNREULATION β1)

51 ΑΡΝΗΤΙΚΗ ΡΥΘΜΙΣΗ β1 ΥΠΟΔΟΧΕΩΝ ΑΡΝΗΤΙΚΗ ΡΥΘΜΙΣΗ+ΑΠΕΥΑΙΣΘΗΤΟΠΟΙΗΣΗ ΑΠΩΛΕΙΑ ΙΚΑΝΟΤΗΤΑΣ ΔΙΑΒΙΒΑΣΗΣ ΜΗΝΥΜΑΤΩΝ ΚΑΤΑ 50-60% ΣΤΟ ΤΕΛΙΚΟ ΣΤΑΔΙΟ Κ.Α.

52 ΛΟΓΩ ΤΩΝ ΔΥΣΜΕΝΩΝ ΣΗΜΑΤΩΝ ΤΩΝ β ΥΠΟΔΟΧΕΩΝ ΑΝΑΠΤΥΧΘΗΚΕ Η ΙΔΕΑ ΧΡΗΣΗΣ ΤΩΝ β ΑΠΟΚΛΕΙΣΤΩΝ ΣΤΗΝ Κ/Α

53 ΧΡΗΣΗ ΤΩΝ β ΑΠΟΚΛΕΙΣΤΩΝ UPREGULATION β1 ΥΠΟΔΟΧΕΩΝ REVERSE REMODELING ΔΟΜΙΚΗ ΒΕΛΤΙΩΣΗ ΚΑΡΔΙΑΣ (ESV) ΛΕΙΤΟΥΡΓΙΚΗ ΒΕΛΤΙΩΣΗ ΚΑΡΔΙΑΣ (EF) ΒΕΛΤΙΩΣΗ ΝΥΗΑ

54

55 3 ΓΕΝΙΕΣ ββ 1ης ΓΕΝΙΑΣ ΜΗ ΕΚΛΕΚΤΙΚΟΙ (αγγειοσύσπαση) 2ης ΓΕΝΙΑΣ ΕΚΛΕΚΤΙΚΟΙ (µη αγγειοσύσπαση) 3ης ΓΕΝΙΑΣ ΑΓΓΕΙΟΔΙΑΣΤΑΛΤΙΚΟΙ (αγγειοδιαστολή)

56 3 ΓΕΝΙΕΣ ΒΒ 1ης ΓΕΝΙΑΣ β1+β2 ΑΠΟΚΛΕΙΣΤΕΣ (αγγειοσύσπαση) 2ης ΓΕΝΙΑΣ β1 ΑΠΟΚΛΕΙΣΤΕΣ Μετοπρολόλη, βισοπρολόλη 3ης ΓΕΝΙΑΣ ΑΓΓΕΙΟΔΙΑΣΤΑΛΤΙΚΟΙ Καρβεδιλόλη, νεµπιβολόλη, βουκινδολόλη

57 ΜΕΤΟΠΡΟΛΟΛΗ 2ης ΓΕΝΙΑΣ β ΑΠΟΚΛΕΙΣΤΗΣ ΣΥΓΓΕΝΕΙΑ ΠΡΟΣ β1/β2 = 75/1

58 MERIT-HF: Benefit of -blockade with/without diabetes All-cause mortality All patients randomized Diabetes Diabetes, severe HF Placebo Events (n) Metoprolol succinate CR/XL Favors metoprolol succinate CR/XL Favors placebo VBWG No diabetes No diabetes, severe HF Hospitalization for CHF All patients randomized Diabetes Diabetes, severe HF No diabetes No diabetes, severe HF* Relative risk (95% CI) *Severe HF = NYHA class III/IV, EF<0.25 Deedwania PC et al. Am Heart J. 2005;149:

59 COMET Trial: Primary Endpoint Analysis 50% 40% Carvedilol Metoprolol All-cause mortality 33,9% 39,5% HR % CI p= % 20% 10% 0%

60 ΒΙΣΟΠΡΟΛΟΛΗ 2ης ΓΕΝΙΑΣ ΑΠΟΚΛΕΙΣΤΗΣ ΣΥΓΓΕΝΕΙΑ ΠΡΟΣ β1/β2 = 120/1

61 Survival studies of -blockade in HF VBWG Favors - blocker Patients (N) Total mortality Placebo/ -blocker NYHA class EF mean P CIBIS-II Bisoprolol /15 6 III/IV 28% MERIT-HF Metoprolol succinate CR/XL /14 5 II-IV 28% COPERNICUS Carvedilol /13 0 III/IV* 20% All pooled / Relative risk and 95% CI *not recorded in COPERNICUS, but placebo mortality indicates III/IV CIBIS-II Investigators. Lancet. 1999;353:9-13. MERIT-HF Study Group. Lancet. 1999;353: Packer M et al. N Engl J Med. 2001;344:

62 ΚΑΡΒΕΔΙΛΟΛΗ 3ης ΓΕΝΙΑΣ ΑΠΟΚΛΕΙΣΤΗΣ ΥΨΗΛΗ ΣΥΓΓΕΝΕΙΑ ΠΡΟΣ α1 ΥΠΟΔΟΧΕΑ

63 COPERNICUS: Death, Hospitalization, or Study Drug Withdrawal in High Risk Patients 30 % o f P a ti e n t s W it h E v e n t HR = 0.67 (CI = ) Placebo Carvedilol Weeks After Randomization Krum H et al. JAMA 2003;289:754-6 Krum et al. JAMA

64 CAPRICORN All-Cause Mortality 1.0 # Pr o p or ti o n E ve nt Fr ee P=0.031 Carvedilol Placebo Year s The CAPRICORN Investigators, Lancet 2001

65 ΝΕΜΠΙΒΟΛΟΛΗ 3ης ΓΕΝΙΑΣ β ΑΠΟΚΛΕΙΣΤΗΣ (ΝΟ) ΙΔΙΑΙΤΕΡΑ β1 ΕΠΙΛΕΚΤΙΚΟΣ

66 Cardioselectivity of Different beta-blockers Ne biv olo l 1 - s el e c ti vi t y Bu cin dol ol Car ved ilol Met opr olo l Bis opr olo l Brixius K. Br J Pharmacol 2001; 193:1330-8

67 Proportion having an event (%) SENIORS Θνησιµότητα κάθε αιτιολογίας ή εισαγωγή στο νοσοκοµείο λόγω καρδιαγγειακού συµβάµατος Nebivolol Placebo Mean Follow up 21 months Hazard Ratio 0.86 [0.74;0.99] p-value = 0.039¹ ¹ adjusted by sex, age and baseline LVEF; unadjusted HR= 0.85 [0.74; 0.99] p-value= No. of events: Nebivolol 332 (31.1%); Placebo 375 (35.3%) 67

68 ΒΟΥΚΙΝΔΟΛΟΛΗ 3ης ΓΕΝΙΑΣ β ΑΝΑΣΤΟΛΕΑΣ ΜΗ ΕΠΙΛΕΚΤΙΚΟΣ ΑΣΘΕΝΗΣ ΣΥΓΓΕΝΕΙΑ ΓΙΑ α1 ΜΕΛΕΤΗ BEST

69 Meta-analysis: -Blockade improves survival in elderly HF patients VBWG -blocker better Placebo better Hazard ratio COPERNICUS Carvedilol (U.S.) CIBIS-II MERIT-HF BEST 0.75 ( ) 0.45 ( ) 0.70 ( ) 0.70 ( ) 0.91 ( ) Overall 0.76 ( ) P = Risk ratio (95% CI) Dulin BR et al. Am J Cardiol.2005;95:896-8.

70 ΝΕΟΤΕΡΟΙ βαποκλειστεσ κ/α (ΙΙ-ΙV) ΜΕΙΩΣΗ ΘΝΗΣΙΜΟΤΗΤΑΣ ΜΕΙΩΣΗ ΝΟΣΗΛΕΙΩΝ ΜΗ ΑΥΞΗΣΗ ΙΚΑΝΟΤΗΤΑΣ ΚΟΠΩΣΗΣ

71 Beta Blockers Used in Clinical Trials Generic Name Initial Daily Dose Target Dose Mean Dose in Clinical Trials Bisoprolol 1.25 mg qd 10 mg qd 8.6 mg/day Carvedilol mg bid mg bid 37 mg/day Nebivolol 1,25 10 mg qd 7,7 mg/day Metoprolol succinate CR/XL mg qd 200 mg qd 159 mg/day

72 Beta Blockers Used in Clinical Trials ΔΟΣΗ ΕΝΑΡΞΗΣ: 1/8-1/16 ΤΗΣ ΔΟΣΗΣ ΣΤΟΧΟΥ ΤΙΤΛΟΠΟΙΗΣΗ: ΑΝΑ 1-2 ΕΒΔΟΜΑΔΕΣ ΕΠΙΜΟΝΗ ΣΤΗΝ ΔΙΑΤΗΡΗΣΗ ΤΟΥ β ΑΠΟΚΛΕΙΣΤΗ (δοσοεξάρτηση) Η ΒΑΡΕΙΑ ΚΑΡΔΙΑΚΗ ΑΝΕΠΑΡΚΕΙΑ: ΠΕΡΙΣΣΟΤΕΡΗ ΒΕΛΤΙΩΣΗ

73 Beta Blockers Used in Clinical Trials ΑΝΟΧΗ ΣΤΟΝ β ΑΝΑΣΤΟΛΕΑ MERIT: 85% COPERNICUS: 95,6% SENIORS: 93%

74 ΝΕΟΤΕΡΟΙ β ΑΠΟΚΛΕΙΣΤΕΣ ΣΤΗΝ ΑΡΤΗΡΙΑΚΗ ΥΠΕΡΤΑΣΗ ΙΔΙΑΙΤΕΡΗ ΜΝΕΙΑ ΣΤΗΝ ΚΑΡΔΙΑΚΗ ΑΝΕΠΑΡΚΕΙΑ ΚΛΑΣΗ ΙΙ-ΙV

75 ΣΑΣ ΕΥΧΑΡΙΣΤΩ