Οι β-αποκλειστές αποτελούν πρώτη θεραπευτική επιλογή για την αρτηριακή υπέρταση?

Οι β-αποκλειστές αποτελούν πρώτη θεραπευτική επιλογή για την αρτηριακή υπέρταση? Δρ. Δημήτρης Π. Παπαδόπουλος-FESC Υπεύθυνος Αντιυπερτασικού Ιατρείου Καρδιολογικής Κλινικής Π.Γ.Ν.Α. «ΛΑΪΚΟ» Clinical Assist. Professor George Washington University Clinical Hypertension Specialist ESH``

Number of people with hypertension (millions) Number of People with Hypertension Aged 20 Years and Older by World Region and Sex in 2000 and 2025 54.3 180 Men 160 2000 140 116.2 120 98.5 100 83.1 80 60.4 57.8 60.0 60 40 40.6 52.5 35.9 37.9 20 0 180 160 140 120 100 80 60 40 20 0 161.8 147.9 Established market countries 59.7 44.0 Former socialist economies 107.3 106.2 102.1 98.5 India Latin America and the Caribbean 2025 72.2 80.4 Middle eastern crescent 151.7 147.5 China Other Asia and islands Sub- Saharian Africa Women 38.4 33.0 38.2 41.6 972 million (333 + 639) 67.3 62.1 73.6 77.1 1.56 billion Overall (developed + developing countries) Kearney et al Lancet 2005;365:217-23

Complications of Hypertension: Hypertension is a risk factor TIA, stroke Peripheral vascular disease LVH, CHD, HF Renal failure TIA = transient ischemic attack; LVH = left ventricular hypertrophy; CHD = coronary heart disease HF = heart failure. Cushman WC. J Clin Hypertens. 2003;5(Suppl):14-22.

Η βξαβεπκέλε κε Nobel αλαθάιπςε ησλ β- αλαζηνιέσλ ήηαλ έλαο από ηνύο ζξηάκβνπο ηεο ζύγρξνλεο θαξκαθνινγίαο. Εθηνηε νη β-αλαζηνιείο έρνπλ θαζηεξσζεί ζαλ αλαγθαία θαη απνηειεζκαηηθά θάξκαθα γηα πνιιέο θαξδηαγγεηαθέο παζήζεηο, όπσο ε ΑΤ, ε θαξδηαθή αλεπάξθεηα, ε ζηεθαληαία λόζνο, ε πξόιεςε ηνπ αηθλίδηνπ ζάλαηνπ, θαη δηάθνξεο αξξπζκίεο.

Καξδηαθή ζπρλόηεηα θαη πξνζδόθηκν δσήο Καλόλαο: 3 ζπζηνιέο ιηγόηεξεο αλά ιεπηό παξάηαζε δσήο θαηά 3 ρξόληα

GOALS OF ANTIHYPERTENSIVE TREATMENT BP reduction Risk Factors HT Prevention NOD Prevention TOD regression/ prevention AF Prevention ESRD CHD CHF Stroke Cognitive Dysfunction Dementia LVH IMT Microalbuminaria Arterial stiffness Endotheliadysfunction Cardiacfibrosis

Proportion of patients with first event (%) BP Reduction and CV Events in LIFE mmhg 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 Systolic Mean Arterial Diastolic 0 6 12 18 24 30 36 42 48 54 Study Month * Mean BP at last visit BP Atenolol 145.4 mmhg* Losartan 144.1 mmhg* Atenolol 102.4 mmhg* Losartan 102.2 mmhg* Losartan 81.3 mmhg* Atenolol 80.9 mmhg* Number at Risk Composite of CV death, stroke and MI 16 14 12 10 8 6 4 2 0 Adjusted Risk Reduction Unadjusted Risk Reduction Atenolol Losartan 13.0%, p=0.021 14.6%, p=0.009 0 6 12 18 24 30 36 42 48 54 60 66 Study Month Losartan 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876 Dahlöf B et al Lancet 2002; 359: 995-1003

Ακινδηπίλε ± Πεξηλδνπξίιε vs. β-απνθιεηζηή ± Γηνπξεηηθό

Αλγόριθμος μείωζης ηης ΑΠ < 140/90 mm Hg ή <130/80 mm Hg ζε διαβηηικούς αζθενείς Ακινδηπίλε 5-10 mg Αηελνιόιε 50-100 mg + + Πεξηλδνπξίιε 4-8 mg + Δνμαδνζίλε GITS 4-8 mg BFZ-K 1.25-2.5 mg + Άιια θάξκαθα π.ρ. κνμνληδίλε/ζπηξνλνιαθηόλε Dahlöf f B et al.. Lancet. 2005;366:895-906. 906.

ASCOT: Preliminary results ALL CAUSE MORTALITY PRIMARY END POINT 0% -2% -4% -6% -8% -10% -12% -14% -16% -14% p=0,005-10% p=0,12 REASON FOR STOPPING THE TRIAL

ASCOT Trial: Endpoints for amlodipine and perindopril versus atenolol and thiazide Non-fatal myocardial infarction (excluding silent) and fatal coronary heart disease Total coronary endpoint Total cardiovascular events and All-cause procedures mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure -4% -9% -14% -13% -13% -11% -19% -16% -16% -24% -29% -24% -23% -34%

Beta-Blockers in Hypertension - Disadvantages Dysmetabolic effects Protection against subclinical organ damage Side effects Less central BP reduction? Less prevention of stroke? Less BP reduction / CVD protection in the elderly?

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

Antihypertensive Treatments and Incidence of New Onset Diabetes Study % Higher Incidence in Patients Using Diuretics, b-blockers CAPPP diuretics, b-blockers 13% vs. captopril CHARM placebo ± SOC 16% vs. candesartan ± SOC INVEST atenolol ± HCTZ or trandolapril 17% vs. atenolol ± HCTZ or trandolapril INSIGHT co-amiloride ± b-blocker 30% vs. nifedipine GITS LIFE atenolol 33% vs. losartan ALLHAT chlorthalidone 18% 43% vs. amlodipine vs. lisinopril HOPE placebo ± SOC 50% vs. ramipril ± SOC ALPINE HCTZ ± atenolol 720% vs. candesartan ± felodipine Lancet 1999;353:611-16. Lancet 2003;362:759-66. JAMA 2003;290:2805-2816. Lancet 2000;356:366-72. ;359:995-1003. JAMA 2002;288:2981-97. N Engl J Med 2000;342:145-53. J Hypertension 2003;21:1563-1574.

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 (0.46-0.72) p < 0.0001 0.67 (0.56-0.80) p < 0.0001 0.75 (0.62-0.90) p = 0.002 0.77 (0.63-0.94) p = 0.009 0.90 (0.75-1.09) p = 0.30 Referent 50 70 90 126 Odds ratio of incident diabetes Incoherence = 0.000017 From Elliott WJ, Lancet 2007; 369: 201

ύκθσλα κε ηηο λέεο επξσπατθέο νδεγίεο: Οη β-αλαζηνιείο εμαθνινπζνύλ λα απνηεινύλ κία από ηηο πξώηεο επηινγέο ηνπ ηαηξνύ ηόζν γηα έλαξμε όζν θαη γηα ζπλέρηζε ηεο ζεξαπείαο Επεηδή νη β-αλαζηνιείο έρνπλ αξλεηηθή επίδξαζε ζε ζεκαληηθέο κεηαβνιηθέο παξακέηξνπο, δελ πξέπεη λα πξνηηκνύληαη ζε ππεξηαζηθνύο κε κεηαβνιηθό ζύλδξνκν ή ηα επηκέξνπο πξνβιήκαηα απηνύ 2007 Guidelines for the Management of Arterial Hypertension: European Heart Journal, June 11, 2007

Αυτό μπορεί να μην ισχύει για τους αγγειοδιασταλτικούς β-αναστολείς, όπως η καρβεδιλόλη και η νεμπιβολόλη, οι οποίοι έχουν λιγότερη ή καθόλου δυσμενή επίπτωση στις μεταβολικές παραμέτρους και εμφανίζουν λιγότερα περιστατικά νέου διαβήτη συγκριτικά με τους κλασικούς β-αναστολείς 2007 Guidelines for the Management of Arterial Hypertension: European Heart Journal, June 11, 2007

Effects of b Blockers on Insulin Sensitivity Carvedilol Pindolol Nebivolol Metoprolol Atenolol Propranolol -40-30 -20-10 0 10 Percentage change (%) 20 Jacob S et al. Am J Hypertens 1998

Επίδραζη ζε μεηαβολικές παραμέηροσς 30 +30% +18% 20 +13% 10 0% carvedilol 0-10 0% -9% -7% atenolol metoprolol -20-30 -22% -21% Εσαιζθηζία ζηην ινζοσλίνη Τριγλσκερίδια HDL Jacob S et al, Am J Hypertens 1998;11:1258-65

Επηβεβαίσζε : Μειέηε GEMINI Καξβεδηιόιε Μεηνπξνιόιε 1235 αζζελείο Δηαβεηηθνί ηύπνπ 2, Τπεξηαζηθνί ΑΠ>130mmHg, ΔΑΠ>80mmHg) ε ΑΜΕΑ / ΑΣ-Ι ηαζεξνπνηεκέλε αληηδηαβεηηθή ζεξαπεία γηα 3 κήλεο ηαζεξνπνηεκέλε αληηππεξηαζηθή ζεξαπεία γηα 1 κήλα Bakris G et al. JAMA 2004;292:2227-2236

Αξηεξηαθή Πίεζε : θαξβεδηιόιε + ΑΜΕΑ/ΑΣ-Ι GEMINI mmhg 160 149.4 131.3 110 87 77.1 60 Έλαξμε Μήλαο 5 10-40 ΑΠ (n=454) ΔΑΠ (n=454) Bakris G et al. JAMA 2004;292:2227-2236

Αληίζηαζε ζηελ ηλζνπιίλε GEMINI HOMA-IR 6.3 6.2 p=0,004 p=0,48 6.1 p=0,004 6 5.9 Έλαξμε Μήλαο 5 5.8 5.7 5.6 Καξβεδηιόιε Μεηνπξνιόιε (n=371) (n=540) Bakris G et al. JAMA 2004;292:2227-2236

Μέζε HbA1c (%) GEMINI Μεηαβνιή ζηε γιπθνδπιησκέλε αηκνζθαηξίλε 7.5 7.4 p=0,004 p<0,001 7.3 7.2 p=0,65 Έλαξμε Μήλαο 5 7.1 7 Καξβεδηιόιε (n=454) Μεηνπξνιόιε (n=657) Bakris G et al. JAMA 2004;292:2227-2236

Celik et al. J Hypertens 2006 Change in Insulin and HOMA Index Induced by Nebivolol and Metoprolol after 24 Wks in HTN 18 Insulin κu/ml * p< 0.006 4 HOMA index * p< 0.008 16 14 3 12 10 8 2 6 4 1 2 0 0 Placebo Nebivolol Placebo Metoprolol Placebo Nebivolol Placebo Metoprolol

Pesant et al. Amer J Therap 1999 Changes in Lipids Induced by Nebivolol and Metoprolol after 24 Wks in HTN 20 TC LDL-C LDL-C/HDL-C TG 15 10 +8.7 +16.3 5 % 0-5 -4.6-2.4-2.7-2.0-10 -15-10.1-11.5 Nebivolol (5 mg) -20 Atenolol (50 mg)

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

Beta-Blockers in Hypertension - Disadvantages Dysmetabolic effects Protection against subclinical organ damage Side effects Less central BP reduction? Less prevention of stroke? Less BP reduction / CVD protection in the elderly? 15805 M

Η ΠΡΟΛΗΦΗ ΣΗ ΒΛΑΒΗ ΣΧΝ ΟΡΓΑΝΧΝ ΣΟΥΧΝ ΑΠΟΣΕΛΕΙ ΕΠΙΠΡΟΘΕΣΟ ΜΕΛΗΜΑ / ΚΟΠΟ ΠΕΡΑΝ ΣΗ ΡΤΘΜΙΗ ΣΗ ΑΠ, ΓΙΑ ΣΗ ΒΕΛΣΙΧΗ ΣΗ ΠΡΟΓΝΧΗ ΣΧΝ ΑΘΕΝΧΝ B. Dahlof Eur H J 2003;5:SF(F 33 -F 39 ).

Specific Protective Effects of Antihypertensive Drugs on Subclinical Organ Damage Diastolic dysfunction? Diuretics Arterial thickening / Atherosclerosis Cognitive dysfunction / Dementia LVH Nephroprotection MA / Proteinuria Betablockers CCB ACEI ARB Endothelial dysfunction Arterial stiffening Coronary Ca ++ depletion Arteriolar remodelling Mancia G, 2006

LIFE: Παπόμοια μείωζη ΑΠ Τποζηποθή ΤΑΚ Change from baseline (%) in LVH determined by electrocardiography 0-2 -4-6 -8-10 -12-14 -16-18 4.4% 10.2% p < 0.0001 Atenolol Losartan 9.0% 15.3% p < 0.0001 Cornell Sokolow-Lyon Voltage-Duration Voltage Product Proportion of patients with first event (%) 16 14 12 10 8 6 4 2 0 Composite of CV Death, stroke and MI Atenolol Losartan Adjusted Risk Reduction: 13.0%, p = 0.021 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) Dahlöf B et al. Lancet 2002;359:995 1003.

Μετα-ανάλσση μελετών σποστρουής ΥΑΚ στην σπέρταση 0 Diuretics b-blockers Caantagonist ACEinhibitors ARBs -2 LV mass reduction (%) -4-6 -8-10 -8% -6% -11% -10% -12-14 -16 80 Μελέηερ; 4,113 αζθενείρ -13% Schmieder RE et al. Am J Med 2003; 115:41-6.

Ορισμός του πάχους του έσω μεσου χιτωνα (ΙΜΤ) Δέξκα Έμσ θαξσηίδα (EC)Έζσ θαξσηίδα (IC) CBM max Μέζνο όξνο ηνπ κέγηζηνπ IMT από 4 καθξηλά ηνηρώκαηα (+ 4 θνληηλά ηνηρώκαηα) ζε CC θαη Bif, ακθνηεξόπιεπξα Δηραζκόο (Bif) Κνηλή θαξσηίδα (CC) 1.0 cm 0.5-1.0 cm 1.0 cm Κνληηλό ηνίρσκα Μαθξηλό ηνίρσκα

Πξόζθαηεο Μειέηεο Αληηππεξηαζηθώλ Παξαγόλησλ ζην Καξσηηδηθό IMT Μειέηε PREVENT PART-2 SECURE BCAPS Αζζέλεηα CHD VD Υς.Κίλδ. VD Θεξαπεπηηθέο αγσγέο Ακινδηπίλε έλαληη Placebo Ρακηπξίιε έλαληη Placebo Ρακηπξίιε έλαληη Placebo Μεηνπξνιόιε έλαληη Placebo Μέηξεζε IMT M max CC-IMT M max Bif Αζζελείο (n) 373 617 732 793 MIDAS ns VHAS ns INSIGHT DAPHNE ELSA HT HT HT HT HT Ιζξαδηπίλε έλαληη HCTZ Βεξαπακίιε έλαληη Χισξνζαιηδόλεο Νηθεδηπίλε GITS έλαληη Cν-Ακηινδίδεο Γνμαδνζίλε έλαληη HCTZ Λαζηδηπηλε - Αηελνινιε M max M max CC-IMT C + Fem IMT-CBM 833 498 324 80 2255

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

PWV (m/sec) Nebivolol but not Atenolol Reduces Arterial Stiffness 4.0 Atenolol Nebivolol 3.9 3.8 3.7 3.6 * ** * p<0.05 vs baseline ** p<0.01 vs baseline n=12 3.5 3.4 3.3 3.2 3.1 3.0 Saline 250 500 Dose (nmol/min) McEniery, et al. Hypertension 2004;44:305

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 ESH Task Force Document, J Hypertens 2009

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

Beta-blockers (BB) and Withdrawal from Side Effects - Data from 15 Placebo-controlled Trials (n > 35000) 3 Depression Fatigue Sexual dysfunction % 2.4 2 1.3 Placebo BB 1 0.5 0.4 0.5 0.3 0 RR 0.94 (0.44-2.01) 2.63 (1.16-5.94) 4.89 (2.98-8.03) 12512 M Ko DT et al., JAMA 2002; 288: 351

Cumulative Incidence of Discontinuation of Initial Antihypertensive Monotherapy over 1 Year (Lombardia Data-base; n = 445356) Diuretics Beta-blockers Alpha-blockers Calcium channel blockers 1.83 (1.81-1.85) 1.64 (1.62-1.67) 1.23 (1.20-1.27) 1.08 (1.06-1.09) ACE-inhibitors Angiotensin-receptor blockers 0.92 (0.90-0.94) 0. 5 1. 0 - + 2. 0 Corrao, Zambon, Parodi, Poluzzi, Baldi, Merlino, Cesana, Mancia, J Hypert 2008; 26: 819-824

MEDICAL RESEARCH COUNCIL TRIAL (MRC) Treating Elderly with Diuretic and Beta Blockers Is Beneficial (1992) Diuretic b-blocker Placebo Total stroke 7.3* 9.0 10.8 Total coronary heart disease 7.7* 12.8 12.7 Total cardiovascular disease 17.4* 24.6 25.2 Total mortality 21.3 26.4 24.7 * significantly better than placebo MRC Working Party. Br Med J 1992; 304:405

The Lancet Vol 366 October 29 2005 13 ηςσαιοποιημένερ μελέηερ (n=105.591) : β- blockers vs other antihypertensive 7 ηςσαιοποιημένερ μελέηερ (n=27.433) : β - blockers vs placebo Aνάλςζη έγινε για όλοςρ ηοςρ β αναζηολείρ και για 3 ςποομάδερ αςηών: > non atenolol b-blockers > Mixed b-blockers and diuretics (>50% of pts started on a b blocker) Atenolol Eξεηάζθηκε η επίδπαζη ζε ΑΕΕ, ΕΜ, θνηηόηηηα όλων ηων αιηιών

Mancia G. et al., J Hypert, Nov 2009 Reappraisal of European Guidelines on Hypertension Management A European Society of Hypertension (ESH) Task Force Document ESH Task Force: G. Mancia, Co-Chairperson (Italy), S. Laurent, Co-Chairperson (France), E. Agabiti-Rosei (Italy), E. Ambrosioni (Italy), M. Burnier (Switzerland), R. Cifkova (Czech Republic), D. Clement (Belgium), A. Coca (Spain), A. Dominiczak (UK), S. Erdine (Turkey), R. Fagard (Belgium), C. Farsang (Hungary), G. Grassi (Italy), SE. Kjeldsen (Norway), W. Kiowski (Switzerland), A. Manolis (Greece), K. Narkiewicz (Poland), P. Nilsson (Sweden), M. Olsen (Denmark), J. Redón (Spain), J. Rodicio (Spain), L. Ruilope (Spain), RE. Schmieder (Germany), HAJ. Struijker-Boudier (The Netherlands), P. van Zwieten (The Netherlands), M. Viigimaa (Estonia), A. Zanchetti (Italy)

2007 Blood pressure targets < 140 / 90 if low and moderate CV risk < 130 / 80 if high CV risk Diabetes Renal dysfunction Established CV disease 2007 ESH Guidelines for the Management of Hypertension. J of hypertension 2009;27:2121 58

2003 ESH/ESC Guidelines Evidence of CV protection with 5 drug classes - Diuretics - Beta-blockers - ACE-inhibitors - Calcium channel blockers - Angiotensin II antagonists All above classes suitable for initiation / maintenance of antihypertensive treatment Effective BP fundamental

2009 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

Beta blockers are still first line therapy in arterial hypertension??? Yes for individual patients and vasodilatory agents